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WO2025034510A1 - Adrenergic antagonists for use in a method for treating cerebral edema or a brain injury - Google Patents

Adrenergic antagonists for use in a method for treating cerebral edema or a brain injury Download PDF

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Publication number
WO2025034510A1
WO2025034510A1 PCT/US2024/040536 US2024040536W WO2025034510A1 WO 2025034510 A1 WO2025034510 A1 WO 2025034510A1 US 2024040536 W US2024040536 W US 2024040536W WO 2025034510 A1 WO2025034510 A1 WO 2025034510A1
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Prior art keywords
tbi
adrenergic
brain
ppa
injury
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French (fr)
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Steven Goldman
Rashad HUSSAIN
Maiken Nedergaard
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University of Rochester
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University of Rochester
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine

Definitions

  • TBI Traumatic brain injury
  • Acute TBI ranges in severity from mild to fatal, and can develop into chronic traumatic encephalopathy, a condition characterized by cognitive decline, behavioral changes, and the intracerebral accumulation of neurofibrillary tangles containing hyperphosphorylated tau protein 3,4 .
  • a particularly dire complication of TBI is cerebral edema, which increases the risk of death by 10-fold 5 and worsens the functional outcomes of those patients who survive the initial injury.
  • the disclosure provides a method for treating a cerebral edema or a brain injury (e.g., an acute brain injury), comprising administering to a subject in need thereof an effective amount of one or more adrenergic antagonists.
  • a cerebral edema or a brain injury e.g., an acute brain injury
  • the brain injury is not an ischemic stroke.
  • the brain injury is not an acute ischemic stroke.
  • the disclosure further features a method for improving glymphatic-lymphatic efflux from the central nervous system (CNS) of a subject, comprising administering to a subject in need thereof an effective amount of one or more adrenergic antagonists.
  • a method for promoting clearance of a substance from the CNS interstitium, brain interstitium and/or spinal cord interstitium of a subject comprising administering to a subject in need thereof an effective amount of one or more adrenergic antagonists.
  • the substance comprises a fluid or a solute.
  • the substance comprises amyloid ⁇ (A ⁇ ), tau, or alpha synuclein.
  • the substance comprises a drug or a metabolite thereof.
  • Each of the above-described method can further comprise identifying the subject in need thereof first before the administering.
  • the one or more adrenergic antagonists can be administered systemically.
  • said administering comprises administering to the subject (A) one or more ⁇ adrenergic antagonists and (B) one or more ⁇ adrenergic antagonists.
  • the ⁇ adrenergic antagonists are selected from the group consisting of an ⁇ 1 adrenergic antagonist and an ⁇ 2 adrenergic antagonist.
  • the ⁇ adrenergic antagonists are selected from the group consisting of a ⁇ 1 adrenergic antagonist, a ⁇ 2 adrenergic antagonist, and a ⁇ 3 adrenergic antagonist.
  • said administering comprises administering to the subject (i) an ⁇ 1 adrenergic antagonist, (ii) an ⁇ 2 adrenergic antagonist, and (iii) a ⁇ adrenergic antagonist.
  • Examples of the ⁇ 1 adrenergic antagonist can be selected from the group consisting of Acepromazine, Alfuzosin, Doxazosin, Phenoxybenzamine, Phentolamine, Prazosin, Tamsulosin, Terazosin, Trazodone, Clomipramine, Doxepin, Trimipramine, Antihistamines, Hydroxyzine, 5-methyl urapidil, chloroethylclonidine, bunazosin, RS17053, L-765,314, nicergoline, ABT-866, cyclazosin, A322312, A 119637, fiduxosin, JTH-601, WB4101, niguldipine, KMD3213, and UIC 14304.
  • Examples of the ⁇ 2 adrenergic antagonist can be selected from the group consisting of Phenoxybenzamine, Phentolamine, Yohimbine, Idazoxan, Atipamezole, and Trazodone.
  • Examples of the ⁇ 1 adrenergic antagonist can be selected from the group consisting of Metoprolol, Atenolol, Bisoprolol, Propranolol, Timolol, Nebivolol, and Vortioxetine.
  • ⁇ 2 adrenergic antagonist can be selected from the group consisting of Butoxamine, Timolol, Propranolol, ICI-118,551, Paroxetine, H35/25, prenaterol, various 4- and 5-[2-hydroxy-3-(isopropylamino)propoxy]benzimidazoles, 1-(t-butyl-amino-3-ol-2- UR 6-23116 /FR: 161118.05100 propyl)oximino-9 fluorene, and various 2-( ⁇ -hydroxyarylmethyl)-3,3-dimethylaziridines.
  • ⁇ 2 antagonists are disclosed in U.S. Pat. No.
  • the brain injury can be a traumatic brain injury or an acute brain injury.
  • the traumatic brain injury is an acute traumatic brain injury.
  • the acute traumatic brain injury results from closed head trauma.
  • the acute traumatic brain injury results from open head and/or penetrating injury-induced trauma.
  • the subject can be a mammal, such as a human. The details of one or more embodiments of the disclosure are set forth in the description below.
  • Figs. 1A-1H show that pan-adrenergic receptor inhibition eliminates edema and improves functional outcomes after traumatic brain injury.
  • Fig. 1a The kinetics of cerebral edema in the mouse brain after TBI were quantified in ipsilateral (triangles) and contralateral (diamonds) hemispheres at 10, 20, 30, 60, and 180 min post-injury.
  • Figs. 2A-2I show that post-TBI suppression of glymphatic efflux is counteracted by pan-adrenergic inhibition.
  • FIG. 2a Schematic diagrams showing fluorescent tracer injection time-lapse imaging with or without TBI and PPA treatment.
  • Fig. 2g Schematic diagram showing CSF production measurement in lateral ventricles with or without TBI and PPA treatment.
  • Fig.2h Quantification of CSF production ( ⁇ l/min, Mean ⁇ SEM; Control 0.11 ⁇ 0.003, TBI 0.045 ⁇ 0.012, and TBI+PPA 0.083 ⁇ 0.006).
  • Figs.3A-3K show that fluid transport by cervical lymphatic vessels is reduced by TBI and restored with pan-adrenergic receptor inhibition.
  • Fig.3A-3K show that fluid transport by cervical lymphatic vessels is reduced by TBI and restored with pan-adrenergic receptor inhibition.
  • FIG. 3a Schematic diagram illustrating UR 6-23116 /FR: 161118.05100 the methodology used for the analysis of fluid transport out of the brain and edema clearance, utilizing DB53 delivery and detection in the femoral vein.
  • FIG. 3b Representative images showing the distribution of DB53 in femoral vein with or without injury and PPA treatment
  • Fig. 3d Schematic showing delivery of a mixture of Texas red conjugated FluoSpheres (1 ⁇ m, 580/605 nm) and FITC-dextran (2 kDa).
  • FIG. 3e Representative images of FITC-dextran signals detected in cervical lymphatic vessels (CLVs) and superficial cervical lymph nodes (sCLN).
  • Fig. 3g Schematic showing two-photon microscopy in exposed CLV and representative superimposed particle tracks (right).
  • Fig. 3h Representative time series of fluorescent particle efflux (Control: grey, TBI: red, TBI+PPA: purple).
  • Figs. 4A-4F show that noradrenergic storm after TBI disrupts contraction wave entrainment but is prevented by PPA treatment.
  • Fig. 4b In vivo recording of contraction frequencies and amplitude in response to different concentrations of NA.
  • Fig. 4c Top: Schematic showing the setup adopted for ex vivo recording of cervical lymphatic vessel contraction pattern and experimental timeline.
  • CVP Central venous pressure
  • Figs. 5A-5K show that efflux of cells/cellular debris through CLVs in the event of TBI is neuronal in origin.
  • Fig.5a Mice implanted with cisterna magna cannulas received BSA-647 injection following TBI or sham hit, with or without PPA treatment, and were imaged by two-photon microscopy followed by brain and lymph node fixation.
  • Fig.5b Dual- channel images of CLVs after TBI and PPA showing debris in green.
  • Fig.5b Dual- channel images of CLVs after TBI and PPA showing debris in green.
  • Fig.5e-g Lymph node slices were imaged using confocal microscopy (40x, NA 1.4, Olympus FV3000).
  • Fig. 5i BSA-647 fluorescence intensity (p ⁇ 0.0001; Control vs. TBI-saline, p ⁇ 0.0001; TBI saline vs. TBI+PPA, p ⁇ 0.0001).
  • Fig. 5i BSA-647 fluorescence intensity (p ⁇ 0.0001; Control vs. TBI-saline, p ⁇ 0.0001; TBI saline vs. TBI+PPA, p ⁇ 0.0001).
  • Fig. 5i BSA-647 fluorescence intensity (p ⁇ 0.0001; Control vs. TBI-sa
  • Fig.6 shows that that brain fluid export is compromised by traumatic brain injury and counteracted by pan-adrenergic inhibition.
  • Cerebrospinal fluid (CSF) exchanges UR 6-23116 /FR: 161118.05100 with interstitial fluid, is collected along perivenous spaces (shown as light blue), and drains out via meningeal lymphatic vessels and soft tissue surrounding nerves and vessels.
  • Light Panel Brain injury suppresses brain fluid export and results in tissue swelling. The reduced outflow in response to injury is attributed to an adrenergic storm, which reduces glymphatic fluid transport as well as cervical lymphatic vessel contraction frequency/amplitude, disrupts entrainment, and reduces downstream volume transfer efficiency.
  • Adrenergic inhibition antagonizes these changes and eliminates acute edema. Treatment with adrenergic receptor antagonists also facilitates the clearance of cellular debris, reducing neuroinflammation and improving functional recovery.
  • Figs.7A and 7B show that effect of individual components of PPA is less efficient in reducing cerebral edema after TBI.
  • Fig. 7a The severity of cerebral edema in the mouse brain was estimated 3 h post-TBI with or without treatment of prazosin (Prz), propranolol (Prpl), and atipamezole (Ati).
  • Fig. 7b Cerebral edema measurement in mice 24 h post-TBI with or without PPA treatment at 23 h.
  • Figs. 8A-8C show that locomotor and anxiety-like behavior of post-traumatic brain injury mice is relieved by PPA treatment.
  • Fig. 8a Mice were evaluated for locomotion, anxiety-like behaviors, and exploration abilities at two and 12 weeks post-TBI, with or without PPA treatment.
  • Fig. 8a Mice were evaluated for locomotion, anxiety-like behaviors, and exploration abilities at two and 12 weeks post-TBI, with or without PPA treatment.
  • Figs. 9A-9G show that transcranial live imaging of tracer movement is as reliable as ex vivo and in vitro slice imaging.
  • Fig. 9a Representative dorsal and ventral views of brain imaged by ex vivo conventional fluorescent microscopy in control, TBI+saline, and TBI+PPA groups performed at (top) day 0 and (bottom) six months post-TBI.
  • Fig. 9a Representative dorsal and ventral views of brain imaged by ex vivo conventional fluorescent microscopy in control, TBI+saline, and TBI+PPA groups performed at (top) day 0 and (bottom) six months post-TBI.
  • Fig. 9b Regression analysis of B
  • FIG. 9c Representative images from confocal microscopy showing vascular ultrastructure, labeled with lectin (red) and BSA-647 tracer (cyan), colocalized/distributed along the blood vessels in non-injury control, TBI+saline, and TBI+PPA groups.
  • Fig.9d Experimental scheme
  • Fig.9e representative images
  • Fig.9f quantification of transcranial time-lapse imaging of Alexa flour 647 conjugated BSA tracer signals in vivo.
  • Figs. 10A-10Q show shows that post-TBI noradrenergic receptor inhibition downregulates IL-4, IL-6, TNF ⁇ , and CXCL10 levels within the brain.
  • Brain samples collected 24 h post-TBI with or without PPA treatment were analyzed for cytokine/chemokine levels both in the ipsilateral and contralateral hemispheres. Data is shown as percentage increase in the chemokine/cytokine levels relative to the contralateral hemisphere.
  • FIG. 11A-11J show that post-TBI noradrenergic receptor inhibition reduces astrocytic hypertrophy, microglial invasion, and subsequent hyper-phosphorylation of tau.
  • FIG. 11a Schematic showing induction of injury followed by a two-week experimental window.
  • Fig. 11b Coronal sections of mouse brain showing the lesion center were immunostained for GFAP (red) and DAPI (blue); the site of injury/damaged somatosensory cortex, enlarged ventricles both on ipsilateral and contralateral sides, and the white matter tract corpus callosum are indicated by yellow arrows, white # symbols, and a white * sign, respectively, in non-injury control, TBI, and TBI+PPA slices.
  • Fig. 11a Schematic showing induction of injury followed by a two-week experimental window.
  • Fig. 11b Coronal sections of mouse brain showing the lesion center were immunostained for GFAP (red) and DAPI (blue); the site of injury/damaged
  • FIG. 11c Brain sections (bregma; AP -0.8 to 2 mm) were immunostained for microglia (Iba-1, red) and pan-nuclear marker (DAPI, blue); the bottom right corner shows the region of interest.
  • FIG. 11e (Top) Schematic showing the experimental time window of western blot and immunohistochemistry experiments for detection of hyper-phosphorylation of tau protein.
  • FIG. 11f Representative images showing hyper- phosphorylation of tau at site Ser262, Tau5, and DAPI in separate sets of mice at six months after TBI, with or without NA pan-adrenergic receptor blockade.
  • Figs. 11g-j Quantification of immunostaining of pTau in the cortex, striatum, and hippocampus for targets (g) pSer262, (h) pT212, (i) pThr205, and (j) Tau5.
  • Figs. 12A and 12B show Western blots of programmed cell death pathway proteins Caspase 7, 3, and 9 at two weeks post-injury, with or without PPA treatment. Brain tissue was collected from control and TBI mice with or without PPA, homogenized in RIPA buffer, and analyzed for the levels of programmed cell death markers Caspase 7, 3, and 9.
  • Fig.12a Schematics showing the tissue collection from ipsilateral and contralateral hemispheres, which was homogenized, followed by protein separation by gel electrophoresis and PVC membrane transfers.
  • Fig. 12b Caspase enzymes (7, 3, 9) were detected on PVC membrane by specific primary antibodies followed by LiCOR secondary antibody incubation and imaging using Odyssey Imager.
  • Figs.13A and 13B show that despite the anticipated disruption of BBB, TBI does not increase the influx of mannitol, a BBB impermeable tracer.
  • Fig. 13a Schematics showing the tissue collection from ipsilateral and contralateral hemispheres, which was homogenized, followed by protein separation by gel electrophoresis and PVC membrane transfers.
  • Fig. 12b Caspase enzymes (7, 3, 9) were detected on PVC membrane by specific primary antibodies followed by LiCOR secondary antibody incubation and imaging using Odyssey Imager.
  • Figs.13A and 13B show that despite the
  • FIG. 13b Schematic illustrating the vascular compartment of the brain and intravenous injection (10 ⁇ L) of radiolabeled UR 6-23116 /FR: 161118.05100 mannitol ( 14 C).
  • Figs. 14A-14C show that post-TBI noradrenergic inhibition restores interstitial fluid flow and tracer dispersion.
  • Fig. 14a Schematic showing fluorescent tracer Direct Blue 53 (DB53) injected into the striatum in pre-cannulated mice, with or without TBI. DB53 was detected in vivo within the live brain 3 h post-TBI by IVIS Spectrum IR imaging.
  • Fig. 14a Schematic showing fluorescent tracer Direct Blue 53 (DB53) injected into the striatum in pre-cannulated mice, with or without TBI. DB53 was detected in vivo within the live brain 3 h post-TBI by IVIS Spectrum IR imaging.
  • DB53 fluorescent tracer Direct Blue 53
  • FIG. 14b Averaged images showing the distribution of DB53 in the brain.
  • Figs. 15A-15C show that DB53 injected into the brain appears in the circulatory system, but TBI delays its appearance while PPA treatment restores its efflux.
  • Fig. 15A-15C show that DB53 injected into the brain appears in the circulatory system, but TBI delays its appearance while PPA treatment restores its efflux.
  • Fig. 15A-15C show that DB53 injected into the brain appears in the circulatory system, but TBI delays
  • FIG. 15a Schematic diagram illustrating the methods used to assess the efflux of tracer from the brain into the circulatory system, thus quantifying fluid transport out of the brain and edema clearance.
  • DB53 was injected into the left striatum, and its appearance within a femoral vein was recorded using time-lapse IVIS spectrum IR imaging.
  • Fig. 15b Representative images showing the distribution of DB53 (640-690 nm) in the femoral vein: Control (top row), TBI- saline (middle row), and TBI+PPA groups (bottom row).
  • Fig. 15b Representative images showing the distribution of DB53 (640-690 nm) in the femoral vein: Control (top row), TBI- saline (middle row), and TBI+PPA groups (bottom row).
  • Figs. 16A-16D show that PPA administration in healthy mice results in enhanced clearance of radiotracers from CSF.
  • Fig.1a Schematic showing the experimental plan; wild- type mice were implanted with cisterna magna cannula 24 h prior to the experiments. The awake mice were injected with radiotracers (one tracer per group), with or without PPA treatment.
  • Figs. 17A and 17B show that radiotracer 22 Na clearance is reduced in TBI and restored with PPA treatment.
  • Fig. 17a Schematic illustrating the CSF compartment of the brain and experimental timeline.
  • Fig.18a Mice, implanted with cisterna magna cannulas were injected with a mixture of FITC dextran and fluorophore Tx Red, lymph nodes were isolated 40-60 min post- injury with or without PPA treatment, and the sizes of lymph nodes (LN) were measured in images acquired using a fluorescent dissecting microscope (MVX10, Olympus). Figs.
  • FIG. 20A-20D show that NA treatment of CLVs ex vivo results in loss of entrainment while preemptive treatment with PPA nullifies the effect.
  • Fig. 20a Image of an UR 6-23116 /FR: 161118.05100 isolated cervical lymphatic vessel with the area used for spatiotemporal map generation marked by a rectangular box.
  • Figs.20b-20d Spatiotemporal maps showing CLV contraction pattern in (Fig.20b) control, (Fig.20c) NA, and (Fig.20d) PPA+NA treatment.
  • Continuous vertical bands correspond to single contraction waves that conduct over the entire length of the vessel. The intensity of each line is inversely proportional to the magnitude of the constriction. All contractions initiate at the top of the segment.
  • FIGs.21A-21E show that PPA treatment does not alter cardiac and respiratory rates in non-injured control mice.
  • FIGs. 22A-22C show that PPA administration increases the high amplitude contraction frequency of cervical lymphatic vessels (CLV).
  • Fig.22a C57Bl6 mice implanted with cisterna magna cannula were injected with FITC dextran (10 ⁇ L) and recorded for contraction frequency (20-40 min post-injection).
  • Fig. 22b Contraction profile (representative segments, length 2 min) of CLV recorded in control (b) and with PPA administration (c) both under 2.5% isoflurane.
  • Fig. 22a Contraction profile (representative segments, length 2 min) of CLV recorded in control (b) and with PPA administration (c) both under 2.5% isoflurane.
  • Fig. 22a Contraction profile (representative segments, length 2 min) of CLV recorded in control (b) and with P
  • Fig.23a Representative images showing whole mount dural lymphatic vessels.
  • Figs. 23b-23c Representative images of the region of interest showing dorsal meningeal lymphatic vessels in the superior sagittal sinus (SSS, b) and transverse sagittal sinus area (TSS, c).
  • Figs. 24A and 24B show that post traumatic linear increase in NA levels is counteracted by PPA treatment.
  • Fig. 24a Semi-Log curve fit of NA levels depicts a steady increase over time.
  • TBI brain injury
  • glymphatic efflux pathways by which CSF ⁇ derived interstitial fluids typically clear the brain are regulated by adrenergic tone, such that high levels of norepinephrine (noradrenaline) suppress fluid egress.
  • TBI and Glymphatic Efflux Pathways TBI is a heterogeneous condition that may occur from many proximal causes, but the many forms of acute TBI are associated with cerebral edema that is both a predictor and cause of long ⁇ term brain injury, cell and tissue loss, and neurological dysfunction.
  • TBI is associated with a high level of systemic adrenergic activation, via the sympathetic release of both norepinephrine and epinephrine.
  • NA levels are significantly increased in TBI patients, and the degree of NA elevation correlates with the severity of injury, functional outcome, and mortality.
  • NA is secreted by brain stem nuclei, including locus coeruleus, while the adrenal medulla is the primary source of NA in blood.
  • CSF is partially or fully drained by outflow pathways that include the meningeal and cervical lymphatic vessels 13,14 , which return fluid via the thoracic duct to the venous circulation 12,15 .
  • Blockade of meningeal or cervical lymphatic vessels accelerates the deposition of amyloid-beta, tau, and synuclein in rodent disease models 13,16,17 , and worsens brain edema as well as infarct volume in stroke 18 .
  • the inventors discovered that excessive levels of noradrenaline suppress glymphatic/lymphatic fluid flow and debris transport, resulting in cerebral edema and that this process can be attenuated by adrenergic inhibition.
  • cerebral edema following traumatic brain injury is neither the result of vascular fluid transudation nor excessive CSF influx but is rather a consequence of impaired fluid efflux via the glymphatic system and its associated lymphatic drainage. It was found that injury-associated abrogation of fluid drainage is under adrenergic control, such that interstitial fluid homeostasis could be rescued by broad adrenergic inhibition.
  • the inventors obtained quantitative measurements of CSF drainage under multiple conditions.
  • TBI-associated interference with the glymphatic/lymphatic system whether via an adrenergic storm or elevated intracranial/central venous pressure, worsens edema and causes the retention of neural debris, consolidating glymphatic occlusion and leading to a feed-forward exacerbation of the initial insult.
  • Noradrenergic Antagonists Certain aspect of this disclosure provides methods for treating a cerebral edema or a traumatic brain injury, for improving glymphatic-lymphatic efflux from the central nervous system (CNS) of a subject, or for promoting clearance of a substance from the CNS interstitium, brain interstitium and/or spinal cord interstitium of a subject. Each of the methods comprises administering to a subject in need thereof one or more adrenergic antagonists.
  • CNS central nervous system
  • adrenergic antagonist As used herein the terms “adrenergic antagonist,” “noradrenergic antagonist,” “adrenergic receptor inhibitor,” “inhibitor of adrenergic receptor,” “adrenergic receptor blocker,” and “blocker of adrenergic receptor” are used interchangeably to refer to any agent that inhibits or blocks the function of adrenergic receptors.
  • Adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of catecholamines like noradrenaline (norepinephrine) and adrenaline (epinephrine). There are five adrenergic receptors, which are divided into two groups.
  • the first group of receptors are the beta ( ⁇ ) adrenergic receptors. There are ⁇ 1, ⁇ 2, and ⁇ 3 receptors.
  • the second group contains the alpha ( ⁇ ) adrenoreceptors. There are ⁇ 1 and ⁇ 2 receptors.
  • antagonists, inhibitors, or blockers of alpha and beta adrenoreceptors are also called alpha blockers and beta blocker, respectively.
  • beta blockers also known as beta-adrenergic blockers and beta-adrenergic antagonists
  • beta blockers include acebutolol (sectral), alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butaxamine, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol (brevibloc), indenolol, labetalol, levobetaxolo
  • the beta blocker can comprise an aryloxypropanolamine derivative.
  • aryloxypropanolamine derivatives include acebutolol, alprenolol, arotinolol, atenolol, betaxolol, bevantolol, bisoprolol, bopindolol, bunitrolol, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, epanolol, indenolol, mepindolol, metipranolol, metoprolol, UR 6-23116 /FR: 161118.05100 moprolol, nadolol, nipradilol, oxprenolol, penbutolol, pindolol, propranolol, talinolol
  • a beta blocker can be, but is not limited to, beta-1 selective beta blocker, beta-2 selective beta blocker, alpha-1/beta adrenergic antagonists, beta-3 selective beta blocker, beta-1 and beta-3 selective beta blocker, a non-selective beta blocker, a beta-1 and beta-2 selective beta-blocker, or a mixture of two or more beta-blockers.
  • Beta-1 selective beta blocker can be selected from the group consisting of acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, esmolol, metoprolol, nebivolol and pharmaceutically acceptable salts and derivatives thereof and their combinations.
  • Non-selective beta blocker can be selected from the group consisting of alprenolol, bucindolol, carteolol, levobunolol, medroxalol, mepindolol, metipranolol, nadolol, oxprenolol, penbutolol, pindolol, propafenone (propafenone is a sodium channel blocking drug that is also a beta-adrenergic receptor antagonist), propranolol, sotalol, timolol and pharmaceutically acceptable salts and derivatives thereof and their combinations.
  • the beta blocker may also have an intrinsic sympathomimetic activity as acebutolol, betaxolol, carteolol, carvedilol, labetalol, oxprenolol, penbutolol, pindolol.
  • alpha blocker also known as alpha-adrenergic blockers or alpha-adrenergic antagonists
  • alpha blocker include amosulalol, atipamezole, arotinolol, dapiprazole, doxazosin, ergoloid mesylates, fenspiride, indoramin, labetalol, nicergoline, prazosin, terazosin, tolazoline, trimazosin, yohimbine, phenoxybenzamine, phentolamine, bunazosin, alfuzosin, tamsulosin, carvedilol, trazodone, mirtazapine, , urapidil, and idazoxan.
  • ⁇ -1 antagonist examples include phenoxybenzamine, phentolamine, prazosin, doxazosin, bunazosin, alfuzosin, terazosin, tamsulosin, yohimbine, labetalol, carvedilol, tolazoline, trazodone, mirtazapine, indoramin, urapidil, and idazoxan.
  • a blocker may comprise a quinazoline derivative.
  • quinazoline derivatives include alfuzosin, bunazosin, doxazosin, prazosin, terazosin and trimazosin.
  • alpha-1- adrenergic antagonists such as prazosin (Minipress®), doxazosin mesylate (Cardura®), prazosin hydrochloride (Minipress®), prazosin, polythiazide (Minizide®), and terazosin hydrochloride (Hytrin®); beta-adrenergic antagonists, such as propranolol (Inderal®), UR 6-23116 /FR: 161118.05100 nadolol (Corgard®), timolol (Blocadren®), metoprolol (Lopressor®), and pindolol (Visken®); combined alpha/beta-adrenergic antagonists, such as labetalol (Normodyne®, Trandate®) and carvedilol (Coreg®).
  • alpha-1- adrenergic antagonists such as prazosin (Minipress®), doxazosin mesylate
  • the adrenergic antagonists include prazosin, atipamezole, and propranolol (respectively, alpha1, alpha2 and beta adrenergic antagonists). Additional embodiments include congeners of these compounds with analogous receptor antagonism.
  • agents sufficient to induce an EEG pattern consistent with slow wave sleep - which is triggered by and downstream of adrenergic inhibition - including daridorexant, tiagabine, trazadone, mirtazapine, olanzapine, gabapentin, pregabalin, and serotonin 5HT2a agonists such as eplivanserin and ritanserin –– may be used in place of or in association with adrenergic antagonists, for the purpose of mitigating post ⁇ TBI cerebral edema and brain injury. See, e.g., Walsh J Clin Sleep Med.2009 Apr 15; 5(2 Suppl): S27–S32.
  • adrenergic antagonist or noradrenergic antagonist are described in US20110195974, US20220049306, US20220364184, US20220362055, US20220267269, US 20220218630, and US 20220117921, the contents of which are incorporated in their entities.
  • alpha 1A antagonists that are selective or specific for alpha 1A and not alpha 1B are listed in U.S. Pat. Nos.
  • derivatives are used interchangeable to refer to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those compounds disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the compounds, or to induce, as a precursor, the same or similar activities and utilities as the compounds.
  • a derivative or analogue may be prodrug, ester, salt, or metabolite of the compound.
  • compositions and Uses are available for the uses or therapies described herein, e.g., intramuscular injections, implants, oral tablets, subcutaneous formulations, intranasal UR 6-23116 /FR: 161118.05100 formulations, buccal formulations, transdermal formulations such as topical gels, and solutions, or topical patches, and the like.
  • the composition can be a solid dosage formulation (e.g., tablet, capsule, granule, powder, sachet, or chewable), solution, gel, suspension, emulsion, shampoo, conditioner, cream, foam, gel, lotion, ointment, transdermal patch, film, tincture, or paste.
  • compositions described herein for treating a disease, preventing a disease, treating a condition, and/or preventing a condition.
  • the composition or formulation of the compound or derivative or analogue or salt thereof may provide a dose adequate to improve glymphatic-lymphatic efflux from the CNS.
  • the pharmaceutically effective amount of the compounds, derivatives, analogues, or salts thereof present in the compositions as disclosed herein may depend on the patient's condition and the mode of administration.
  • Pharmaceutical compositions containing any of the compounds described herein or derivative or analogue or salt thereof may further comprise a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be formulated (e.g., using the same excipients in the same ratios and/or comprising the same dose strength) or administrated in the same way as commercially available drugs, prodrugs, derivative products, including but not limited to prazosin (Minipress®), doxazosin mesylate (Cardura®), prazosin hydrochloride (Minipress®), prazosin, polythiazide (Minizide®), and terazosin hydrochloride (Hytrin®); beta-adrenergic antagonists, such as propranolol (Inderal®), nadolol (Corgard®), timolol (Blocadren®), metoprolol (Lopressor®), and pindolol (Visken®); combined alpha/beta-adrenergic antagonists, such as labetalol (Normodyne®, Trandate®) and carvedilol (Coreg
  • the FDA-approved labels for each of these products are available at the website of the FDA, including with respect to their formulation, dosing, and administration.
  • the compounds and agents described above and related compositions are useful in methods of (i) improving glymphatic-lymphatic efflux from the CNS of a subject, (ii) promoting clearance of a waste product from the CNS interstitium, brain interstitium and/or spinal cord interstitium of a subject, and (iii) treating a cerebral edema, a traumatic brain injury, a neurodegenerative disease, or others disclosed herein in a subject.
  • the compounds, agents, or compositions can be administered in a therapeutically effective amount by any of the accepted modes of administration.
  • Suitable dosage ranges depend upon numerous factors such as the severity of the disease or condition UR 6-23116 /FR: 161118.05100 to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved.
  • One of ordinary skill in the art of treating such diseases or conditions will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compounds of the present disclosure for a given disease or condition.
  • the compounds or compositions of the present disclosure can be administered as pharmaceutical formulations including those suitable for, oral (including buccal and sub-lingual), nasal, pulmonary, topical, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • a pharmaceutical composition described herein can be formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral (e.g., intravenous, intradermal, or subcutaneous), oral (e.g., inhalation), transdermal (topical), and transmucosal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl parabens
  • antioxidants
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, CREMOPHOR (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, UR 6-23116 /FR: 161118.05100 glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating an active compound or agent in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • typical methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally can include an inert diluent or an edible carrier.
  • the active compound or agent can be incorporated with excipients and used in the form of tablets, troches, or capsules, e.g., gelatin capsules.
  • Oral compositions can also be prepared using a fluid carrier.
  • compositions can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such as sucrose or saccharin
  • the active agent or compound can be delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable UR 6-23116 /FR: 161118.05100 propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable UR 6-23116 /FR: 161118.05100 propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • a gas such as carbon dioxide
  • a nebulizer e.g., a gas such as carbon dioxide
  • Systemic administration of a compound or agent can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds can be formulated into ointments, salves, gels, or creams as generally known in the art.
  • the therapeutic composition may preferably be administered as needed. For example, for severe conditions, about 1-4 times per day on a daily basis can be used.
  • the therapeutic composition may alternatively be administered on a weekly, bi-weekly, tri- weekly, weekly or monthly basis until the condition is treated or remediated as desired.
  • the administration may initially begin on a daily basis and then, in response to clinical improvement, transition to a weekly, monthly, etc. administration.
  • the composition of the present invention may also be used to maintain a user in edema free condition.
  • the effective dose of a composition comprising one or more compounds/agents as described herein can be administered to a patient once.
  • the effective dose of a composition can be administered to a patient repeatedly.
  • Patients can be administered a therapeutic amount of a composition comprising a compound/agent at 0.0001 mg/kg to 100 mg/kg, such as 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 40 mg/kg or 50 mg/kg.
  • a composition comprising a compound/agent can be administered over a period of time, such as over a 5-minute, 10-minute, 15-minute, 20-minute, or 25-minute period.
  • the administration is repeated, for example, on a regular basis, such as hourly for 3 hours, 6 hours, 12 hours or longer or such as biweekly (i.e., every two weeks) for one month, two months, three months, four months or longer.
  • a regular basis such as hourly for 3 hours, 6 hours, 12 hours or longer or such as biweekly (i.e., every two weeks) for one month, two months, three months, four months or longer.
  • the treatments can be administered on a less frequent basis. For example, after administration biweekly for three months, administration can be repeated once per month, for six months or a year or longer.
  • compositions comprising a compound/agent can reduce levels of a marker or symptom of, for example, by at least 10%, at least 15%, at least 20%, at UR 6-23116 /FR: 161118.05100 least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% or more.
  • the compositions can be provided in a suitable form or a unit dosage containing about 0.001 to about 100 milligrams of active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • An effective amount of the drug can be supplied at a dosage level of from about 0.0001 mg/kg to about 100 mg/kg of body weight per day.
  • the compound or derivative or analogue or salt thereof may be provided in gel or cream forms in doses of 20 to 200 mg per day.
  • compound, derivative, analogue, or salt thereof are provided in a gel at doses of 50 to 100 mg/day, particularly 50 mg/day, 75 mg/day and 100 mg/day.
  • Transdermal patches can used to deliver compound or derivative or analogue or salt thereof of 1 to 10 mg per day, particularly, 4 to 6 mg/day.
  • the compound or derivative or analogue or salt thereof may also be provided by means of a buccal gel at a dose of 10 mg/day to 100 mg/day.
  • the dose can be a buccal gel is 40 to 80 mg/day.
  • the dose can be 60 mg/day.
  • the methods and compositions described herein may be used for increasing glymphatic system efflux and interstitial waste clearance. Accordingly, the methods and compositions can be used for perverting or treating traumatic brain injury, including acute traumatic brain injury, and various related disorders associated with or caused by brain edema. In some embodiments, the method disclosed herein can be used for treating or preventing a brain injury. Any type of brain injury can be treated by administration of the therapeutic agent (e.g., the antagonists) described herein.
  • the brain injury may for example be traumatic brain injury, non-traumatic brain injury, elevated intracranial pressure, or secondary brain injury.
  • the term “brain injury” refers to a condition in which the brain is damaged by injury caused by an event.
  • an “injury” is an alteration in cellular or molecular integrity, activity, level, robustness, state, or other alteration that is traceable to an event.
  • an injury includes a physical, mechanical, chemical, biological, functional, infectious, or other modulator of cellular or molecular characteristics.
  • An event can include a physical trauma such as a single or repetitive impact (percussive) or a biological abnormality such as a stroke resulting from either blockade or leakage of a blood vessel.
  • An event is UR 6-23116 /FR: 161118.05100 optionally an infection by an infectious agent.
  • a person of skill in the art recognizes numerous equivalent events that are encompassed by the terms injury or event.
  • brain injury refers to a condition that results in central nervous system damage, irrespective of its pathophysiological basis.
  • stroke is classified into hemorrhagic and non-hemorrhagic.
  • hemorrhagic stroke include cerebral hemorrhage, subarachnoid hemorrhage, and intracranial hemorrhage secondary to cerebral arterial malformation, while examples of non-hemorrhagic stroke include cerebral infarction.
  • intra-axial hemorrhage blood inside the brain
  • extra-axial hemorrhage blood inside the skull but outside the brain.
  • Intra-axial hemorrhage is due to intra-parenchymal hemorrhage or intra-ventricular hemorrhage (blood in the ventricular system).
  • the intra-axial hemorrhage is caused by brain trauma, hemorrhagic stroke and/or spontaneous bleeding into the brain.
  • the intraparenchymal hemorrhage, intraventricular hemorrhage, or intraventricular traumatic diffuse bleeding is caused by brain trauma, hemorrhagic stroke and/or spontaneous bleeding into the brain.
  • the term “traumatic brain injury” or “TBI” refer to traumatic injuries to the brain which occur when physical trauma causes brain damage. For example, TBI can result from a closed head injury or a penetrating head injury.
  • a TBI can be caused by a forceful bump, blow, or jolt to the head or body, or from an object that pierces the skull and enters the brain.
  • a “traumatic brain injury” or “brain trauma” occurs when an external force traumatically injures the brain.
  • TBI can be classified based on severity, mechanism (closed or penetrating head injury), or other features (e.g., occurring in a specific location or over a widespread area).
  • a traumatic brain injury can occur as a consequence of a focal impact upon the head, by a sudden acceleration/deceleration within the cranium or by a complex combination of both movement and sudden impact, as well as blast waves, or penetration by a projectile or sharp, or dull object.
  • the Glasgow Coma Scale (GCS), the most commonly used system for classifying TBI severity, grades a person's level of consciousness on a scale of 3-15 based on verbal, motor, and eye-opening reactions to stimuli.
  • GCS Glasgow Coma Scale
  • a TBI with a GCS of 13 or above is mild, 9-12 is moderate, and 8 or below is severe. Similar systems exist for young children. From the diagnostic point of view, it is further distinguished between open and closed TBIs.
  • An open TBI is considered to be an injury in UR 6-23116 /FR: 161118.05100 which the protective barrier under the bone (cerebral meninges, dura mater) is mechanically destroyed and the brain is in contact with the external environment through this opening.
  • an open TBI is associated with the exit of liquor and brain tissue debris.
  • a closed TBI the skull or cranium remains intact, and the primary damage of the brain (trauma) is characterized by local lesions such as contusions or hematomas and/or diffuse cerebral tissue damage.
  • the term “cranium” when referred to herein is the set of out of the neurocranium (braincase) and the viscerocranium (craniofacial) existing bony and cartilaginous head skeleton of vertebrates. “Intracranial” means within the cranium. In accordance with the above, traumatic brain injury of any severity can be treated by the administration of the therapeutic agent(s) described herein.
  • the patient to be treated may, for example, have been diagnosed with complicated mild, moderate, or severe traumatic brain injury.
  • patient to be treated may have been diagnosed with traumatic brain injury of a Glasgow Coma Score (GCS) ⁇ 3.
  • GCS Glasgow Coma Score
  • the patient being assessed of having a Glasgow Coma Score (GCS) ⁇ 3 may require intracranial pressure (ICP) monitoring and thus may be taken care of in an intensive care unit (ICU).
  • ICP intracranial pressure
  • ICU intensive care unit
  • the patient does not require ICP monitoring and can, thus, be treated in a normal hospital ward.
  • non-traumatic brain injury refers to brain injuries that do not involve ischemia or external mechanical force (e.g., stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, brain hemorrhage, brain infections, brain tumor, among others).
  • a “non-traumatic brain injury” does not involve external mechanical force to acquire a brain injury.
  • causes for non-traumatic brain injury may include lack of oxygen, glucose, or blood.
  • Infections can cause encephalitis (brain swelling), meningitis (meningeal swelling), or cell toxicity as e.g. caused by fulminant hepatic failure, as can tumors or poisons.
  • encephalitis brain swelling
  • meningitis meningeal swelling
  • cell toxicity as e.g. caused by fulminant hepatic failure
  • These injuries can occur through stroke, heart attack, near-drowning, strangulation or a diabetic coma, poisoning or other chemical causes such as alcohol abuse or drug overdose, infections or tumors and degenerative conditions such as Alzheimer's disease and Parkinson's disease.
  • stroke An acute neurodegenerative disease is represented by “stroke”, which refers to the loss of brain function due to disturbances in the blood supply to the brain, especially when it occurs quickly, and is often associated with cerebrovascular disease.
  • non-traumatic brain injury that can be treated with the therapeutic agent described here, may be ischemic/hypoxic/hemorrhagic brain injury (e.g. stroke), post-resuscitation (after e.g. cardiac arrest), subarachnoid haemorrhage, anticoagulation-induced haemorrhage or non-traumatic brain injury that is caused by inflammation and infection.
  • brain injury also refers to subclinical brain injury, spinal cord injury, and anoxic-ischemic brain injury.
  • subclinical brain injury (SCI) refers to brain injury without overt clinical evidence of brain injury. A lack of clinical evidence of brain injury when brain injury actually exists could result from degree of injury, type of injury, level of consciousness, medications particularly sedation and anesthesia.
  • secondary brain trauma refers to damage to the brain of a patient post-acute brain injury, i.e., during the secondary injury phase of a TBI.
  • “Chronic traumatic encephalopathy (CTE)” is a neurodegenerative disease that is most often identified in postmortem autopsies of individuals exposed to repetitive head impacts, such as boxers and football players.
  • the neuropathology of CTE is characterized by the accumulation of hyperphosphorylated tau protein in a pattern that is unique from that of other neurodegenerative diseases, including Alzheimer's disease.
  • the clinical features of CTE are often progressive, leading to dramatic changes in mood, behavior, and cognition, frequently resulting in debilitating dementia. In some cases, motor features, including Parkinsonism, can also be present.
  • Acute traumatic encephalopathy “ATE” refers to the early post-TBI injury-related changes that are the root cause of long term degenerative processes seen in CTE, including neuroinflammatory processes which affect the process of accumulating aggregation of neuronal proteins such as Tau, which are pathological hallmarks of CTE.
  • chronic brain injury refers to a subject who has suffered a brain injury from three months post-injury onward with continuing symptoms from the brain injury.
  • sub-acute brain injury refers to a subject who has suffered a brain injury from about 2-5 days post injury.
  • the “spinal cord injury” refers to a condition in which the spinal cord receives compression/detrition due to a vertebral fracture or dislocation to cause dysfunction.
  • anoxic-ischemic brain injury refers to deprivation of oxygen supply to brain tissue resulting in compromised brain function and includes cerebral hypoxia.
  • anoxic-ischemic brain injury includes focal cerebral ischemia, global cerebral ischemia, hypoxic hypoxia (i.e., limited oxygen in the environment causes reduced brain function, such as with divers, aviators, mountain climbers, and fire fighters, all of whom are at risk for this kind of cerebral hypoxia), obstructions in the lungs (e.g., hypoxia resulting from choking, strangulation, the crushing of the windpipe).
  • the therapeutic agent(s) and method described herein can be used to treat an infection such as meningitis, which is an acute inflammation of the membranes covering the brain and spinal cord, known collectively as the meninges.
  • the inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs.
  • Encephalitis is another example of an infection that can be treated with the therapeutic agent and method described herein.
  • the inflammation may be Systemic Inflammatory Response Syndrome (SIRS).
  • SIRS Systemic Inflammatory Response Syndrome
  • brain trauma non- traumatic or traumatic brain injury
  • secondary brain injury refers to a variety of events that take place in the minutes and days following the injury.
  • Secondary injury events may include local changes for example damage to the blood-brain barrier, release of factors that cause inflammation, free radical overload, excessive release of the neurotransmitter glutamate (excitotoxicity), influx of calcium and sodium ions into neurons, and dysfunction of mitochondria. Injured axons in the brain's white matter may separate from their cell bodies as a result of secondary injury, potentially killing those neurons.
  • Other factors in secondary injury are changes in the blood flow to the brain; repeated transient disintegrity of the blood brain barrier; ischemia (insufficient blood flow); cerebral hypoxia (insufficient oxygen in the brain); cerebral oedema (swelling of the brain); and raised intracranial pressure (the pressure within the skull).
  • a secondary brain injury that can be treated as described herein may comprise a condition selected from the group consisting of edema formation from local or global hypoxia, ischemia, inflammation with and without infection, UR 6-23116 /FR: 161118.05100 acute and chronic neuroinflammation after traumatic brain injury and neoplasms with both benign neoplasms and malignant neoplasms being treatable. Accordingly, the disclosure provides methods for treating one or more of the brain- injury-related conditions or disorders described herein.
  • the disclosure provides a method of treating a subject (e.g., a human patient) suffering from brain injury, wherein the method comprises administering to the subject within a first time period after the occurrence of the brain injury a therapeutically effective amount(s) of one or more therapeutic agents described herein (e.g., one or more adrenergic antagonists).
  • the first time period can be less than 48 hours, such as less than 36, 24, 18, 12, 6, or 3 hours.
  • the first time period can be more than 48 hours, such as more than 3, 4, 5, 6, or 7 days.
  • the method comprises administering to the subject after a second time period after the occurrence of the brain injury a therapeutically effective amount(s) of one or more therapeutic agents described herein (e.g., one or more adrenergic antagonists).
  • the second time period can be 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, 24 hours, or 48 hours.
  • the second time period can be more than 48 hours, such as 3, 4, 5, 6, or 7 days.
  • noradrenergic receptor inhibition hours or days after brain injury can still boost the lymphatic export and clearance of fluid, macromolecular proteins, and cellular debris, and serve to sharply reduce the consequent neuroinflammation, tau accumulation, and cognitive loss.
  • Such clearance substantially reduces post-TBI inflammation, with reductions in astrogliosis, microglial activation, and cytokine accumulation, the latter as evidenced by lower post-traumatic levels of IL1 ⁇ , IL-4, and IL-6 (see, e.g., Figs.10-11).
  • the method can comprise administering to the subject a therapeutically effective amount(s) of one or more therapeutic agents described herein (i) within a first time period after the occurrence of the brain injury as disclosed above and then (ii) after a second time period after the occurrence of the brain injury as disclosed above.
  • the method disclosed herein can be used for treating onset of a neurodegenerative disease in the brain and/or spinal cord (or CNS) of a subject by increasing glymphatic-lymphatic efflux and/or clearance.
  • reactive gliosis is reduced, thereby delaying or preventing onset of the neurodegenerative disease.
  • Reactive gliosis decreases or prevents interstitial waste clearance. Reactive gliosis decreases Aqp4-dependent bulk flow and reduces the volume of the extracellular space, impeding ISF solute clearance, including waste products, from the brain and spinal cord. Reactive gliosis is known in the art to be associated with neurodegenerative diseases such as Alzheimer's disease. Increasing gliosis is also observed in the aging mammalian brain. Reactive gliosis is also associated with certain autoimmune inflammatory disorders, notably multiple sclerosis. It has also been observed in the CNS of individuals suffering from amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • increasing glymphatic system efflux and/or clearance of waste products from the CNS can be used, in certain embodiments, to delay, prevent, decrease or reduce reactive gliosis and its neurodegenerative consequences.
  • reactive gliosis is reduced, delayed or prevented.
  • the method comprises the step of administering a therapeutic agent to the subject that increases or promotes glymphatic system clearance.
  • a method for promoting clearance of a waste product e.g., a brain, spinal cord or CNS waste product
  • a waste product e.g., a brain, spinal cord or CNS waste product
  • the agent can be or comprise, for example, one or more of the adrenergic antagonists described herein.
  • the brain, spinal cord or CNS waste product is amyloid ⁇ ( ⁇ ) (e.g., soluble ⁇ ), tau or alpha synuclein.
  • the method is also suitable for promoting clearance of virtually any brain waste product known in the art.
  • the method comprises the step of administering a therapeutic agent (for example, one or more of the adrenergic antagonists described herein) to the subject that increases or promotes glymphatic efflux and/or clearance.
  • a therapeutic agent for example, one or more of the adrenergic antagonists described herein
  • the methods and compositions described herein can be used for slowing, delaying or preventing accumulation of a brain waste product. Accordingly, a method is provided for slowing, delaying or preventing accumulation of a waste product in the central nervous system of a subject comprising the step of increasing glymphatic efflux, thereby increasing the clearance of the waste product from the central nervous system.
  • the method comprises the step of administering a therapeutic agent (for example, one or more of the adrenergic antagonists described herein) to the subject that increases or promotes glymphatic efflux.
  • a therapeutic agent for example, one or more of the adrenergic antagonists described herein
  • the brain waste product is amyloid ⁇ ( ⁇ ) (e.g., UR 6-23116 /FR: 161118.05100 soluble ⁇ ) tau, or alpha synuclein.
  • the method is also suitable for slowing, delaying or preventing accumulation of virtually any brain waste product known in the art.
  • a method is provided for decreasing, reducing, delaying onset of, or preventing amyloid ⁇ ( ⁇ ), tau and/or alpha synuclein accumulation in brain interstitium of a subject.
  • the method comprises the step of administering an agent (for example, one or more of the adrenergic antagonists described herein) to the subject that increases or promotes glymphatic efflux.
  • an agent for example, one or more of the adrenergic antagonists described herein.
  • the methods and compositions described herein can be used for increasing clearance of a therapeutic or modulatory agent from the brain interstitium of a subject. Accordingly, a method is provided for increasing clearance of a therapeutic or modulatory agent from the brain interstitium of a subject.
  • the therapeutic or modulatory agent can be any known in the art, e.g., therapeutic or functionalized nanoparticle, chemotherapy agent, antineoplastic agent, immune modulator, antibody based therapeutic, viral vector, liposome or RNA-based therapeutic construct.
  • the method comprises the step of increasing glymphatic efflux in the manner disclosed herein.
  • the patient or subject can be one having a neurological disorder or neurodegenerative disease, including, without limitation: Alzheimer's disease (AD), stroke, epilepsy, dementia, muscular dystrophy (MD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), cystic fibrosis, Angelman's syndrome, Liddle syndrome, Parkinson's disease, Pick's disease, Paget's disease, cancer, traumatic brain injury, etc.
  • the neurological disorder is selected from: a neuropathy, an amyloidosis, cancer (e.g.
  • Neuropathy disorders are diseases or abnormalities of the nervous system characterized by inappropriate or uncontrolled nerve signaling or lack thereof, and include, but are not limited to, chronic pain (including nociceptive pain), pain caused by an injury to body tissues, including cancer-related pain, neuropathic pain (pain caused by abnormalities in the nerves, spinal cord, or brain), and psychogenic pain (entirely or mostly related to a psychological disorder), headache, migraine, neuropathy, and symptoms and syndromes often accompanying such neuropathy disorders such as vertigo or nausea.
  • Amyloidoses are a group of diseases and disorders associated with extracellular proteinaceous deposits in the CNS, including, but not limited to, secondary amyloidosis, age- UR 6-23116 /FR: 161118.05100 related amyloidosis, Alzheimer's Disease (AD), mild cognitive impairment (MCI), Lewy body dementia, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis (Dutch type); the Guam Parkinson-Dementia complex, cerebral amyloid angiopathy, Huntington's disease, progressive supranuclear palsy, multiple sclerosis; Creutzfeld Jacob disease, Parkinson's disease, transmissible spongiform encephalopathy, HIV-related dementia, amyotropic lateral sclerosis (ALS), inclusion-body myositis (IBM), and ocular diseases relating to beta-amyloid deposition (i.e., macular degeneration, drusen-related optic neuropathy, and cataract).
  • AD Alzheimer's Disease
  • Cancers of the CNS are characterized by aberrant proliferation of one or more CNS cell (i.e., a neural cell) and include, but are not limited to, glioma, glioblastoma multiforme, meningioma, astrocytoma, acoustic neuroma, chondroma, oligodendroglioma, medulloblastomas, ganglioglioma, Schwannoma, neurofibroma, neuroblastoma, and extradural, intramedullary or intradural tumors.
  • a neurological drug may be selected that is a chemotherapeutic agent.
  • Viral or microbial infections of the CNS include, but are not limited to, infections by viruses (i.e., influenza, HIV, poliovirus, rubella,), bacteria (i.e., Neisseria sp., Streptococcus sp., Pseudomonas sp., Proteus sp., E. coli, S.
  • viruses i.e., influenza, HIV, poliovirus, rubella
  • bacteria i.e., Neisseria sp., Streptococcus sp., Pseudomonas sp., Proteus sp., E. coli, S.
  • aureus Pneumococcus sp., Meningococcus sp., Haemophilus sp., and Mycobacterium tuberculosis
  • fungi i.e., yeast, Cryptococcus neoformans
  • parasites i.e., toxoplasma gondii
  • amoebas resulting in CNS pathophysiologies including, but not limited to, meningitis, encephalitis, myelitis, vasculitis and abscess, which can be acute or chronic.
  • Inflammation of the CNS includes, but is not limited to, inflammation that is caused by an injury to the CNS, which can be a physical injury (i.e., due to accident, surgery, brain trauma, spinal cord injury, concussion) and an injury due to or related to one or more other diseases or disorders of the CNS (i.e., abscess, cancer, viral or microbial infection).
  • an injury to the CNS which can be a physical injury (i.e., due to accident, surgery, brain trauma, spinal cord injury, concussion) and an injury due to or related to one or more other diseases or disorders of the CNS (i.e., abscess, cancer, viral or microbial infection).
  • Ischemia of the CNS refers to a group of disorders relating to aberrant blood flow or vascular behavior in the brain or the causes therefor, and includes, but is not limited to: focal brain ischemia, global brain ischemia, stroke (i.e., subarachnoid hemorrhage and intracerebral hemorrhage), and aneurysm.
  • Neurodegenerative diseases are a group of diseases and disorders associated with neural cell loss of function or death in the CNS, and include, but are not limited to: Parkinson's disease (PD), Alzheimer's disease (AD), Alzheimer's disease with Lewy bodies, Lewy body dementia, and mixed dementia, or associated with traumatic brain injury or UR 6-23116 /FR: 161118.05100 ischemic (e.g., diffuse ischemic) brain injury, vascular dementia, frontotemporal dementia or chronic traumatic encephalopathy, adrenoleukodystrophy, Alexander's disease, Alper's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease, cockayne syndrome, corticobasal degeneration, degeneration caused by or associated with an amyloidosis, Friedreich's ataxia, frontotemporal lobar degeneration, Kennedy's disease, multiple system atrophy, multiple sclerosis, primary lateral sclerosis, progressive supranuclear palsy, spinal muscular
  • Kit and Articles of Manufacture in another aspect, this disclosure provides a kit or an article of manufacture containing materials useful for the methods described above.
  • the article of manufacture comprises a container and a label or package insert on or associated with the container.
  • Suitable containers include, for example, bottles, vials, syringes, solution bags, etc.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container holds a composition which is by itself or combined with another composition effective (1) for improving delivery of a composition to a target site, (e.g., central nervous system interstitium, brain interstitium and/or a spinal cord interstitium of a subject) or (2) for treating, preventing and/or diagnosing one or more of the conditions mentioned above.
  • a target site e.g., central nervous system interstitium, brain interstitium and/or a spinal cord interstitium of a subject
  • the container may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • the label or package insert indicates that the composition is used for treating the condition of choice.
  • the article of manufacture may comprise (a) a first container with a composition contained therein, wherein the composition comprises an agent that enhances glymphatic system efflux and (b) a second container with a composition contained therein, wherein the composition comprises an agent that enhances glymphatic system influx.
  • the article of manufacture may comprise a third container with a composition contained therein, wherein the composition comprises a therapeutic agent or imaging agent.
  • the article of manufacture in this embodiment of the invention may further comprise a package insert indicating that the compositions can be used to treat a particular condition.
  • the article of manufacture may further comprise a fourth container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution.
  • BWFI bacteriostatic water for injection
  • phosphate-buffered saline such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution.
  • BWFI bacteriostatic water for injection
  • phosphate-buffered saline such as phosphate-buffered saline
  • Ringer's solution such as phosphate-buffered saline
  • dextrose solution such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and de
  • the kit or article of manufacture further comprises instructional materials containing directions (i.e., protocols) for the practice of the methods described herein (e.g., instructions for using the kit for administering a composition).
  • instructional materials typically comprise written or printed materials, they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this invention. Such media include, but are not limited to, electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD-ROM), and the like. Such media may include addresses to internet sites that provide such instructional materials.
  • prodrug or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form any of the compounds of the present disclosure.
  • the present disclosure includes within its scope, prodrugs of the compounds described herein. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • prodrug may also refer to a naturally occurring precursor of a drug.
  • UR 6-23116 /FR: 161118.05100 The term "biologically active metabolite” means a pharmacologically active product produced through metabolism in the body of a specified compound as disclosed herein or salt thereof.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 alkyl) 4 - salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • an effective amount refers to the amount of an agent needed to alleviate at least one or more symptom of the disease or disorder, and relates to a sufficient amount of pharmacological composition to provide the desired effect.
  • the term UR 6-23116 /FR: 161118.05100 "therapeutically effective amount” therefore refers to an amount of the agent that is sufficient to provide a beneficial effect when administered to a typical subject.
  • An effective amount as used herein, in various contexts, would also include an amount sufficient to delay the development of a symptom of the disease, alter the course of a symptom disease (for example but not limited to, slowing the progression of a symptom of the disease), or reverse a symptom of the disease. Thus, it is not generally practicable to specify an exact "effective amount”.
  • an appropriate "effective amount” can be determined by one of ordinary skill in the art using only routine experimentation. Effective amounts, toxicity, and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dosage can vary depending upon the dosage form employed and the route of administration utilized.
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50/ED50. Compositions and methods that exhibit large therapeutic indices are preferred.
  • a therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 as determined in cell culture, or in an appropriate animal model.
  • Levels in plasma can be measured, for example, by high performance liquid chromatography.
  • the effects of any particular dosage can be monitored by a suitable bioassay.
  • the dosage can be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.
  • the terms “decrease,” “reduced”, “reduction”, and “inhibit” are all used herein to mean a decrease by a statistically significant amount.
  • “reduce,” “reduction” or “decrease” or “inhibit” typically means a decrease by at least 10% as compared to a reference level (e.g.
  • a decrease can be preferably down to a level accepted as within the range of normal for an individual without a given disorder.
  • the terms “improve,” “increased”, “increase”, “enhance”, or “activate” are all used herein to mean an increase by a statically significant amount.
  • the terms “improve,” “increased,” “increase”, “enhance”, or “activate” can mean an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level.
  • an "increase” is a statistically significant increase in such level.
  • a "subject” or “individual” means a human or animal. Usually the animal is a vertebrate such as a primate, rodent, domestic animal or game animal. Primates include chimpanzees, cynomologous monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters.
  • domestic and game animals include cows, horses, pigs, sheep, goats, deer, bison, buffalo, feline species, e.g., domestic cat, canine species, e.g., dog, fox, wolf, avian species, e.g., chicken, emu, ostrich, and fish, e.g., trout, catfish and salmon.
  • the subject is a mammal, e.g., a human or a non-human mammal.
  • the mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but is not limited to these examples. Mammals other than humans can be advantageously used as subjects that represent animal models of disorders.
  • a subject can be male or female.
  • a subject can be one who has been previously diagnosed with or identified as suffering from or having a condition or disorder in need of treatment or one or more complications related to such a condition or disorder, and optionally, have already undergone treatment for such a condition or disorder or the one or more complications related to the condition or disorder.
  • a subject can also be one who has not been previously diagnosed as having a condition or disorder or one or more complications related to the condition or disorder.
  • a subject can be one who exhibits one or more risk factors for the condition or disorder or one or more complications related to the condition or disorder or a subject who does not exhibit risk factors.
  • a "subject in need" of treatment for a particular condition or disorder can be a subject having that condition or disorder, diagnosed as having that condition or disorder, or at risk of developing that condition or disorder.
  • the term “administering,” refers to the placement of an agent as disclosed herein into a subject by a method or route which results in at least partial delivery of the agent at a desired site.
  • Pharmaceutical compositions comprising the agents disclosed herein can be administered by any appropriate route which results in an effective treatment in the subject.
  • the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject.
  • Such methods include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, ophthalmic administration, intraaural administration, intracerebral administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration.
  • Administration can be continuous or intermittent.
  • a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition.
  • a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.
  • parenteral administration and “administered parenterally” refers to modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • unit dosage” formulations are those containing a dose or sub-dose of the administered ingredient adapted for a particular timed delivery.
  • exemplary “unit dosage” formulations are those containing a daily dose or unit or daily sub-dose or a weekly dose or unit or weekly sub-dose and the like.
  • the terms “treat,” “treatment,” “treating,” or “amelioration” refer to therapeutic treatments, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a condition associated with a disease or disorder.
  • the term “treating” includes reducing or alleviating at least one adverse effect or symptom of UR 6-23116 /FR: 161118.05100 a condition, disease or disorder associated with a disorder. Treatment is generally "effective” if one or more symptoms or clinical markers are reduced.
  • treatment is "effective" if the progression of a disease is reduced. That is, “treatment” includes not just the improvement of symptoms or markers, but also a slowing of, progress or worsening of symptoms compared to what would be expected in the absence of treatment. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptom(s), diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, remission (whether partial or total), and/or decreased mortality, whether detectable or undetectable.
  • treatment also includes providing relief from the symptoms or side-effects of the disease (including palliative treatment).
  • a “therapeutically effective amount” is an amount sufficient to remedy a disease state or symptoms, particularly a state or symptoms associated with the disease state, or otherwise prevent, hinder, retard or reverse the progression of the disease state or any other undesirable symptom associated with the disease in any way whatsoever.
  • the terms “prevent”, “preventing”, “prevention” and the like are used interchangeably herein to mean inhibit, hinder, retard, reduce or otherwise delay the development of and/or progression of a condition or disorder (such as TBI) or a symptom thereof, in a subject.
  • the term “prevent” and variations thereof does not necessarily imply the complete prevention of the specified event. Rather, the prevention may be to an extent, and/or for a time, sufficient to produce the desired effect.
  • Prevention may be inhibition, retardation, reduction or otherwise hindrance of the event, activity or function. Such preventative effects may be in magnitude and/or be temporal in nature.
  • a "prophylactically effective amount” is an amount of a pharmaceutical composition that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of the disease state, or reducing the likelihood of the onset (or reoccurrence) of the disease state or associated symptoms.
  • the full therapeutic or prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a therapeutically or prophylactically effective amount may be administered in one or more administrations.
  • the term "pharmaceutical composition” refers to the active agent in combination with a pharmaceutically acceptable carrier e.g. a carrier commonly used in the pharmaceutical industry.
  • a pharmaceutically acceptable carrier e.g. a carrier commonly used in the pharmaceutical industry.
  • pharmaceutically acceptable is employed herein to UR 6-23116 /FR: 161118.05100 refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the term “pharmaceutically acceptable carrier or excipient” refers to a carrier medium or an excipient which does not interfere with the effectiveness of the biological activity of the active ingredient(s) of the composition and which is not excessively toxic to the host at the concentrations at which it is administered.
  • a pharmaceutically acceptable carrier or excipient is preferably suitable for topical formulation.
  • the term includes, but is not limited to, a solvent, a stabilizer, a solubilizer, a tonicity enhancing agent, a structure-forming agent, a suspending agent, a dispersing agent, a chelating agent, an emulsifying agent, an anti-foaming agent, an ointment base, an emollient, a skin protecting agent, a gel-forming agent, a thickening agent, a pH adjusting agent, a preservative, a penetration enhancer, a complexing agent, a lubricant, a demulcent, a viscosity enhancer, a bioadhesive polymer, or a combination thereof.
  • a "neurological disorder” refers to a disease or disorder which affects the CNS and/or which has an etiology in the CNS.
  • Exemplary CNS diseases or disorders include, but are not limited to, neuropathy, amyloidosis, cancer, an ocular disease or disorder, viral or microbial infection, inflammation, ischemia, neurodegenerative disease, seizure, behavioral disorders, and a lysosomal storage disease.
  • neurological disorders include, but are not limited to, neurodegenerative diseases (including, but not limited to, Lewy body disease, postpoliomyelitis syndrome, Shy-Draeger syndrome, olivopontocerebellar atrophy, Parkinson's disease, multiple system atrophy, striatonigral degeneration, tauopathies (including, but not limited to, Alzheimer disease and supranuclear palsy), prion diseases (including, but not limited to, bovine spongiform encephalopathy, scrapie, Creutzfeldt-Jakob syndrome, kuru, Gerstmann-Straussler-Scheinker disease, chronic wasting disease, and fatal familial insomnia), bulbar palsy, motor neuron disease, and nervous system heterodegenerative disorders (including, but not limited to, Canavan disease, Huntington's disease, neuronal ceroid-lipofuscinosis, Alexander's disease, Tourette's syndrome, Menkes kinky hair syndrome, Cockayne syndrome, Halervorden-Spatz syndrome, la
  • compositions, methods, and respective component(s) thereof are essential to the method or composition, yet open to the inclusion of unspecified elements, whether essential or not.
  • consisting of refers to compositions, methods, and respective components thereof UR 6-23116 /FR: 161118.05100 as described herein, which are exclusive of any element not recited in that description of the embodiment.
  • consisting essentially of refers to those elements required for a given embodiment. The term permits the presence of elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment.
  • Example 1 This example descibes material and methods used in Examples 2-12 bellow.
  • C57BL/6-Tg; Slc1a2-G-CaMP7 mice were obtained from RIKEN Brain Science Institute 56,57 . All mice were housed under standard laboratory conditions with ad libitum access to food and water. All experiments were approved by the University Committee on Animal Resources (UCAR), University of Rochester Medical Center, or the Animal Care and Use Committee at the University of Missouri School of Medicine and followed standards of the Accreditation of Laboratory Animal Care (AAALAC).
  • UCAR University Committee on Animal Resources
  • AALAC Accreditation of Laboratory Animal Care
  • the device was modified/angled such that the metal rod was positioned horizontally to better serve the hit-and-run injury purpose.
  • a polished stainless- steel tip (3 mm diameter) struck the mouse head with a speed of 5.2 mm/s and 0.1 s of contact time.
  • the impactor was positioned perpendicular to the skull at the loading point between the ipsilateral eye and midline on the horizontal side and the eye with bregma on the vertical side. Following the impact, the animal fell onto a soft pad underneath.
  • the above- described hit-and-run model was adopted from Ren et al. (2013) 58 and can be configured to induce mild, moderate, or severe injury. This study is based on the moderate injury paradigm due to the focus on TBI-induced cerebral edema. TBI is variable in the clinic and so is the outcome of the “hit-and-run” TBI model, thus replicating real-life occurrences 59-61 .
  • the inventors are overcoming the variability by including a fairly large number of mice in each group.
  • mice were injected i.p. with saline or a cocktail of noradrenergic receptor inhibitors/antagonists (PPA): prazosin hydrochloride (10 ⁇ g/gm, P7791, Sigma Aldrich), propranolol hydrochloride (10 ⁇ g/gm, P8688, Sigma Aldrich), and atipamezole (1 ⁇ g/gm, A9611, Sigma Aldrich) followed by 2 subsequent doses with 24 h interval.
  • PPA noradrenergic receptor inhibitors/antagonists
  • mice were killed by decapitation at different time points after injury (10 min, 20 min, 30 min, 1 h, and 3 h) and the brains were quickly removed. The olfactory bulb and cerebellum were discarded while the ipsilateral and contralateral hemispheres were placed on pre-weighed slides for determination of wet weight and then dried in an oven at 85 oC for 48-72 h. Dry weight was measured on the same digital balance and the two weights were used to calculate the fractional water content of tissue per gram of dry weight 62 .
  • Behavior Tests Mice were assessed with a battery of behavior tests, including neurological severity score, rota rod, wire grip, open field, novel object, and Morris water maze.
  • IVIS Spectrum IR imaging Mice were implanted with an intra-striatal cannula as described above 45 , subjected to TBI or sham hit, treated with PPA or saline i.p. injection, and maintained under anesthesia (1.5-2% isoflurane, administered through nose cones fitting within the imaging apparatus), and the IR signals were recorded/imaged (excitation/emission; 640/690 nm) through the intact skull and femoral region using the IVIS Spectrum IR imager (PerkinElmer Inc.).
  • the syringe was emptied into the UR 6-23116 /FR: 161118.05100 heparinized vial (1.5ml, Eppendorf) before the plasma was separated by centrifugation (1000rpm, 10 min, 4 °C) and frozen at -80°C for further processing.
  • Cerebral Microdialysis and Analysis of Extracellular Concentration of Noradrenaline A dialysis guide cannula was positioned at the prefrontal cortex. The coordinates were AP + 2.1 mm, ML + 0.3 mm from bregma, and DV -0.7 mm from dura. The guide cannula was secured to the skull with dental cement. After implantation, mice were allowed to recover for 2-3 days as described previously 12 .
  • aCSF cerebrospinal fluid
  • Dialysates (30 ⁇ l, twice an hour) were collected in 0.5 ml Eppendorf tubes (placed on ice) from freely moving animals in their home cage, with or without TBI and PPA treatment up to 12 h post-injury.
  • Noradrenaline Concentrations of noradrenaline were determined in 10 ⁇ l samples by HPLC with electrochemical detection as per an established protocol 12,31 .
  • the stationary phase was a Prodigy C18 column (100 x 2 mm I.D., 3 ⁇ m particle size, YMC Europe, Schermbeck, Germany).
  • the mobile phase consisted of 55 mM sodium acetate, 1 mM octane sulfonic acid, 0.1 mM Na2EDTA, and 7% acetonitrile, adjusted to pH 3.7 with 0.1 M acetic acid, and with degassing using an online degasser, with isocratic flow at 0.55 ml/min.
  • the electrochemical detection was accomplished using an amperometric detector (Antec Decade from Antec, Leiden, The Netherlands) with a glass carbon electrode set at +0.7 V, with an Ag + /AgCl reference electrode. The output was recorded using the CSW system (Data Apex, Prague, The Czech Republic), which was used to calculate the electrochemical peak areas.
  • Influx of Radiolabeled 22 Na The influx of radionuclide was estimated as described previously 56 . Briefly, the radionuclide 22 Na (NaCl, Perkin Elmer) diluted either in aCSF or normal saline (final radioactivity concentrations 0.1 ⁇ Ci/ ⁇ l) were infused (10 ⁇ l, 2 ⁇ l/min) via CM in pre- canulated mice.
  • PE10 tubing was inserted surgically into the femoral artery, and the 22 Na was infused at the same rate as in the CM.
  • Mice received TBI or sham hit followed immediately by i.p. injection of saline or PPA, administered less than 2 min before the start of the 22 Na infusion.
  • the cerebral hemispheres were harvested 30 min after the start of 22 Na infusion, homogenized by Solvable (Perkin Elmer) overnight, followed by addition of scintillation cocktail (5 ml/vial).
  • the radioactivity content (Max beta energy: UR 6-23116 /FR: 161118.05100 0.546 MeV (89.8%), annihilation photons: 0.511 MeV (180%)) was measured using a liquid scintillation counter (LS6500 Multipurpose Scintillation Counter, Beckman) 56 . Data were background-subtracted and calculated as a percentage of the total 22 Na dose administered (CPMbrain-CPMblank)/CPMctrl x100% and compared statistically across the groups using GraphPad Prism.
  • the inner diameter was tracked at 30-60 fps from brightfield images of the vessel as described previously 34 . Pressures were transiently set to 10 cmH 2 O immediately after setup and the vessel was stretched axially to remove slack, which minimized longitudinal bowing and associated diameter-tracking artifacts. Spontaneous contractions typically began within 15-30 min of warm-up at a pressure of 2 or 3 cmH 2 O, and the vessel was allowed to stabilize at 37 °C for 30-60 min before beginning an experimental protocol. A suffusion line connected to a peristaltic pump exchanged the chamber contents with Krebs buffer at a rate of 0.5 ml/min.
  • each vessel was perfused with Ca 2+ -free Krebs buffer containing 3 mM EGTA for 20 min, and the passive diameter was recorded at the pressure used in the protocol.
  • Contractile Function parameters After an experiment, custom-written analysis programs (LabVIEW) were used to detect peak end-diastolic diameter (EDD), end-systolic diameter (ESD), and contraction frequency (FREQ) on a contraction-by-contraction basis. These data were used to calculate parameters that characterize lymphatic vessel contractile function. Each of the parameters represents the average of the respective values from all the recorded contractions at a given NE concentration during a 2 min period.
  • EDD avg and FREQ avg represent the average EDD and frequency during the baseline period before the addition of a drug to the bath.
  • GCaMP7 mice were injected with BSA647 (66 kDa, Invitrogen) to visualize CLVs; further image processing and contrast adjustment enabled the inventors to identify the dark particle efflux as cells and debris, with possible colocalization with GCaMP7 cells.
  • Vital signs ECG and respiration
  • ECG and respiration were recorded synchronously (3 kHz, ThorSync software) with the acquisition. Images were processed and analyzed using ImageJ and customized MATLAB scripts 30,56 .
  • Lymphatic Vessel Contraction Measurements Measurements of the in vivo CLV contraction amplitude and frequency (Fig.4b) were obtained by analyzing imaging time series using ImageJ and custom MATLAB scripts. The vessel diameter (Fig.
  • the volume flow rate was estimated as the average flow speed multiplied by the approximate cross-sectional area of the vessel, where D is the median vessel diameter.
  • the retrograde flow percentage was computed by identifying the fraction of each time series in which fluid was flowing in the direction opposite the net transport, as in prior work 56,64 .
  • Cell and Cellular Debris Efflux Two-photon image time series were analyzed to estimate size distributions and volumetric efflux rates of cells/cellular debris, which appeared as dark objects in the intraluminal dextran (green) channel. For each image, a dynamic background image (average of the adjacent 15 frames in time) was added then a Gaussian blur was computed and subtracted to improve lighting uniformity.
  • Each image was slightly smoothed by applying a 3x3 pixel moving average and a region of interest (ROI) was selected for analysis.
  • the ROI was binarized using the MATLAB function “imbinarize” with an adaptive threshold and the particles inside the ROI were fit to ellipses using the MATLAB function “regionprops”.
  • the particle volume was estimated as , where is the semimajor axis length, is the semiminor axis length, and The inventors estimated . Average particle distributions per unit volume were estimated (based on the ROI size), then multiplied by the estimated volume flow rate.
  • UR 6-23116 /FR 161118.05100 Lumped Parameter Lymphatic Vessel Simulations Flow through cervical lymphatic vessels was simulated using a lumped parameter model based on previous studies 65-67 .
  • a series of four lymphangions was simulated with a lymphangion length of 0.2 cm, minimum valve resistance of 0.0375 mmHg ⁇ min/ ⁇ l, maximum valve resistance of 12.5 mmHg ⁇ min/ ⁇ l, active tension ranging from 7.5x10 -4 to 2.25x10 -3 mmHg ⁇ cm, contraction frequency ranging from 0.5 to 10 min -1 , inlet pressure 1.58 mmHg, outlet pressure 1.73 mmHg, and external pressure of 1.50 mmHg; all other parameters matched those of Bertram et al.
  • the inventors solved a system of algebraic constraint equations using MATLAB’s nonlinear equation solvers (fzero and fsolve), and then The inventors integrated a system of ODEs in time using a fourth-order Runge-Kutta method.
  • the inventors modeled conditions of different contraction amplitude by varying the active tension from 7.5x10 -4 to 2.25x10 -3 mmHg ⁇ cm with the contraction frequency fixed at 10 min -1 .
  • the inventors modeled conditions of variable contraction frequency by varying the frequency from 0.5 to 10 min -1 with the active tension fixed at 1.4x10 -3 mmHg ⁇ cm. Presented results come from the fourth (final) lymphangion in the simulation.
  • Image Averaging and Analyzes Images were acquired using the following microscopes: wide field fluorescent/epifluorescent microscope (MVX 10, Olympus), M205 FA fluorescence stereomicroscope equipped with an Xcite 200DC light source, and A12801-01 W-View GEMINI (Leica Inc.), Montage/slid scanning microscope (Olympus), FV 500 confocal microscope (IX81, Olympus), SP8 confocal microscope (Leica Microsystems), FV3000 confocal microscope (Olympus), and two/multiphoton galvoresonance scanner (Thorlabs Inc.). Field of view, regions of interest, resolution, and other acquisition factors were standardized, and fluorescence intensity was estimated using image processing plugins in ImageJ.
  • NSS Neurological severity score
  • mice were assessed independently three times consecutively on each measurement day. Data are presented graphically for beam walk, round stick balance, and overall NSS. Wire grip testing Vestibulomotor function, as described by Petraglia et al. (2014) J Neurotrauma 31, 1211-1224, was assessed using wire grip testing immediately after injury and again at two weeks post-TBI. In brief, mice (8-10/group) were suspended by the tail and placed on a metallic wire hanging between two upright bars, 50 cm above the lab bench. The time and manner in which the mouse retained ahold of the wire were noted and blindly scored on a 0-5 scale. The average score of three consecutive trials at intervals of 5 min was used in the analysis.
  • Rota-rod The motor function was assessed by placing each mouse on a circular rotating rod (Rota Rod Device, Ugo Basile) with speed gradually increasing from 5-40 rpm over 15 min, which provides a sensitive and efficient index for assessing motor impairment after TBI (Hamm, R. J., et al. Journal of neurotrauma 11, 187-196, (1994)). Mice (12-18/group) were trained in the rota-rod 24 h prior to the actual trial. Each experimental trial consisted of three consecutive mountings at intervals of 30 min. A composite mean group score was then calculated for the different treatment groups.
  • mice (12/group) were evaluated for their spontaneous locomotor activity, speed of movement, and anxiety-like behavior after placement in an uncovered rectangular open field UR 6-23116 /FR: 161118.05100 measuring 60 x 40 cm 2 .
  • mice were placed in the box for 10 min, and their movements were recorded with an overhead video camera and analyzed later for total distance traveled, the velocity of movement, number and length of freezing episodes, and percentage time spent in the center of the open field using Anymaze software (San Diego Instruments).
  • Spatial Learning and Memory Deficits Spatial learning and memory deficits were evaluated using the Morris water maze test as described by Vorhees and Williams (2010) Nature protocols 1, 848-858.
  • mice must memorize distal visual cues to navigate a direct path to a hidden platform just under the water surface, starting from different quadrants at the perimeter of the tank.
  • the mice were placed in a circular pool of diameter 120 cm and filled to a depth of 30 cm with water (made opaque with skim milk), 22oC, equipped with a 10 x 10 cm 2 hidden platform submerged 5 mm below the surface.
  • Visual cues were pasted at distinct places along the inner sides of the tub. Mice were introduced into the pool at four different points and allowed to swim until they found the hidden platform or until 60 s elapsed; the platform location remained constant. Mice that failed to locate the platform within the time limit were guided to it and allowed to rest and orient themselves for 15 s.
  • the outlet end of the PE10 tubing which was filled with aCSF, was connected to a pressure transducer (World Precision Instruments) (Min Rivas, F. et al. J R Soc Interface 17, 20200593, (2020)).
  • UR 6-23116 /FR 161118.05100
  • Cerebral Blood Flow (CBF) Anesthetized mice were placed in a stereotaxic apparatus, the scalp was incised, the skin flap was removed, the skull surface was disinfected with isopropanol wipes, and a fiber optic probe was fixed to the skull at a point directly above the middle cerebral artery (AP 1 mm, ML 5.0 mm) using cyanoacrylate glue.
  • the optical fiber was connected to the laser Doppler flowmetry apparatus (PF5010 Laser Doppler Perfusion Module, PR 418-2, Perimed) and signals were read and recorded by Axoscope (Min Rivas, F. et al. J R Soc Interface 17, 20200593, (2020)).
  • Axoscope Min Rivas, F. et al. J R Soc Interface 17, 20200593, (2020)
  • ECG and Respiration The respiratory and cardiac rhythms of mice anesthetized with a mixture of ketamine/xylazine (100 mg/kg, 10 mg/kg) were recorded using a small animal physiological monitoring system (Harvard Apparatus). The recording duration was synchronized with the Thorlabs 2P imager while performing lymphatic vessel imaging experiments (Min Rivas, F. et al. J R Soc Interface 17, 20200593, (2020)).
  • mice received 10 ⁇ l of bovine serum albumin (BSA) conjugated Alexa flour 647 (A34785, Invitrogen) infused into the CM at a rate of 2 ⁇ l/min using a Harvard Instrument Syringe Pump (Series 11 Elite). After 1 h, mice were decapitated, and the brains were removed and immersion-fixed in 4% paraformaldehyde (PFA) in phosphate-buffered saline (PBS; Sigma) overnight at 4 oC.
  • BSA bovine serum albumin
  • Alexa flour 647 Alexa flour 647
  • PFA phosphate-buffered saline
  • a burr hole was drilled over the target coordinates relative to bregma (AP -0.6 mm, ML -2.0 mm, DV -3.25 mm), and a cannula with removable cap (C315DC/SP, 0.1 mm projection, Plastic One Inc) was fitted through the hole and secured in place using cyanoacrylate/dental cement mixture (NC9991371, Fisher Scientific).
  • the cap was replaced 24 h later with PE10 tubing connected to a 10 ⁇ l Hamilton syringe pump, and the tracer (4% Direct Blue 53, DB53, MW 960 Da, 1 ⁇ l) was delivered into the left striatum at a flow rate of 0.2 ⁇ l/min.
  • mice were perfused trans-cardially with 4% PFA in PBS and the brain was removed and post-fixed in the same medium overnight. The next morning, the brain was either sliced into coronal sections (50 ⁇ m thick) using a vibratome (Leica Biosystems) or placed in cryoprotectant (30% w/v sucrose solution in PBS) for 42-72 h, until sinking.
  • rabbit anti-GFAP (1:300, AB5804, Millipore
  • mouse anti-GFAP (1:300, ab10062, Abcam)
  • rabbit anti-Iba1 (1:500, 019-19741, Wako Chemicals
  • mouse anti-Tau5 (1:300, MA5-12808, Thermo Fisher Scientific
  • rabbit anti-pTau-Thr212 (1:300, 44-740G, Thermo Fisher Scientific
  • rabbit anti-pTau-Ser262 (1:300, 44-750G, Thermo Fisher Scientific
  • rabbit anti-pTau-Thr205 (1:300, 44738G, Thermo Fisher Scientific
  • rabbit anti-pTau-Ser404 (1:300, 44-758G, Thermo Fisher Scientific).
  • Protein concentration was measured by the Pierce bicinchoninic acid UR 6-23116 /FR: 161118.05100 protein assay (BCA, 23227; Thermo Scientific) and adjusted as 2 ⁇ g/ ⁇ l for blotting. Samples were prepared in 4x Laemmli buffer (1610747, BioRad) supplemented with 5% ⁇ - mercaptoethanol and heated to 95 oC for 5 min. Proteins were separated using a standard SDS PAGE protocol with Mini-PROTEAN TGX (4-20% pre-cast stain-free gels, 456-8049, BioRad) (Hussain, R. et al. J Neurosci 37, 397-412, (2017)).
  • mice anti- ⁇ -Actin (1:5000, #3700S; Cell Signaling Technology
  • rabbit anti-GAPDH (1:5000, #5174S; Cell Signaling Technology
  • mouse anti-Tau (1:700, MA5-12808, Thermo Fisher Scientific)
  • rabbit anti- pTau-Thr212 (1:700, 44-740G, Thermo Fisher Scientific
  • rabbit anti-pTau-Ser262 (1:700, 44-750G, Thermo Fisher Scientific
  • rabbit anti-pTau-Thr205 (1:700, 44738G, Thermo Fisher Scientific
  • rabbit anti-pTau-Ser404 (1:700, 44-758G, Thermo Fisher Scientific).
  • Time-lapse imaging was performed both for FITC (excitation/emission 480/510 nm) and Tx-red (excitation/emission, 560/630 nm) channels using an Olympus MVX10 microscope equipped with a PRIOR Lumen LED and Hamamatsu ORCA-Flash4.0 V2 Digital CMOS camera, or a Leica M205 FA fluorescence stereomicroscope, equipped with an Xcite 200DC light source and a Hamamatsu ORCA- Flash4.0 V2 Digital CMOS camera. Images were acquired using the Cell Sense (Olympus) and LAS X software (Leica) and exported in TIFF format for further analysis.
  • FITC excitation/emission 480/510 nm
  • Tx-red excitation/emission, 560/630 nm
  • Olympus MVX10 microscope equipped with a PRIOR Lumen LED and Hamamatsu ORCA-Flash4.0 V2 Digital CMOS camera
  • Leica M205 FA fluorescence stereomicroscope equipped with an
  • Example 2 Adrenergic inhibition eliminates post-TBI edema
  • the inventors first assessed the dynamics of cerebral edema and CSF influx in the “Hit-and-Run” TBI model in mice 19 .
  • a significant increase in brain water content was UR 6-23116 /FR: 161118.05100 evident 30 min after injury in the ipsilateral hemisphere, and at 180 min in the contralateral hemisphere (Fig. 1a).
  • TBI suppresses glial-dependent CSF flow through the perivascular spaces, which defines glymphatic flow 19 .
  • the inventors broadly inhibited adrenergic receptors.
  • the pharmacological cocktail included prazosin (an ⁇ 1 receptor antagonist), atipamezole (an ⁇ 2 antagonist), and propranolol (a broad ⁇ receptor antagonist); as such, it was designated as PPA, and was administered 12 intraperitoneally (i.p.) to mice shortly after exposing them to “Hit-and-Run” head injury 19 . Strikingly, PPA treatment virtually eliminated cerebral edema (Fig. 1a). Among the separate components of PPA, prazosin and propranolol individually reduced edema to some extent, but the beneficial effect was sharply potentiated by combining the three NA receptor antagonists (Fig.7a).
  • Example 5 Adrenergic inhibition attenuated post-traumatic inflammation and pTau accumulation
  • TBI induced a significant increase in the concentrations of several interleukins (IL- 1 ⁇ , IL-4, IL6, and IL-12p70), as well as chemokines (CXCL1 (KC), CXCL10, MCP-1, and MIP-2) in the ipsilateral hemisphere within 24 hours (Fig. 10d-i, k, m).
  • a single dose of PPA proved sufficient to significantly reduce the levels of IL-4, IL-6, and CXCL10 (Fig.10).
  • the inventors further extended the study to investigate the long-term effects (6 months) of TBI (Fig. 11).
  • PPA treatment after TBI resulted in a marked decrease in astrogliosis and microglial activation (Fig.11a-d), as well as a downregulation of Caspase 3, 7, and 9 (Fig. 12).
  • Western blot analysis showed that post-TBI PPA treatment suppressed the accumulation of hyperphosphorylated tau, in particular at sites T404, Th205, and Ser262 (Fig. 11e).
  • Immunohistochemistry also revealed an overall higher accumulation of total (Tau5) and phosphorylated tau (Ser262, T212, Thr205) in the TBI group, which was broadly decreased in PPA-treated mice (Fig.11f-j).
  • Example 6 Neither transudation nor CSF over-production underlies post-traumatic edema CSF is a major contributor to post-stroke edema 23 .
  • the two fluid compartments were separately tagged by intravenous (i.v.) or intracisternal CSF administration, respectively, of radioactive sodium ( 22 Na) shortly ( ⁇ 5 min) after TBI (Fig.2e- UR 6-23116 /FR: 161118.05100 f).
  • the brains were harvested 30 min later, and the 22 Na content was quantified in each cerebral hemisphere. When blood was labeled with 22 Na, no significant differences in 22 Na content were noted in either hemisphere (Fig. 2e).
  • DB53 diffuses freely in the brain but binds tightly to albumin when exported, and is UR 6-23116 /FR: 161118.05100 thereby retained within the vascular compartment for durations measured in days 25,26 .
  • the DB53 signal within the femoral vein correlates directly to total DB53 glymphatic/lymphatic clearance from the brain. Continuous imaging over the femoral region (Fig.
  • the inventors first confirmed that CLV drainage was suppressed after TBI 29 by injecting a mixture of FITC-dextran (2 kDa) and Texas Red-microspheres (1 ⁇ m diameter) into CSF and quantifying their outflow in superficial and deep cervical lymph nodes (Fig. 3d-f).
  • Fig. 3d-f A detailed analysis of tracer intensity, lymph node size, and area of tracer distribution further confirmed these findings (Figs. 3e-f; Fig. 18).
  • Time-lapse imaging revealed rhythmic contractions of the CLVs and the opening/closing of valves associated with active pumping that directed net transport of the CSF tracers.
  • the inventors tracked the microspheres by analyzing high-speed two-photon in vivo recordings (Fig.3g-h) and noted a characteristic pulsatile pattern peaking every 7-10 s (Fig. 3h).
  • the microsphere efflux frequency coincided with CLV contractions, but not with cardiac or respiratory cycles (Fig. 19).
  • microsphere counts were greatly reduced after TBI, but PPA partially restored the particle efflux count (Fig.3h).
  • Automated particle tracking velocimetry 30 showed UR 6-23116 /FR: 161118.05100 that the average speed was lower in the TBI group (Fig.
  • the inventors also monitored the temporal changes in the NA concentration of microdialysis samples after TBI 31 collected in the contralateral hemisphere, which revealed multiple delayed peaks in NA, which rose to levels 5-8-fold higher than both baseline and in uninjured controls (Fig. 4a). These TBI-triggered increases in NA, both in the plasma and brain, were largely eliminated by PPA administration (Fig.4a; Fig. 24). It thus seems plausible that the excessive increases in NA observed in plasma and brain interstitial fluid (Fig. 4a) directly suppress fluid transport by the meningeal and cervical lymphatic vessels, which normally serve to return fluid from CNS to the systemic venous circulation 14,32,33 .
  • Example 10 PPA support of CSF clearance is attended by normalization of cardiovascular parameters
  • Fig. 4b To assess if the post-traumatic failure of lymphatic transport is a direct consequence of the adrenergic storm, different concentrations of NA were topically applied to exposed superficial cervical lymphatic vessels (Fig. 4b). NA reduced the contraction frequency and amplitude in a dose-dependent manner while the effect was partially restored by PPA administration (Fig.4b).
  • Fig. 4c To study the effect of NA in isolation, the inventors excised and cannulated the cervical lymphatic vessels and quantified contraction parameters under a constant internal pressure from 0.5-3 cm H 2 O with or without NA treatment.
  • NA administration ex vivo disrupted contraction wave entrainment (Fig.4c), which is critical for lymph propulsion against an adverse pressure gradient 34 , as would be the case if central venous pressure were elevated after TBI.
  • the inventors tracked the vessel's outer diameter pixel by pixel and generated spatiotemporal and Fast Fourier Transform maps (Fig. 20 and Fig. 4c), which revealed fully entrained contraction waves at conduction speeds ⁇ 10 mm/sec, as well as a single, predominant frequency component at ⁇ 10 min -1 in the absence of NA.
  • the addition of NA resulted in lower conduction speeds, shorter conduction lengths, and multiple pacemaker sites (Fig. 4d), indicative of a loss of entrainment (Fig. 4c); these effects were all prevented by PPA treatment.
  • Example 12 Meningeal lymphatics direct glymphatic outflow to the cervical lymphatics Several studies have reported that meningeal lymphatic vessels are chiefly responsible for collecting brain waste before emptying into cervical lymphatic vessels 13,32 .
  • CSF tracers FITC-Dextran (2 kDa) and Texas Red microspheres (1 ⁇ m)
  • SSS superior sagittal sinus
  • TSS transverse sagittal sinus
  • Ketamine influences the locus coeruleus norepinephrine network, with a dependency on norepinephrine transporter genotype - a placebo controlled fMRI study.
  • 53 Pitkanen, A., Narkilahti, S., Bezvenyuk, Z., Haapalinna, A. & Nissinen, J. Atipamezole, an alpha(2)-adrenoceptor antagonist, has disease modifying effects on epileptogenesis in rats.
  • 54 Nemoto, E. M. Dynamics of cerebral venous and intracranial pressures.

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Abstract

The present disclosure relates to treatment of brain injuries and associated conditions or disorders.

Description

UR 6-23116 PCT /FR: 161118.05101 Noradrenergic Antagonism as a Means of Increasing Glymphatic Efflux for the Treatment for Acute Traumatic Brain Injury CROSS REFERENCE TO RELATED APPLICATION This application claims priority to U.S. Provisional Application No. 63/517,677 filed on August 4, 2023. The content of the application is incorporated herein by reference in its entirety. GOVERNMENT INTERESTS This invention was made with government support under W81XWH-22-1-0676, and W81XWH-16-1-0555 awarded by the Defense Health Agency, Medical Research and Development Branch. The government has certain rights in the invention. FIELD OF THE INVENTION This disclosure relates to treatment of brain injuries, such as traumatic brain injury, and associated conditions or disorders. BACKGROUND Traumatic brain injury (TBI) affects roughly 55-74 million people per year worldwide1,2. Acute TBI ranges in severity from mild to fatal, and can develop into chronic traumatic encephalopathy, a condition characterized by cognitive decline, behavioral changes, and the intracerebral accumulation of neurofibrillary tangles containing hyperphosphorylated tau protein3,4. A particularly dire complication of TBI is cerebral edema, which increases the risk of death by 10-fold5 and worsens the functional outcomes of those patients who survive the initial injury. Absent effective means of preventing post‐traumatic edema in the acute setting, current treatment approaches to TBI are limited, and post‐TBI morbidity is high. There is a need for therapy to treat post‐traumatic edema and TBI. SUMMARY This disclosure addresses the need mentioned above in a number of aspects. In one aspect, the disclosure provides a method for treating a cerebral edema or a brain injury (e.g., an acute brain injury), comprising administering to a subject in need thereof an effective amount of one or more adrenergic antagonists. In one embodiment, the brain injury is not an ischemic stroke. In one embodiment, the brain injury is not an acute ischemic stroke. UR 6-23116 /FR: 161118.05100 The disclosure further features a method for improving glymphatic-lymphatic efflux from the central nervous system (CNS) of a subject, comprising administering to a subject in need thereof an effective amount of one or more adrenergic antagonists. Also within the scope of this disclosure is a method for promoting clearance of a substance from the CNS interstitium, brain interstitium and/or spinal cord interstitium of a subject, comprising administering to a subject in need thereof an effective amount of one or more adrenergic antagonists. In one embodiment, the substance comprises a fluid or a solute. In another embodiment, the substance comprises amyloid β (Aβ), tau, or alpha synuclein. In a further embodiment, the substance comprises a drug or a metabolite thereof. Each of the above-described method can further comprise identifying the subject in need thereof first before the administering. In each of the above-described method, the one or more adrenergic antagonists can be administered systemically. In one embodiment, said administering comprises administering to the subject (A) one or more α adrenergic antagonists and (B) one or more β adrenergic antagonists. In one embodiment, the α adrenergic antagonists are selected from the group consisting of an α1 adrenergic antagonist and an α2 adrenergic antagonist. In one embodiment, the β adrenergic antagonists are selected from the group consisting of a β1 adrenergic antagonist, a β2 adrenergic antagonist, and a β3 adrenergic antagonist. In one embodiment, said administering comprises administering to the subject (i) an α1 adrenergic antagonist, (ii) an α2 adrenergic antagonist, and (iii) a β adrenergic antagonist. Examples of the α1 adrenergic antagonist can be selected from the group consisting of Acepromazine, Alfuzosin, Doxazosin, Phenoxybenzamine, Phentolamine, Prazosin, Tamsulosin, Terazosin, Trazodone, Clomipramine, Doxepin, Trimipramine, Antihistamines, Hydroxyzine, 5-methyl urapidil, chloroethylclonidine, bunazosin, RS17053, L-765,314, nicergoline, ABT-866, cyclazosin, A322312, A 119637, fiduxosin, JTH-601, WB4101, niguldipine, KMD3213, and UIC 14304. Examples of the α2 adrenergic antagonist can be selected from the group consisting of Phenoxybenzamine, Phentolamine, Yohimbine, Idazoxan, Atipamezole, and Trazodone. Examples of the β1 adrenergic antagonist can be selected from the group consisting of Metoprolol, Atenolol, Bisoprolol, Propranolol, Timolol, Nebivolol, and Vortioxetine. Examples of the β2 adrenergic antagonist can be selected from the group consisting of Butoxamine, Timolol, Propranolol, ICI-118,551, Paroxetine, H35/25, prenaterol, various 4- and 5-[2-hydroxy-3-(isopropylamino)propoxy]benzimidazoles, 1-(t-butyl-amino-3-ol-2- UR 6-23116 /FR: 161118.05100 propyl)oximino-9 fluorene, and various 2-(α-hydroxyarylmethyl)-3,3-dimethylaziridines. Other examples of β2 antagonists are disclosed in U.S. Pat. No. 4908387 and US 20110195974, each of which are is herein incorporated by reference in its entirety. Examples of the β3 adrenergic antagonist can be selected from the group consisting of L-748,328, L-748,337 and SR 59230A. In the above-described methods, the brain injury can be a traumatic brain injury or an acute brain injury. In one embodiment, the traumatic brain injury is an acute traumatic brain injury. In one embodiment, the acute traumatic brain injury results from closed head trauma. In one embodiment, the acute traumatic brain injury results from open head and/or penetrating injury-induced trauma. In one example, the subject can be a mammal, such as a human. The details of one or more embodiments of the disclosure are set forth in the description below. Other features, objectives, and advantages of the disclosure will be apparent from the description and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. Figs. 1A-1H show that pan-adrenergic receptor inhibition eliminates edema and improves functional outcomes after traumatic brain injury. Fig. 1a, The kinetics of cerebral edema in the mouse brain after TBI were quantified in ipsilateral (triangles) and contralateral (diamonds) hemispheres at 10, 20, 30, 60, and 180 min post-injury. Comparison of brain water content in the ipsilateral hemisphere at 30 min post-TBI and onward (ipsilateral group comparison; F7, 146=19.55, p<0.0001: control vs 30-180 min, p=0.0031, p<0.0001, P<0.0001, respectively) and contralateral hemisphere; a significant difference is not evident until 180 min (contralateral group comparison; F7, 146=19.55, p<0.0001: control vs 180 min, p=0.0107), ipsilateral vs contralateral hemisphere comparisons (30 min, p=0.003; 60 min, p=0.003; 180 min, p=0.0007). TBI-saline and TBI+PPA treatment comparison at 30 min (ipsilateral, p<0.0001; contralateral, p=0.812) and 180 min (ipsilateral, p<0.0001; contralateral, p=0.0017). Fig.1b, Experimental scheme for behavioral assessment of control, TBI, and TBI+PPA mice Figs. 1c-e, Neurological severity score (NSS, n=97, 12-18 per group, F2,88=2.88, p<0.0001, TBI vs TBI+PPA; p=0.0323, p=0.0028, p=0.0084 on Day 0, two weeks and 12 weeks, respectively); separate graphs of performance on beam walk and UR 6-23116 /FR: 161118.05100 round stick balance shown in panel d-e. Fig. 1f, Rotarod falling latency at two weeks post- TBI with or without PPA treatment and compared with non-injury control (n=62, 17-24 per group, F2,59=9.006, p<0.0001, Control vs TBI: p=0.0008; TBI vs TBI+PPA: p=0.001). Fig. 1g, String suspension grip scores (n=31, 9-13 per group, F2,28=5.43, p<0.0001, TBI vs TBI+PPA p=0.0114). Fig. 1h, Morris water maze test performed at two weeks post-TBI (F8,105=3.625, p<0.0001, TBI vs TBI+PPA p=0.0009). Data (n=7-13 mice per group) plotted as mean±SE, groups compared by one-way or two-way ANOVA, followed by Tukey's multiple comparison test. Figs. 2A-2I show that post-TBI suppression of glymphatic efflux is counteracted by pan-adrenergic inhibition. Fig. 2a, Schematic diagrams showing fluorescent tracer injection time-lapse imaging with or without TBI and PPA treatment. Figs. 2b-c, Transcranial time- lapse imaging of Alexa fluor 647 conjugated BSA tracer (F2, 728=211.3, P<0.0001, Control vs TBI, p<0.0001, TBI vs TBI+PPA, p=0.0003). Fig.2d, Mean pixel intensity of BSA-647 in the representative sections of different regions of the brain in control, TBI-saline, and TBI- PPA treated groups at Day 0 (24-30 slices per group, F2, 75=6.77, p=0.002, Control vs TBI, p=0.005, TBI vs TBI+PPA, p=0.006) and 6-month post-TBI (24-30 slices per group, F2, 81=14.11, p<0.0001, Control vs TBI, p<0.0001, TBI vs TBI+PPA, p=0.0393). Fig. 2e, Schematic diagram showing the vascular compartment of the brain; the radiotracer 22Na was injected into the vasculature and radioactivity shown as percentage of injected 22Na dose in non-injured control, TBI-saline, and TBI+PPA groups; Ipsilateral 22Na (F2,29=1.242; Control vs TBI, p=0.8336, TBI vs TBI+PPA, p=0.2815), contralateral 22Na (F2,26=6.577, p=0.0049; Control vs TBI, p=0.0034, TBI vs TBI+PPA, p=0.1557). Fig.2f, Schematic diagram showing CSF compartment; 22Na was injected into the CM and radioactivity shown as percentage of injected 22Na dose in control, TBI, and TBI+PPA; Ipsilateral 22Na (p=0.0087, F2,17=6.348; Control vs TBI, p=0.040, TBI vs TBI+PPA, p=0.0185), contralateral 22Na (F2,16=0.0656, p=0.9367). Fig. 2g, Schematic diagram showing CSF production measurement in lateral ventricles with or without TBI and PPA treatment. Fig.2h, Quantification of CSF production (µl/min, Mean±SEM; Control 0.11±0.003, TBI 0.045±0.012, and TBI+PPA 0.083±0.006). i, Cumulative CSF production. Data (n=5-13 mice per group) plotted as mean±SE, groups compared by one-way or two-way ANOVA, followed by Tukey's multiple comparison test. Scale: 2.5 mm. Figs.3A-3K show that fluid transport by cervical lymphatic vessels is reduced by TBI and restored with pan-adrenergic receptor inhibition. Fig. 3a, Schematic diagram illustrating UR 6-23116 /FR: 161118.05100 the methodology used for the analysis of fluid transport out of the brain and edema clearance, utilizing DB53 delivery and detection in the femoral vein. Fig. 3b, Representative images showing the distribution of DB53 in femoral vein with or without injury and PPA treatment Fig. 3c, DB53 fluorescence intensity (fold) (F1,11=35.24, p<0.0001; TBI-saline vs TBI+PPA, p=0.0003). Fig. 3d, Schematic showing delivery of a mixture of Texas red conjugated FluoSpheres (1 µm, 580/605 nm) and FITC-dextran (2 kDa). Fig. 3e, Representative images of FITC-dextran signals detected in cervical lymphatic vessels (CLVs) and superficial cervical lymph nodes (sCLN). Fig.3f, Quantification of fluorescence intensity in superficial (Control vs TBI, p=0.0004, TBI vs TBI+PPA, p=0.0384) and deep cervical lymph nodes (p<0.0001; Control vs TBI, p<0.0001, TBI vs TBI+PPA, p=0.068). Fig. 3g, Schematic showing two-photon microscopy in exposed CLV and representative superimposed particle tracks (right). Fig. 3h, Representative time series of fluorescent particle efflux (Control: grey, TBI: red, TBI+PPA: purple). Fig. 3i, CLV median diameter, Fig.3j, Mean fluorescent particle speeds (F2,20=7.105, p=0.0047; Control vs TBI, p=0.002; TBI vs TBI+PPA, p=0.047), volume flow rates (F2,20=6.45, p=0.0069; Control vs TBI, p=0.002; TBI vs TBI+PPA, p=0.023), and retrograde flow percentages (F2,20=4.941, p=0.0120; Control vs TBI, p=0.0194; TBI vs TBI+PPA, p=0.56). Fig. 3k, Numerical simulation predicting change in volume flow rate as a function of CLV contraction frequency and amplitude. Data, 5-8 mice/group (c, i, j), 13-19 mice/group (f), plotted as mean±SE, groups were compared by one-way or two-way ANOVA, followed by either Dunn’s multiple comparison test (f) or Tukey’s multiple comparison test (c, i, j). Scale: b, 1 cm; e, 2.5 mm; g, 25 µm. Figs. 4A-4F show that noradrenergic storm after TBI disrupts contraction wave entrainment but is prevented by PPA treatment. Fig.4a, Left: Noradrenaline levels in plasma collected from injured and non-injured mice with or without PPA treatment within 10 min of injury (F2, 23=11.67, p=0.003; Control vs TBI, p=0.002, TBI vs TBI+PPA, p=0.001). Middle: Schematic showing CSF sampling by microdialysis up to 12 h post-injury, Right: Noradrenaline (NA) levels in the interstitial space (F2,69=14.8, p<0.0001). Fig. 4b, In vivo recording of contraction frequencies and amplitude in response to different concentrations of NA. Fig. 4c, Top: Schematic showing the setup adopted for ex vivo recording of cervical lymphatic vessel contraction pattern and experimental timeline. Bottom left: image of an isolated, pressurized superior cervical lymphatic vessel with corresponding Fast Fourier Transform (FFT) map. Bottom right: FFT maps of vessels with PPA-pretreatment (10 ng/ml) UR 6-23116 /FR: 161118.05100 prior to NA administration. Fig. 4d, Conduction and peacemaking parameters of cervical lymphatic vessels with or without NA and PPA; conduction speed (F2, 25=8.45, p=0.0016; Control vs NA, p=0.0021; NA vs NA+PPA, p=0.0173), conduction length (F2, 25=375.5, p<0.0001; Control vs NA, p<0.0001; NA vs NA+PPA, p<0.0001), and number of pace making sites (F2, 25=4.174, p=0.0273; Control vs NA, p=0.076; NA vs NA+PPA, p=0.0429). Fig.4e, Measurements of: mean arterial pressure (MAP, F2,24=10.56, p=0.0005; Control vs TBI 0.0003, TBI vs TBI+PPA, 0.135), cerebral blood flow (CBF, F2,24=6.613, p=0.0052; Control vs TBI, 0.0071, TBI vs TBI+PPA, 0.021), and intracranial pressure (ICP, F2,24=7.847, p=0.002; Control vs TBI 0.0027, TBI vs TBI+PPA, 0.0182). Fig. 4f, Central venous pressure (CVP) recorded using jugular vein catheter (F2, 22=7.762, p=0.0028, Control vs. TBI-saline, p=0.0293; TBI saline vs. TBI+PPA, p=0.0029). Data (n=5-9 mice/group (a, b, e, f), 6-11 mice/group (d)) was compared by one-way or two-way ANOVA, followed by Bonnferoni’s multiple comparison test (a) or Tukey’s multiple comparison test (b, d, e, f). Scale: 5 mm. Figs. 5A-5K show that efflux of cells/cellular debris through CLVs in the event of TBI is neuronal in origin. Fig. 5a, Mice implanted with cisterna magna cannulas received BSA-647 injection following TBI or sham hit, with or without PPA treatment, and were imaged by two-photon microscopy followed by brain and lymph node fixation. Fig.5b, Dual- channel images of CLVs after TBI and PPA showing debris in green. Fig.5c, Quantification of the number of cells/debris that exits via CLV per minute (F2,525=9.75, p<0.0001; Control vs. TBI-saline, p=0.975; TBI saline vs. TBI+PPA, p=0.0094). Fig. 5d, GCaMP7 expression in cortical neurons and astrocytes; Figs.5e-g, Lymph node slices were imaged using confocal microscopy (40x, NA 1.4, Olympus FV3000). Fig.5h, GCaMP7-green fluorescence intensity (p<0.0001; Control vs. TBI-saline, p=0.0008; TBI saline vs. TBI+PPA, p<0.0001). Fig. 5i, BSA-647 fluorescence intensity (p<0.0001; Control vs. TBI-saline, p<0.0001; TBI saline vs. TBI+PPA, p<0.0001). Fig. 5j, Total debris area computed by thresholding GCaMP7-green images (p<0.0001; Control vs. TBI-saline, p=0.045; TBI saline vs. TBI+PPA, p<0.0001). Fig.5k, Total debris area computed by thresholding BSA-647 images (p<0.0001; Control vs. TBI-saline, p=0.035; TBI saline vs. TBI+PPA, p=0.032). Data (n=6-8 mice/group, 8-10 slices/mouse) was analyzed by the Kruskal-Wallis test followed by Dunn’s multiple comparison test where applicable. Scale: 50 µm. Fig.6 shows that that brain fluid export is compromised by traumatic brain injury and counteracted by pan-adrenergic inhibition. (Left Panel) Cerebrospinal fluid (CSF) exchanges UR 6-23116 /FR: 161118.05100 with interstitial fluid, is collected along perivenous spaces (shown as light blue), and drains out via meningeal lymphatic vessels and soft tissue surrounding nerves and vessels. (Right Panel) Brain injury suppresses brain fluid export and results in tissue swelling. The reduced outflow in response to injury is attributed to an adrenergic storm, which reduces glymphatic fluid transport as well as cervical lymphatic vessel contraction frequency/amplitude, disrupts entrainment, and reduces downstream volume transfer efficiency. Adrenergic inhibition antagonizes these changes and eliminates acute edema. Treatment with adrenergic receptor antagonists also facilitates the clearance of cellular debris, reducing neuroinflammation and improving functional recovery. Figs.7A and 7B show that effect of individual components of PPA is less efficient in reducing cerebral edema after TBI. Fig. 7a, The severity of cerebral edema in the mouse brain was estimated 3 h post-TBI with or without treatment of prazosin (Prz), propranolol (Prpl), and atipamezole (Ati). Experimental groups (n=35, 6-8 mice per group) were compared by one-way ANOVA (p=0.014, F4, 30=3.73) followed by Dunnett’s multiple comparisons test (Sham-Control vs TBI, p=0.025, TBI vs Prz (p=0.044), Prpl (p=0.72), and Ati (p=0.99). Fig. 7b, Cerebral edema measurement in mice 24 h post-TBI with or without PPA treatment at 23 h. Experimental groups (n=23, 7-9 mice per group) compared by one- way ANOVA (p=0.001, F2, 20=9.387) followed by Dunnett’s multiple comparisons test (Sham-Control vs TBI, p=0.0007, TBI vs TBI+PPA, p=0.036). Figs. 8A-8C show that locomotor and anxiety-like behavior of post-traumatic brain injury mice is relieved by PPA treatment. Fig. 8a, Mice were evaluated for locomotion, anxiety-like behaviors, and exploration abilities at two and 12 weeks post-TBI, with or without PPA treatment. Fig. 8b, Two-week evaluation (n=42, 11-18 mice/group): average speed (one-way ANOVA, F2, 39=10.5, p=0.0002, Tukey’s multiple comparison test; Control vs TBI, P=0.0072; TBI-saline vs TBI-PPA, p=0.7065), total distance traveled (one-way ANOVA, F2,32=6.829, p=0.0034, Tukey’s multiple comparison test; Control vs TBI, P=0.0060, TBI-saline vs TBI-PPA, p=0.0134), number of freeze episodes (one-way ANOVA, F2,43=7.18, p=0.0020, Tukey’s multiple comparison test; Control vs TBI, P=0.0017; TBI-saline vs TBI-PPA, p=0.0287), and freeze time per episode (one-way ANOVA, F2,32=6.304, p=0.0049, Tukey’s multiple comparison test; Control vs TBI, P=0.026; TBI-saline vs TBI-PPA, p=0.0064). Fig.8c, Twelve-week evaluation (n=33, 11-13 mice/group): average speed (one-way ANOVA, F2,36=0.2578, p=0.7741), total distance traveled (one-way ANOVA, F2,36=0.4837, p=0.6205), number of freeze episodes (one-way UR 6-23116 /FR: 161118.05100 ANOVA, F2,34=15.58, p<0.0001, Tukey’s multiple comparison test; Control vs TBI, P<0.0001; TBI-saline vs TBI-PPA, p=0.0029), and freeze time per episode (one-way ANOVA, F2,30=15.62, p<0.0001, Tukey’s multiple comparison test; Control vs TBI, P<0.0001; TBI-saline vs TBI-PPA, p=0.0001). Figs. 9A-9G show that transcranial live imaging of tracer movement is as reliable as ex vivo and in vitro slice imaging. Fig. 9a, Representative dorsal and ventral views of brain imaged by ex vivo conventional fluorescent microscopy in control, TBI+saline, and TBI+PPA groups performed at (top) day 0 and (bottom) six months post-TBI. Fig. 9b, Regression analysis of BSA-647 fluorescence intensity for quantifying association of (top) transcranial in vivo vs ex vivo dorsal and (bottom) transcranial in vivo vs in vitro slices (R2=0.802 and 0.821, respectively). Fig. 9c, Representative images from confocal microscopy showing vascular ultrastructure, labeled with lectin (red) and BSA-647 tracer (cyan), colocalized/distributed along the blood vessels in non-injury control, TBI+saline, and TBI+PPA groups. Fig.9d, Experimental scheme, Fig.9e, representative images, and Fig.9f, quantification of transcranial time-lapse imaging of Alexa flour 647 conjugated BSA tracer signals in vivo. Fig. 9g, Mean pixel intensity of BSA-647 in different regions of the brain (n=5/group, multiple slices averaged per mouse): dorsal cortex (one-way ANOVA, F2,12=17.59, p=0.0003, Tukey’s multiple comparison test; Control vs TBI, P=0.0002; TBI- saline vs TBI-PPA, p=0.0098), striatum (one-way ANOVA, F2,12=1.621, p=0.238), hippocampus (one-way ANOVA, F2,12=4.413, p=0.0366, Tukey’s multiple comparison test; Control vs TBI, P=0.0292; TBI-saline vs TBI-PPA, p=0.331), lateral cortex (one-way ANOVA, F2,12=8.807, p=0.0044, Tukey’s multiple comparison test; Control vs TBI, P=0.0038; TBI-saline vs TBI-PPA, p=0.0423), corpus callosum (one-way ANOVA, F2,12=1.737, p=0.217), and hypothalamus (one-way ANOVA, F2,12=11.33, p=0.0017, Tukey’s multiple comparison test; Control vs TBI, P=0.0018; TBI-saline vs TBI-PPA, p=0.587). Scale: (a, c) 5 mm, (e) 100 µm. Figs. 10A-10Q show shows that post-TBI noradrenergic receptor inhibition downregulates IL-4, IL-6, TNFα, and CXCL10 levels within the brain. Brain samples collected 24 h post-TBI with or without PPA treatment were analyzed for cytokine/chemokine levels both in the ipsilateral and contralateral hemispheres. Data is shown as percentage increase in the chemokine/cytokine levels relative to the contralateral hemisphere. Experimental groups were compared by one-way ANOVA followed by Dunnett’s multiple comparisons test (n=24, 7-9 mice/group). UR 6-23116 /FR: 161118.05100 Figs. 11A-11J show that post-TBI noradrenergic receptor inhibition reduces astrocytic hypertrophy, microglial invasion, and subsequent hyper-phosphorylation of tau. Fig. 11a, Schematic showing induction of injury followed by a two-week experimental window. Fig. 11b, Coronal sections of mouse brain showing the lesion center were immunostained for GFAP (red) and DAPI (blue); the site of injury/damaged somatosensory cortex, enlarged ventricles both on ipsilateral and contralateral sides, and the white matter tract corpus callosum are indicated by yellow arrows, white # symbols, and a white * sign, respectively, in non-injury control, TBI, and TBI+PPA slices. Fig. 11c, Brain sections (bregma; AP -0.8 to 2 mm) were immunostained for microglia (Iba-1, red) and pan-nuclear marker (DAPI, blue); the bottom right corner shows the region of interest. Fig. 11d, Quantification of immunofluorescence of GFAP (F2,15=11.6, p=0.0007), number of microglia (F2,9=2.879, p=0.108), and Iba-1 immunostaining (F2, 25=14.96, p=0.004). Fig. 11e, (Top) Schematic showing the experimental time window of western blot and immunohistochemistry experiments for detection of hyper-phosphorylation of tau protein. (Bottom) Western blot analysis was performed in whole brain homogenates for tau targets: pTauT404, pTauThr205, and pTauSer262. Fig. 11f, Representative images showing hyper- phosphorylation of tau at site Ser262, Tau5, and DAPI in separate sets of mice at six months after TBI, with or without NA pan-adrenergic receptor blockade. Figs. 11g-j, Quantification of immunostaining of pTau in the cortex, striatum, and hippocampus for targets (g) pSer262, (h) pT212, (i) pThr205, and (j) Tau5. Data (3-5 mice per group) analyzed by one-way ANOVA, followed by post-hoc Tukey’s test. Scale: (b) 250 µm, (c) 100 µm, (f) 25 µm. Figs. 12A and 12B show Western blots of programmed cell death pathway proteins Caspase 7, 3, and 9 at two weeks post-injury, with or without PPA treatment. Brain tissue was collected from control and TBI mice with or without PPA, homogenized in RIPA buffer, and analyzed for the levels of programmed cell death markers Caspase 7, 3, and 9. Fig.12a, Schematics showing the tissue collection from ipsilateral and contralateral hemispheres, which was homogenized, followed by protein separation by gel electrophoresis and PVC membrane transfers. Fig. 12b, Caspase enzymes (7, 3, 9) were detected on PVC membrane by specific primary antibodies followed by LiCOR secondary antibody incubation and imaging using Odyssey Imager. Figs.13A and 13B show that despite the anticipated disruption of BBB, TBI does not increase the influx of mannitol, a BBB impermeable tracer. Fig. 13a. Schematic illustrating the vascular compartment of the brain and intravenous injection (10 µL) of radiolabeled UR 6-23116 /FR: 161118.05100 mannitol (14C). Fig. 13b. Experimental scheme; the radiotracer 14C labeled Mannitol was injected through an intra-arterial catheter immediately after TBI, and brain samples were collected 30 min later, weighed, and dissolved overnight. Their radioactivity was then measured using a liquid scintillation counter. Radioactivity data (n=21, 6-9 mice per group) is shown as percentage of the total injected dose in the vasculature. Group means were compared by one-way ANOVA (p=0.003, F2, 18=8.13) followed by Tukey's multiple comparison test; Control vs TBI, p=0.025; TBI vs TBI+PPA, p=0.0027; Control vs TBI+PPA, p=0.73. Figs. 14A-14C show that post-TBI noradrenergic inhibition restores interstitial fluid flow and tracer dispersion. Fig. 14a, Schematic showing fluorescent tracer Direct Blue 53 (DB53) injected into the striatum in pre-cannulated mice, with or without TBI. DB53 was detected in vivo within the live brain 3 h post-TBI by IVIS Spectrum IR imaging. Fig. 14b, Averaged images showing the distribution of DB53 in the brain. Fig. 14c, IR quantification shown as radiant efficiency is compared among the experimental groups: Control, TBI-saline, and TBI+PPA (n=19, 6-7 mice per group, one-way ANOVA, p<0.0.0001, F2,16=23.5, Tukey’s multiple comparison test; Control vs TBI-saline, p<0.0001, TBI-saline vs TBI+PPA, p=0.005). Scale bars: 5 mm. Figs. 15A-15C show that DB53 injected into the brain appears in the circulatory system, but TBI delays its appearance while PPA treatment restores its efflux. Fig. 15a, Schematic diagram illustrating the methods used to assess the efflux of tracer from the brain into the circulatory system, thus quantifying fluid transport out of the brain and edema clearance. DB53 was injected into the left striatum, and its appearance within a femoral vein was recorded using time-lapse IVIS spectrum IR imaging. Fig. 15b, Representative images showing the distribution of DB53 (640-690 nm) in the femoral vein: Control (top row), TBI- saline (middle row), and TBI+PPA groups (bottom row). Fig. 15c, DB53 IR signals from different experimental groups are quantified, and values shown as radiant efficiency (n=15, 5 mice per group, two-way ANOVA, F2,156=242.1, p<0.0001, Tukey’s multiple comparison test; Control vs. TBI-saline, p<0.0001; TBI saline vs. TBI+PPA, p<0.0001). Figs. 16A-16D show that PPA administration in healthy mice results in enhanced clearance of radiotracers from CSF. Fig.1a, Schematic showing the experimental plan; wild- type mice were implanted with cisterna magna cannula 24 h prior to the experiments. The awake mice were injected with radiotracers (one tracer per group), with or without PPA treatment. Blood was collected 30 min post-injection, centrifuged for plasma extraction, UR 6-23116 /FR: 161118.05100 mixed with a scintillation cocktail (Ultima Gold, PerkinElmer), and analyzed in liquid scintillation counter for C-14 and Na-22 radioactivity (LS6500 Multi-purpose Scintillation Counter, Beckman Coulter, GA, USA). Figs. 16b, 16c and 16d, Radioactivity was detected in the plasma samples injected with C-14 mannitol (Fig. 16b), C-14 inulin (Fig. 16c), and Na-22 Saline (Fig.16d). Data analyzed for mean and SE; group means were compared using student t-test (unpaired): Mannitol (n=14, 7 mice per group, F6,6=3.584, p=0.0065), Inulin (n=7, 3-4 mice per group, F2,3=1.146, p=0.014), and Na-22 (n=17, 7-10 mice per group, F6,9=5.892, p<0.0001). Figs. 17A and 17B show that radiotracer 22Na clearance is reduced in TBI and restored with PPA treatment. Fig. 17a, Schematic illustrating the CSF compartment of the brain and experimental timeline. Fig. 17b, Quantification of radiotracer within the blood plasma with or without TBI and PPA treatment (one-way ANOVA, p=0.009, F2, 17 = 6.29, Tukey’s multiple comparison test; Control vs TBI, p=0.037, TBI vs TBI+PPA, p=0.011, Control vs TBI+PPA, p=0.88). Figs. 18A-18C show comparison of size of cervical lymph nodes upon injury and PPA treatment. Fig.18a, Mice, implanted with cisterna magna cannulas were injected with a mixture of FITC dextran and fluorophore Tx Red, lymph nodes were isolated 40-60 min post- injury with or without PPA treatment, and the sizes of lymph nodes (LN) were measured in images acquired using a fluorescent dissecting microscope (MVX10, Olympus). Figs. 18b- 18c, LN diameter and tracer distribution area (n= 22, 6-10 mice per group, multiple cervical lymph nodes) were compared using one-way ANOVA; Diameter; p=0.6886, F2, 22 = 0.3796, Tracer distribution area; p=0.0006, F2, 22 = 10.46, Tukey’s multiple comparison test, Control vs TBI 0.001, TBI vs TBI+PPA, 0.005), Scale: 500 µm. Figs.19A and 19B show that TBI alters cardiac but not respiratory rates in mice. The respiratory and cardiac rhythms of anesthetized mice were recorded using a small animal physiological monitoring system (Harvard Apparatus). The recording duration was synchronized with the Thorlabs 2P imager while performing lymphatic vessel imaging experiments. Fig.19a, Heart rate (n=28, 8-11 mice per group, one-way ANOVA, F2,25=6.2, p=0.0065, Tukey’s multiple comparison test; Control vs TBI, p=0.0123, TBI vs TBI+PPA, p=0.9332) and Fig. 19b, respiratory rate (n=28, 8-11 mice per group, one-way ANOVA, F2,25=1.101, p=0.3482; Control vs TBI, p=0.8876; TBI vs TBI+PPA, p=0.3407). Figs. 20A-20D show that NA treatment of CLVs ex vivo results in loss of entrainment while preemptive treatment with PPA nullifies the effect. Fig. 20a, Image of an UR 6-23116 /FR: 161118.05100 isolated cervical lymphatic vessel with the area used for spatiotemporal map generation marked by a rectangular box. Figs.20b-20d, Spatiotemporal maps showing CLV contraction pattern in (Fig.20b) control, (Fig.20c) NA, and (Fig.20d) PPA+NA treatment. Continuous vertical bands correspond to single contraction waves that conduct over the entire length of the vessel. The intensity of each line is inversely proportional to the magnitude of the constriction. All contractions initiate at the top of the segment. Horizontal lines are diameter tracking artifacts due to small pieces of fat or connective tissue remaining on the outside of the vessel that rotated during contraction. Figs.21A-21E show that PPA treatment does not alter cardiac and respiratory rates in non-injured control mice. The respiratory and cardiac rhythms of mice were recorded using a small animal physiological monitoring system (Harvard Apparatus). Group means were compared by student t-test; Fig. 21a, Heart rate (4-6 mice per group, p=0.456), Fig. 21b, Respiration rate (4-5 mice per group, p=0.233). Fig. 21c, Mean arterial pressure (7 mice per group, p=0.026), Fig. 21d, Cerebral blood flow (9 mice per group, p=0.291), e, Intracranial pressure (8 mice per group, p=0.0048). Figs. 22A-22C show that PPA administration increases the high amplitude contraction frequency of cervical lymphatic vessels (CLV). Fig.22a, C57Bl6 mice implanted with cisterna magna cannula were injected with FITC dextran (10 µL) and recorded for contraction frequency (20-40 min post-injection). Fig. 22b, Contraction profile (representative segments, length 2 min) of CLV recorded in control (b) and with PPA administration (c) both under 2.5% isoflurane. Fig. 23c, High amplitude contraction (>1.5- fold change in diameter) was quantified and shown as a box blot. Data (n=17, 8-9 mice per group, 1-2 representative recordings/mice), were analyzed for mean and SE. Groups were compared using a student t-test (F15, 13 = 1.523, p=0.0004). Figs.23A-23E show that dorsal meningeal lymphatic vessel dysfunction is evident in hit-and-run type TBI. Mice injected with fluorescent tracer FITC-Dextran (2 kDa, green) and Tx-Red fluospheres (1 µm, red) were evaluated for outflow potential via dorsal meningeal lymphatic vessels, with or without injury and subsequent treatment of PPA or saline, respectively. Fig.23a, Representative images showing whole mount dural lymphatic vessels. Figs. 23b-23c, Representative images of the region of interest showing dorsal meningeal lymphatic vessels in the superior sagittal sinus (SSS, b) and transverse sagittal sinus area (TSS, c). Tracer intensity was measured (using Image J, semi-automated fluorescence intensity method) and compared among treatment groups; control (n=7), TBI (n=5), and UR 6-23116 /FR: 161118.05100 TBI+PPA (n=6), by one-way ANOVA Tukey’s multiple comparison test (GraphPad Prism). Fig. 23d, Meningeal lymphatics in SSS, FITC-Dextran (left, p=0.019, F2, 15 = 5.182), Tx- Red Fluospheres (right, p=0.004, F, 2, 15 = 8.147). e, Meningeal lymphatic vessels in TSS: FITC-Dextran (left, p=0.0028, F2, 15 = 8.944) and Tx-Red fluospheres (right, p=0.0004, F2, 15 = 13.53). Figs. 24A and 24B show that post traumatic linear increase in NA levels is counteracted by PPA treatment. Fig. 24a, Semi-Log curve fit of NA levels depicts a steady increase over time. Fig. 24b, Cumulative area under the curve of NA levels with or without injury and PPA treatment (n=15, 4-7 mice per group, F2, 12=2.75, p=0.0019; Control vs TBI, p=0.0017, TBI vs TBI+PPA, p=0.0118). DETAILED DESCRIPTION OF THE INVENTION This disclosure relates to treatments for brain injury, such as TBI, and associated injuries or conditions. Certain aspects of this disclosure are based, at least in part, on an unexpected discovery that the glymphatic efflux pathways by which CSF‐derived interstitial fluids typically clear the brain are regulated by adrenergic tone, such that high levels of norepinephrine (noradrenaline) suppress fluid egress. TBI and Glymphatic Efflux Pathways TBI is a heterogeneous condition that may occur from many proximal causes, but the many forms of acute TBI are associated with cerebral edema that is both a predictor and cause of long‐term brain injury, cell and tissue loss, and neurological dysfunction. Absent effective means of preventing post‐traumatic edema in the acute setting, current treatment approaches to TBI are limited, and post‐TBI morbidity is high. There is an unmet need for therapy to prevent or treat post‐traumatic edema and TBI. The present disclosure addresses this unmet need, by focusing on a proximal cause of post‐traumatic cerebral edema, the failure of the brain’s glymphatic system to clear interstitial fluid. As disclosed herein, TBI is associated with a high level of systemic adrenergic activation, via the sympathetic release of both norepinephrine and epinephrine. Noradrenaline (NA) levels are significantly increased in TBI patients, and the degree of NA elevation correlates with the severity of injury, functional outcome, and mortality. NA is secreted by brain stem nuclei, including locus coeruleus, while the adrenal medulla is the primary source of NA in blood. UR 6-23116 /FR: 161118.05100 Under physiological conditions, CSF is partially or fully drained by outflow pathways that include the meningeal and cervical lymphatic vessels13,14, which return fluid via the thoracic duct to the venous circulation12,15. Blockade of meningeal or cervical lymphatic vessels accelerates the deposition of amyloid-beta, tau, and synuclein in rodent disease models13,16,17, and worsens brain edema as well as infarct volume in stroke18. Investigating a murine model of TBI, the inventors discovered that excessive levels of noradrenaline suppress glymphatic/lymphatic fluid flow and debris transport, resulting in cerebral edema and that this process can be attenuated by adrenergic inhibition. For example, it was unexpected to find that systemic inhibition of this post‐TBI “adrenergic storm” via administration of a combination of adrenergic antagonists, sufficient to concurrently suppress alpha1, alpha2 and beta adrenergic receptors, prevented post‐TBI cerebral edema, by sustaining glymphatic efflux. This pan‐adrenergic inhibition is sufficient to prevent cerebral edema‐associated injury following TBI, thereby mitigating the extent of tissue injury and ultimately limiting the degree of post‐TBI neurological dysfunction. Brain swelling is a significant cause of morbidity and mortality after TBI. It is reported here that acute post-traumatic edema follows the suppression of glymphatic/lymphatic fluid transport in response to the excessive systemic release of noradrenaline. Quantitative flow analysis showed that the contractility of cervical lymphatic vessels was suppressed as a consequence of the adrenergic storm after TBI. Pan-adrenergic receptor inhibition normalized central venous pressure, partly restored glymphatic and cervical lymphatic flow, eliminated brain edema, and improved functional outcome. Post- traumatic inhibition of adrenergic signaling also boosted lymphatic export of cellular debris from the traumatic lesion, sharply reducing secondary inflammation and tau accumulation. Accordingly, this disclosure provides a novel therapeutic approach for perverting or treating traumatic brain injury, including acute traumatic brain injury. Furthermore, as disclosed herein, cerebral edema following traumatic brain injury is neither the result of vascular fluid transudation nor excessive CSF influx but is rather a consequence of impaired fluid efflux via the glymphatic system and its associated lymphatic drainage. It was found that injury-associated abrogation of fluid drainage is under adrenergic control, such that interstitial fluid homeostasis could be rescued by broad adrenergic inhibition. By injecting fluorescent microspheres into the CSF, and then quantifying their movement through cervical lymphatic vessels based on particle tracking velocimetry, the inventors obtained quantitative measurements of CSF drainage under multiple conditions. UR 6-23116 /FR: 161118.05100 The analysis demonstrated that noradrenergic receptor inhibition after TBI boosted the lymphatic export of fluid, macromolecular proteins, and cellular debris, and served to sharply reduce the consequent neuroinflammation, tau accumulation, and cognitive loss of untreated mice. Although data discussed herein suggest that PPA treatment improves functional recovery by resolving edema, NA receptors are broadly expressed and a direct effect of PPA on other cell types cannot be excluded37,38. Clinically, NA levels rise significantly after TBI and correlate positively with the severity of injury and mortality9,10. This disclosure confirmed these observations in the “Hit-and-Run” TBI model, which, unlike other rodent models of TBI, avoids the prolonged use of anesthesia, thus better replicating typical clinical circumstances (Fig.4a). Anesthesia is increasingly recognized for its ability to alter not only neural activity but also brain fluid flow39, perhaps by the potent inhibition of adrenergic signaling by most anesthetic regimens, in particular those with central α2 adrenergic agonism40-42. Despite the increase in NA, which acts as a potent vasoconstrictor40,42, neither the mean arterial pressure (MAP) nor cerebral blood flow (CBF) increased after TBI. Instead, a significant decrease in MAP was noted (Fig. 4e), supporting the clinical observation that systemic hypotension is common after TBI. NA antagonist administration improved prognoses in the treatment of coma and has been linked to more rapid recovery and decreased mortality following TBI. Alpha-1 (α1) adrenergic receptor inhibition helps to alleviate delayed post-TBI symptoms insomnia and nightmares after trauma, while early treatment with α2 receptor antagonists may reduce the chances of post-traumatic seizures. None had pinpointed the role of the adrenergic storm after TBI in modulating CSF fluid flow, or the importance of restoring the latter to clinical outcome. It was observed that a rapid influx of CSF was responsible for the initial edema which developed in a model of focal stroke. The complete blockage of the middle cerebral artery triggered a rapid wave of spreading ischemia, which constricted the surrounding vasculature, and thereby accelerated the influx of CSF from the perivascular space into the tissue parenchyma. In contrast to regions of ischemic stroke, cerebral blood flow is reduced by only 25% following TBI (Fig.4e), so its associated tissue edema develops at a slower pace. Since post-TBI edema is largely a consequence of the reduced fluid and solute clearance that attends adrenergic storm, it thus lends itself to treatment by adrenergic receptor inhibition. UR 6-23116 /FR: 161118.05100 Efflux of CSF to the cervical lymph nodes is reduced in the event of TBI. In that regard, the inventors confirmed that ex vivo NA administration to excised and cannulated cervical lymphatic vessels led to the loss of contraction wave entrainment (Fig. 4c), which was reversed with PPA treatment. Finally, central venous pressure, which is increased in TBI and in the “Hit-and-Run” TBI model (Fig. 4f), may play a critical role. The thoracic lymphatic duct, containing all the effluents from the brain, empties into the subclavian vein, in a process dependent upon the pressure difference between the two, which regulates the patency of a valve at the thoracic duct outlet. If increased central venous pressure prevents that valve from opening, fluid will be retained in lymphatic vessels, and hence lymphatic backflow will increase, resulting in glymphatic stasis, as observed here (Figs.3-4). The accumulation of tissue and cellular debris has been noted to impede repair across a broad range of injuries and insults. This disclosure contributes to the art and addresses the unmet need mentioned above by showing that following TBI and its attendant structural damage, cellular components and contents are released into the brain interstitium, and are then - in part - cleared by bulk flow via the glymphatic and cervical lymphatic systems. The inventors directly observed cellular debris in cervical lymphatic vessels, and using a transgenic reporter line (GCaMP7), established its neuronal and glial cellular origin (Fig. 5). The post-TBI suppression of glymphatic/lymphatic efflux resulted in the retention of this debris within the neuropil, while PPA treatment facilitated its efflux. Such clearance substantially reduced post-TBI inflammation, with reductions in astrogliosis, microglial activation, and cytokine accumulation, the latter as evidenced by lower post-traumatic levels of IL1β, IL-4, and IL-6 (Figs.10-11). Thus, this disclosure advances the understanding of those components of brain fluid transport that contribute to TBI-induced cerebral edema (Schematic Fig. 6). A traditional concept of physiology is that brain fluid homeostasis is locally regulated by an interchange of fluid between the vascular compartment and neuropil. Yet, this disclosure here showed that intravascular fluid transudation did not contribute significantly to edema formation after TBI, which was rather caused by the noradrenergic interruption of glymphatic/lymphatic drainage. TBI-associated interference with the glymphatic/lymphatic system, whether via an adrenergic storm or elevated intracranial/central venous pressure, worsens edema and causes the retention of neural debris, consolidating glymphatic occlusion and leading to a feed-forward exacerbation of the initial insult. The findings suggest that this cascade of events can be UR 6-23116 /FR: 161118.05100 reversed by pan-adrenergic inhibition, with the subsequent improvement and normalization of both sensorimotor and cognitive functions in the injured mouse brain. Noradrenergic Antagonists Certain aspect of this disclosure provides methods for treating a cerebral edema or a traumatic brain injury, for improving glymphatic-lymphatic efflux from the central nervous system (CNS) of a subject, or for promoting clearance of a substance from the CNS interstitium, brain interstitium and/or spinal cord interstitium of a subject. Each of the methods comprises administering to a subject in need thereof one or more adrenergic antagonists. As used herein the terms “adrenergic antagonist,” “noradrenergic antagonist,” “adrenergic receptor inhibitor,” “inhibitor of adrenergic receptor,” “adrenergic receptor blocker,” and “blocker of adrenergic receptor” are used interchangeably to refer to any agent that inhibits or blocks the function of adrenergic receptors. Adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of catecholamines like noradrenaline (norepinephrine) and adrenaline (epinephrine). There are five adrenergic receptors, which are divided into two groups. The first group of receptors are the beta (β) adrenergic receptors. There are β1, β2, and β3 receptors. The second group contains the alpha (α) adrenoreceptors. There are α1 and α2 receptors. As used herein antagonists, inhibitors, or blockers of alpha and beta adrenoreceptors are also called alpha blockers and beta blocker, respectively. Non-limiting examples of beta blockers (also known as beta-adrenergic blockers and beta-adrenergic antagonists) include acebutolol (sectral), alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butaxamine, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol (brevibloc), indenolol, labetalol, levobetaxolol, levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivolol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol, practolol, pronethalol, propranolol (inderal), sotalol (betapace), sulfinalol, talinolol, tertatolol, timolol, toliprolol and xibinolol. In certain embodiments, the beta blocker can comprise an aryloxypropanolamine derivative. Non-limiting examples of aryloxypropanolamine derivatives include acebutolol, alprenolol, arotinolol, atenolol, betaxolol, bevantolol, bisoprolol, bopindolol, bunitrolol, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, epanolol, indenolol, mepindolol, metipranolol, metoprolol, UR 6-23116 /FR: 161118.05100 moprolol, nadolol, nipradilol, oxprenolol, penbutolol, pindolol, propranolol, talinolol, tertatolol, timolol and toliprolol. Additional examples are described in US20220049306, US20220364184, US20220362055, US20220267269, US 20220218630, and US 20220117921, the contents of which are incorporated in their entities. Examples also include a derivative and/or a pharmaceutically acceptable salt of any one of those described above. In some embodiments, a beta blocker can be, but is not limited to, beta-1 selective beta blocker, beta-2 selective beta blocker, alpha-1/beta adrenergic antagonists, beta-3 selective beta blocker, beta-1 and beta-3 selective beta blocker, a non-selective beta blocker, a beta-1 and beta-2 selective beta-blocker, or a mixture of two or more beta-blockers. Beta-1 selective beta blocker can be selected from the group consisting of acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, esmolol, metoprolol, nebivolol and pharmaceutically acceptable salts and derivatives thereof and their combinations. Non-selective beta blocker can be selected from the group consisting of alprenolol, bucindolol, carteolol, levobunolol, medroxalol, mepindolol, metipranolol, nadolol, oxprenolol, penbutolol, pindolol, propafenone (propafenone is a sodium channel blocking drug that is also a beta-adrenergic receptor antagonist), propranolol, sotalol, timolol and pharmaceutically acceptable salts and derivatives thereof and their combinations. The beta blocker may also have an intrinsic sympathomimetic activity as acebutolol, betaxolol, carteolol, carvedilol, labetalol, oxprenolol, penbutolol, pindolol. Non-limiting examples of alpha blocker (also known as alpha-adrenergic blockers or alpha-adrenergic antagonists) include amosulalol, atipamezole, arotinolol, dapiprazole, doxazosin, ergoloid mesylates, fenspiride, indoramin, labetalol, nicergoline, prazosin, terazosin, tolazoline, trimazosin, yohimbine, phenoxybenzamine, phentolamine, bunazosin, alfuzosin, tamsulosin, carvedilol, trazodone, mirtazapine, , urapidil, and idazoxan. Examples of α-1 antagonist include phenoxybenzamine, phentolamine, prazosin, doxazosin, bunazosin, alfuzosin, terazosin, tamsulosin, yohimbine, labetalol, carvedilol, tolazoline, trazodone, mirtazapine, indoramin, urapidil, and idazoxan. In certain embodiments, a blocker may comprise a quinazoline derivative. Non-limiting examples of quinazoline derivatives include alfuzosin, bunazosin, doxazosin, prazosin, terazosin and trimazosin. Some antagonists/blockers are commercially available. These include alpha-1- adrenergic antagonists, such as prazosin (Minipress®), doxazosin mesylate (Cardura®), prazosin hydrochloride (Minipress®), prazosin, polythiazide (Minizide®), and terazosin hydrochloride (Hytrin®); beta-adrenergic antagonists, such as propranolol (Inderal®), UR 6-23116 /FR: 161118.05100 nadolol (Corgard®), timolol (Blocadren®), metoprolol (Lopressor®), and pindolol (Visken®); combined alpha/beta-adrenergic antagonists, such as labetalol (Normodyne®, Trandate®) and carvedilol (Coreg®). In one embodiment of this disclosure, the adrenergic antagonists include prazosin, atipamezole, and propranolol (respectively, alpha1, alpha2 and beta adrenergic antagonists). Additional embodiments include congeners of these compounds with analogous receptor antagonism. In another embodiment of this disclosure, agents sufficient to induce an EEG pattern consistent with slow wave sleep - which is triggered by and downstream of adrenergic inhibition - including daridorexant, tiagabine, trazadone, mirtazapine, olanzapine, gabapentin, pregabalin, and serotonin 5HT2a agonists such as eplivanserin and ritanserin –– may be used in place of or in association with adrenergic antagonists, for the purpose of mitigating post‐TBI cerebral edema and brain injury. See, e.g., Walsh J Clin Sleep Med.2009 Apr 15; 5(2 Suppl): S27–S32. Additional examples of adrenergic antagonist or noradrenergic antagonist are described in US20110195974, US20220049306, US20220364184, US20220362055, US20220267269, US 20220218630, and US 20220117921, the contents of which are incorporated in their entities. Still other example of alpha 1A antagonists that are selective or specific for alpha 1A and not alpha 1B are listed in U.S. Pat. Nos. 5,807,856,, 6,894,052, 6,890,921, 6,593,474, 6,399,614, 6,358,959, 6,124,319, 6,071,915, 5,661,163, 5,620,993, 5,403,847, 4,760,071, and 4,110,449, all of which are herein incorporated by reference in their entirety. Examples also include a derivative and/or a pharmaceutically acceptable salt of any one of those described above. As used herein, the terms "derivative," "variant," and "analogue" are used interchangeable to refer to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those compounds disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the compounds, or to induce, as a precursor, the same or similar activities and utilities as the compounds. A derivative or analogue may be prodrug, ester, salt, or metabolite of the compound. Compositions and Uses Various compositions are available for the uses or therapies described herein, e.g., intramuscular injections, implants, oral tablets, subcutaneous formulations, intranasal UR 6-23116 /FR: 161118.05100 formulations, buccal formulations, transdermal formulations such as topical gels, and solutions, or topical patches, and the like. In some embodiments, the composition can be a solid dosage formulation (e.g., tablet, capsule, granule, powder, sachet, or chewable), solution, gel, suspension, emulsion, shampoo, conditioner, cream, foam, gel, lotion, ointment, transdermal patch, film, tincture, or paste. Further provided herein are methods and uses of the compositions described herein for treating a disease, preventing a disease, treating a condition, and/or preventing a condition. The composition or formulation of the compound or derivative or analogue or salt thereof may provide a dose adequate to improve glymphatic-lymphatic efflux from the CNS. The pharmaceutically effective amount of the compounds, derivatives, analogues, or salts thereof present in the compositions as disclosed herein may depend on the patient's condition and the mode of administration. Pharmaceutical compositions containing any of the compounds described herein or derivative or analogue or salt thereof may further comprise a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition may be formulated (e.g., using the same excipients in the same ratios and/or comprising the same dose strength) or administrated in the same way as commercially available drugs, prodrugs, derivative products, including but not limited to prazosin (Minipress®), doxazosin mesylate (Cardura®), prazosin hydrochloride (Minipress®), prazosin, polythiazide (Minizide®), and terazosin hydrochloride (Hytrin®); beta-adrenergic antagonists, such as propranolol (Inderal®), nadolol (Corgard®), timolol (Blocadren®), metoprolol (Lopressor®), and pindolol (Visken®); combined alpha/beta-adrenergic antagonists, such as labetalol (Normodyne®, Trandate®) and carvedilol (Coreg®). The FDA-approved labels for each of these products are available at the website of the FDA, including with respect to their formulation, dosing, and administration. The compounds and agents described above and related compositions are useful in methods of (i) improving glymphatic-lymphatic efflux from the CNS of a subject, (ii) promoting clearance of a waste product from the CNS interstitium, brain interstitium and/or spinal cord interstitium of a subject, and (iii) treating a cerebral edema, a traumatic brain injury, a neurodegenerative disease, or others disclosed herein in a subject. In general, the compounds, agents, or compositions can be administered in a therapeutically effective amount by any of the accepted modes of administration. Suitable dosage ranges depend upon numerous factors such as the severity of the disease or condition UR 6-23116 /FR: 161118.05100 to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases or conditions will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compounds of the present disclosure for a given disease or condition. Thus, the compounds or compositions of the present disclosure can be administered as pharmaceutical formulations including those suitable for, oral (including buccal and sub-lingual), nasal, pulmonary, topical, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. A pharmaceutical composition described herein can be formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral (e.g., intravenous, intradermal, or subcutaneous), oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, CREMOPHOR (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, UR 6-23116 /FR: 161118.05100 glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating an active compound or agent in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, typical methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Oral compositions generally can include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound or agent can be incorporated with excipients and used in the form of tablets, troches, or capsules, e.g., gelatin capsules. Oral compositions can also be prepared using a fluid carrier. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. For administration by inhalation, the active agent or compound can be delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable UR 6-23116 /FR: 161118.05100 propellant, e.g., a gas such as carbon dioxide, or a nebulizer. Such methods include those described in U.S. Pat. No.6,468,798. Systemic administration of a compound or agent can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds can be formulated into ointments, salves, gels, or creams as generally known in the art. The therapeutic composition may preferably be administered as needed. For example, for severe conditions, about 1-4 times per day on a daily basis can be used. In addition, the therapeutic composition may alternatively be administered on a weekly, bi-weekly, tri- weekly, weekly or monthly basis until the condition is treated or remediated as desired. Furthermore, the administration may initially begin on a daily basis and then, in response to clinical improvement, transition to a weekly, monthly, etc. administration. Rather than being used solely as a treatment aid, the composition of the present invention may also be used to maintain a user in edema free condition. In certain embodiments, the effective dose of a composition comprising one or more compounds/agents as described herein can be administered to a patient once. In certain embodiments, the effective dose of a composition can be administered to a patient repeatedly. Patients can be administered a therapeutic amount of a composition comprising a compound/agent at 0.0001 mg/kg to 100 mg/kg, such as 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 40 mg/kg or 50 mg/kg. A composition comprising a compound/agent can be administered over a period of time, such as over a 5-minute, 10-minute, 15-minute, 20-minute, or 25-minute period. The administration is repeated, for example, on a regular basis, such as hourly for 3 hours, 6 hours, 12 hours or longer or such as biweekly (i.e., every two weeks) for one month, two months, three months, four months or longer. After an initial treatment regimen, the treatments can be administered on a less frequent basis. For example, after administration biweekly for three months, administration can be repeated once per month, for six months or a year or longer. Administration of a composition comprising a compound/agent can reduce levels of a marker or symptom of, for example, by at least 10%, at least 15%, at least 20%, at UR 6-23116 /FR: 161118.05100 least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% or more. For certain administrations, the compositions can be provided in a suitable form or a unit dosage containing about 0.001 to about 100 milligrams of active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. An effective amount of the drug can be supplied at a dosage level of from about 0.0001 mg/kg to about 100 mg/kg of body weight per day. The compound or derivative or analogue or salt thereof may be provided in gel or cream forms in doses of 20 to 200 mg per day. In one embodiment, compound, derivative, analogue, or salt thereof are provided in a gel at doses of 50 to 100 mg/day, particularly 50 mg/day, 75 mg/day and 100 mg/day. Transdermal patches can used to deliver compound or derivative or analogue or salt thereof of 1 to 10 mg per day, particularly, 4 to 6 mg/day. The compound or derivative or analogue or salt thereof may also be provided by means of a buccal gel at a dose of 10 mg/day to 100 mg/day. In one embodiment, the dose can be a buccal gel is 40 to 80 mg/day. In one class of this embodiment, the dose can be 60 mg/day. Therapeutic Methods The methods and compositions described herein may be used for increasing glymphatic system efflux and interstitial waste clearance. Accordingly, the methods and compositions can be used for perverting or treating traumatic brain injury, including acute traumatic brain injury, and various related disorders associated with or caused by brain edema. In some embodiments, the method disclosed herein can be used for treating or preventing a brain injury. Any type of brain injury can be treated by administration of the therapeutic agent (e.g., the antagonists) described herein. The brain injury may for example be traumatic brain injury, non-traumatic brain injury, elevated intracranial pressure, or secondary brain injury. The term “brain injury” refers to a condition in which the brain is damaged by injury caused by an event. As used herein, an “injury” is an alteration in cellular or molecular integrity, activity, level, robustness, state, or other alteration that is traceable to an event. For example, an injury includes a physical, mechanical, chemical, biological, functional, infectious, or other modulator of cellular or molecular characteristics. An event can include a physical trauma such as a single or repetitive impact (percussive) or a biological abnormality such as a stroke resulting from either blockade or leakage of a blood vessel. An event is UR 6-23116 /FR: 161118.05100 optionally an infection by an infectious agent. A person of skill in the art recognizes numerous equivalent events that are encompassed by the terms injury or event. More specifically, the term “brain injury” refers to a condition that results in central nervous system damage, irrespective of its pathophysiological basis. Among the most frequent origins of a “brain injury” are stroke and traumatic brain injury (TBI). A “stroke” is classified into hemorrhagic and non-hemorrhagic. Examples of hemorrhagic stroke include cerebral hemorrhage, subarachnoid hemorrhage, and intracranial hemorrhage secondary to cerebral arterial malformation, while examples of non-hemorrhagic stroke include cerebral infarction. A distinction is made between intra-axial hemorrhage (blood inside the brain) and extra-axial hemorrhage (blood inside the skull but outside the brain). Intra-axial hemorrhage is due to intra-parenchymal hemorrhage or intra-ventricular hemorrhage (blood in the ventricular system). In various embodiments, the intra-axial hemorrhage is caused by brain trauma, hemorrhagic stroke and/or spontaneous bleeding into the brain. Likewise, in various embodiments the intraparenchymal hemorrhage, intraventricular hemorrhage, or intraventricular traumatic diffuse bleeding is caused by brain trauma, hemorrhagic stroke and/or spontaneous bleeding into the brain. The term “traumatic brain injury” or “TBI” refer to traumatic injuries to the brain which occur when physical trauma causes brain damage. For example, TBI can result from a closed head injury or a penetrating head injury. A TBI can be caused by a forceful bump, blow, or jolt to the head or body, or from an object that pierces the skull and enters the brain. A “traumatic brain injury” or “brain trauma” occurs when an external force traumatically injures the brain. TBI can be classified based on severity, mechanism (closed or penetrating head injury), or other features (e.g., occurring in a specific location or over a widespread area). A traumatic brain injury can occur as a consequence of a focal impact upon the head, by a sudden acceleration/deceleration within the cranium or by a complex combination of both movement and sudden impact, as well as blast waves, or penetration by a projectile or sharp, or dull object. The Glasgow Coma Scale (GCS), the most commonly used system for classifying TBI severity, grades a person's level of consciousness on a scale of 3-15 based on verbal, motor, and eye-opening reactions to stimuli. In general, it is agreed that a TBI with a GCS of 13 or above is mild, 9-12 is moderate, and 8 or below is severe. Similar systems exist for young children. From the diagnostic point of view, it is further distinguished between open and closed TBIs. An open TBI is considered to be an injury in UR 6-23116 /FR: 161118.05100 which the protective barrier under the bone (cerebral meninges, dura mater) is mechanically destroyed and the brain is in contact with the external environment through this opening. Often, an open TBI is associated with the exit of liquor and brain tissue debris. In a closed TBI the skull or cranium remains intact, and the primary damage of the brain (trauma) is characterized by local lesions such as contusions or hematomas and/or diffuse cerebral tissue damage. The term “cranium” when referred to herein is the set of out of the neurocranium (braincase) and the viscerocranium (craniofacial) existing bony and cartilaginous head skeleton of vertebrates. “Intracranial” means within the cranium. In accordance with the above, traumatic brain injury of any severity can be treated by the administration of the therapeutic agent(s) described herein. Thus, the patient to be treated may, for example, have been diagnosed with complicated mild, moderate, or severe traumatic brain injury. In another illustrative example, patient to be treated may have been diagnosed with traumatic brain injury of a Glasgow Coma Score (GCS)≥3. The patient being assessed of having a Glasgow Coma Score (GCS)≥3 may require intracranial pressure (ICP) monitoring and thus may be taken care of in an intensive care unit (ICU). However, it is also possible that the patient does not require ICP monitoring and can, thus, be treated in a normal hospital ward. This may be in particular the case if the patient exhibits a TBI with a GCS of 9 or more, for example, a mild TBI (with a GCS above 13, see above) or a moderate TBI with a GCS of 9-12. A “non-traumatic brain injury” refers to brain injuries that do not involve ischemia or external mechanical force (e.g., stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, brain hemorrhage, brain infections, brain tumor, among others). In one example, a “non-traumatic brain injury” does not involve external mechanical force to acquire a brain injury. Causes for non-traumatic brain injury may include lack of oxygen, glucose, or blood. Infections can cause encephalitis (brain swelling), meningitis (meningeal swelling), or cell toxicity as e.g. caused by fulminant hepatic failure, as can tumors or poisons. These injuries can occur through stroke, heart attack, near-drowning, strangulation or a diabetic coma, poisoning or other chemical causes such as alcohol abuse or drug overdose, infections or tumors and degenerative conditions such as Alzheimer's disease and Parkinson's disease. An acute neurodegenerative disease is represented by “stroke”, which refers to the loss of brain function due to disturbances in the blood supply to the brain, especially when it occurs quickly, and is often associated with cerebrovascular disease. This can occur following ischemia (lack of blood flow) caused by UR 6-23116 /FR: 161118.05100 blockage (thrombosis, arterial embolism), or a haemorrhage of central nervous system (CNS), or intracranial blood-vessels. As a result, the affected area of the brain cannot function normally. In accordance with the above, non-traumatic brain injury that can be treated with the therapeutic agent described here, may be ischemic/hypoxic/hemorrhagic brain injury (e.g. stroke), post-resuscitation (after e.g. cardiac arrest), subarachnoid haemorrhage, anticoagulation-induced haemorrhage or non-traumatic brain injury that is caused by inflammation and infection. The term “brain injury” also refers to subclinical brain injury, spinal cord injury, and anoxic-ischemic brain injury. The term “subclinical brain injury” (SCI) refers to brain injury without overt clinical evidence of brain injury. A lack of clinical evidence of brain injury when brain injury actually exists could result from degree of injury, type of injury, level of consciousness, medications particularly sedation and anesthesia. As used herein, “secondary brain trauma” refers to damage to the brain of a patient post-acute brain injury, i.e., during the secondary injury phase of a TBI. “Chronic traumatic encephalopathy (CTE)” is a neurodegenerative disease that is most often identified in postmortem autopsies of individuals exposed to repetitive head impacts, such as boxers and football players. The neuropathology of CTE is characterized by the accumulation of hyperphosphorylated tau protein in a pattern that is unique from that of other neurodegenerative diseases, including Alzheimer's disease. The clinical features of CTE are often progressive, leading to dramatic changes in mood, behavior, and cognition, frequently resulting in debilitating dementia. In some cases, motor features, including Parkinsonism, can also be present. Acute traumatic encephalopathy “ATE” refers to the early post-TBI injury-related changes that are the root cause of long term degenerative processes seen in CTE, including neuroinflammatory processes which affect the process of accumulating aggregation of neuronal proteins such as Tau, which are pathological hallmarks of CTE. As used herein, “chronic brain injury” refers to a subject who has suffered a brain injury from three months post-injury onward with continuing symptoms from the brain injury. As used herein, “sub-acute brain injury” refers to a subject who has suffered a brain injury from about 2-5 days post injury. The “spinal cord injury” refers to a condition in which the spinal cord receives compression/detrition due to a vertebral fracture or dislocation to cause dysfunction. As used UR 6-23116 /FR: 161118.05100 herein, the term “anoxic-ischemic brain injury” refers to deprivation of oxygen supply to brain tissue resulting in compromised brain function and includes cerebral hypoxia. For example, anoxic-ischemic brain injury includes focal cerebral ischemia, global cerebral ischemia, hypoxic hypoxia (i.e., limited oxygen in the environment causes reduced brain function, such as with divers, aviators, mountain climbers, and fire fighters, all of whom are at risk for this kind of cerebral hypoxia), obstructions in the lungs (e.g., hypoxia resulting from choking, strangulation, the crushing of the windpipe). In some examples, the therapeutic agent(s) and method described herein can be used to treat an infection such as meningitis, which is an acute inflammation of the membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs. Encephalitis is another example of an infection that can be treated with the therapeutic agent and method described herein. In another example, the inflammation may be Systemic Inflammatory Response Syndrome (SIRS). In addition to the damage caused at the moment of injury, brain trauma (non- traumatic or traumatic brain injury) causes “secondary injury” or secondary brain injury”, which refers to a variety of events that take place in the minutes and days following the injury. These processes, which include alterations in cerebral blood flow and the pressure within the skull, contribute substantially to the damage from the initial injury. Secondary injury events may include local changes for example damage to the blood-brain barrier, release of factors that cause inflammation, free radical overload, excessive release of the neurotransmitter glutamate (excitotoxicity), influx of calcium and sodium ions into neurons, and dysfunction of mitochondria. Injured axons in the brain's white matter may separate from their cell bodies as a result of secondary injury, potentially killing those neurons. Other factors in secondary injury are changes in the blood flow to the brain; repeated transient disintegrity of the blood brain barrier; ischemia (insufficient blood flow); cerebral hypoxia (insufficient oxygen in the brain); cerebral oedema (swelling of the brain); and raised intracranial pressure (the pressure within the skull). In addition to local alterations, systemic influences from SIRS, infections, low or elevated blood glucose levels, low or very high blood pressure, low oxygen, or low or elevated carbon dioxide levels may also cause secondary and additional brain injury. Thus, a secondary brain injury that can be treated as described herein may comprise a condition selected from the group consisting of edema formation from local or global hypoxia, ischemia, inflammation with and without infection, UR 6-23116 /FR: 161118.05100 acute and chronic neuroinflammation after traumatic brain injury and neoplasms with both benign neoplasms and malignant neoplasms being treatable. Accordingly, the disclosure provides methods for treating one or more of the brain- injury-related conditions or disorders described herein. In one embodiment, the disclosure provides a method of treating a subject (e.g., a human patient) suffering from brain injury, wherein the method comprises administering to the subject within a first time period after the occurrence of the brain injury a therapeutically effective amount(s) of one or more therapeutic agents described herein (e.g., one or more adrenergic antagonists). In one example, the first time period can be less than 48 hours, such as less than 36, 24, 18, 12, 6, or 3 hours. In another example, the first time period can be more than 48 hours, such as more than 3, 4, 5, 6, or 7 days. In some embodiments, the method comprises administering to the subject after a second time period after the occurrence of the brain injury a therapeutically effective amount(s) of one or more therapeutic agents described herein (e.g., one or more adrenergic antagonists). In one example, the second time period can be 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, 24 hours, or 48 hours. In another example, the second time period can be more than 48 hours, such as 3, 4, 5, 6, or 7 days. As disclosed herein, it is unexpected that noradrenergic receptor inhibition hours or days after brain injury can still boost the lymphatic export and clearance of fluid, macromolecular proteins, and cellular debris, and serve to sharply reduce the consequent neuroinflammation, tau accumulation, and cognitive loss. Such clearance substantially reduces post-TBI inflammation, with reductions in astrogliosis, microglial activation, and cytokine accumulation, the latter as evidenced by lower post-traumatic levels of IL1β, IL-4, and IL-6 (see, e.g., Figs.10-11). In some embodiments, the method can comprise administering to the subject a therapeutically effective amount(s) of one or more therapeutic agents described herein (i) within a first time period after the occurrence of the brain injury as disclosed above and then (ii) after a second time period after the occurrence of the brain injury as disclosed above. In some other embodiments, the method disclosed herein can be used for treating onset of a neurodegenerative disease in the brain and/or spinal cord (or CNS) of a subject by increasing glymphatic-lymphatic efflux and/or clearance. In one embodiment of the method, reactive gliosis is reduced, thereby delaying or preventing onset of the neurodegenerative disease. UR 6-23116 /FR: 161118.05100 Reactive gliosis decreases or prevents interstitial waste clearance. Reactive gliosis decreases Aqp4-dependent bulk flow and reduces the volume of the extracellular space, impeding ISF solute clearance, including waste products, from the brain and spinal cord. Reactive gliosis is known in the art to be associated with neurodegenerative diseases such as Alzheimer's disease. Increasing gliosis is also observed in the aging mammalian brain. Reactive gliosis is also associated with certain autoimmune inflammatory disorders, notably multiple sclerosis. It has also been observed in the CNS of individuals suffering from amyotrophic lateral sclerosis (ALS). Thus, increasing glymphatic system efflux and/or clearance of waste products from the CNS can be used, in certain embodiments, to delay, prevent, decrease or reduce reactive gliosis and its neurodegenerative consequences. In another embodiment of the method, reactive gliosis is reduced, delayed or prevented. In another embodiment, the method comprises the step of administering a therapeutic agent to the subject that increases or promotes glymphatic system clearance. A method is provided for promoting clearance of a waste product (e.g., a brain, spinal cord or CNS waste product) from the brain interstitium and/or spinal cord interstitium of a subject comprising the step of administering an agent to the subject that increases or promotes glymphatic efflux and/or clearance, whereby clearance of the waste product from the brain interstitium and/or spinal cord interstitium is promoted. The agent can be or comprise, for example, one or more of the adrenergic antagonists described herein. In some embodiments of the method, the brain, spinal cord or CNS waste product is amyloid β (Αβ) (e.g., soluble Αβ), tau or alpha synuclein. The method is also suitable for promoting clearance of virtually any brain waste product known in the art. In one embodiment, the method comprises the step of administering a therapeutic agent (for example, one or more of the adrenergic antagonists described herein) to the subject that increases or promotes glymphatic efflux and/or clearance. The methods and compositions described herein can be used for slowing, delaying or preventing accumulation of a brain waste product. Accordingly, a method is provided for slowing, delaying or preventing accumulation of a waste product in the central nervous system of a subject comprising the step of increasing glymphatic efflux, thereby increasing the clearance of the waste product from the central nervous system. In one embodiment, the method comprises the step of administering a therapeutic agent (for example, one or more of the adrenergic antagonists described herein) to the subject that increases or promotes glymphatic efflux. In an embodiment, the brain waste product is amyloid β (Αβ) (e.g., UR 6-23116 /FR: 161118.05100 soluble Αβ) tau, or alpha synuclein. The method is also suitable for slowing, delaying or preventing accumulation of virtually any brain waste product known in the art. In a specific embodiment, a method is provided for decreasing, reducing, delaying onset of, or preventing amyloid β (Αβ), tau and/or alpha synuclein accumulation in brain interstitium of a subject. The method comprises the step of administering an agent (for example, one or more of the adrenergic antagonists described herein) to the subject that increases or promotes glymphatic efflux. The methods and compositions described herein can be used for increasing clearance of a therapeutic or modulatory agent from the brain interstitium of a subject. Accordingly, a method is provided for increasing clearance of a therapeutic or modulatory agent from the brain interstitium of a subject. The therapeutic or modulatory agent can be any known in the art, e.g., therapeutic or functionalized nanoparticle, chemotherapy agent, antineoplastic agent, immune modulator, antibody based therapeutic, viral vector, liposome or RNA-based therapeutic construct. In one embodiment, the method comprises the step of increasing glymphatic efflux in the manner disclosed herein. The patient or subject can be one having a neurological disorder or neurodegenerative disease, including, without limitation: Alzheimer's disease (AD), stroke, epilepsy, dementia, muscular dystrophy (MD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), cystic fibrosis, Angelman's syndrome, Liddle syndrome, Parkinson's disease, Pick's disease, Paget's disease, cancer, traumatic brain injury, etc. In some embodiments, the neurological disorder is selected from: a neuropathy, an amyloidosis, cancer (e.g. involving the CNS or brain), an ocular disease or disorder, a viral or microbial infection, inflammation (e.g. of the CNS or brain), ischemia, neurodegenerative disease, seizure, behavioral disorder, lysosomal storage disease, etc. Neuropathy disorders are diseases or abnormalities of the nervous system characterized by inappropriate or uncontrolled nerve signaling or lack thereof, and include, but are not limited to, chronic pain (including nociceptive pain), pain caused by an injury to body tissues, including cancer-related pain, neuropathic pain (pain caused by abnormalities in the nerves, spinal cord, or brain), and psychogenic pain (entirely or mostly related to a psychological disorder), headache, migraine, neuropathy, and symptoms and syndromes often accompanying such neuropathy disorders such as vertigo or nausea. Amyloidoses are a group of diseases and disorders associated with extracellular proteinaceous deposits in the CNS, including, but not limited to, secondary amyloidosis, age- UR 6-23116 /FR: 161118.05100 related amyloidosis, Alzheimer's Disease (AD), mild cognitive impairment (MCI), Lewy body dementia, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis (Dutch type); the Guam Parkinson-Dementia complex, cerebral amyloid angiopathy, Huntington's disease, progressive supranuclear palsy, multiple sclerosis; Creutzfeld Jacob disease, Parkinson's disease, transmissible spongiform encephalopathy, HIV-related dementia, amyotropic lateral sclerosis (ALS), inclusion-body myositis (IBM), and ocular diseases relating to beta-amyloid deposition (i.e., macular degeneration, drusen-related optic neuropathy, and cataract). Cancers of the CNS are characterized by aberrant proliferation of one or more CNS cell (i.e., a neural cell) and include, but are not limited to, glioma, glioblastoma multiforme, meningioma, astrocytoma, acoustic neuroma, chondroma, oligodendroglioma, medulloblastomas, ganglioglioma, Schwannoma, neurofibroma, neuroblastoma, and extradural, intramedullary or intradural tumors. For cancer, a neurological drug may be selected that is a chemotherapeutic agent. Viral or microbial infections of the CNS include, but are not limited to, infections by viruses (i.e., influenza, HIV, poliovirus, rubella,), bacteria (i.e., Neisseria sp., Streptococcus sp., Pseudomonas sp., Proteus sp., E. coli, S. aureus, Pneumococcus sp., Meningococcus sp., Haemophilus sp., and Mycobacterium tuberculosis) and other microorganisms such as fungi (i.e., yeast, Cryptococcus neoformans), parasites (i.e., toxoplasma gondii) or amoebas resulting in CNS pathophysiologies including, but not limited to, meningitis, encephalitis, myelitis, vasculitis and abscess, which can be acute or chronic. Inflammation of the CNS includes, but is not limited to, inflammation that is caused by an injury to the CNS, which can be a physical injury (i.e., due to accident, surgery, brain trauma, spinal cord injury, concussion) and an injury due to or related to one or more other diseases or disorders of the CNS (i.e., abscess, cancer, viral or microbial infection). Ischemia of the CNS, as used herein, refers to a group of disorders relating to aberrant blood flow or vascular behavior in the brain or the causes therefor, and includes, but is not limited to: focal brain ischemia, global brain ischemia, stroke (i.e., subarachnoid hemorrhage and intracerebral hemorrhage), and aneurysm. Neurodegenerative diseases are a group of diseases and disorders associated with neural cell loss of function or death in the CNS, and include, but are not limited to: Parkinson's disease (PD), Alzheimer's disease (AD), Alzheimer's disease with Lewy bodies, Lewy body dementia, and mixed dementia, or associated with traumatic brain injury or UR 6-23116 /FR: 161118.05100 ischemic (e.g., diffuse ischemic) brain injury, vascular dementia, frontotemporal dementia or chronic traumatic encephalopathy, adrenoleukodystrophy, Alexander's disease, Alper's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease, cockayne syndrome, corticobasal degeneration, degeneration caused by or associated with an amyloidosis, Friedreich's ataxia, frontotemporal lobar degeneration, Kennedy's disease, multiple system atrophy, multiple sclerosis, primary lateral sclerosis, progressive supranuclear palsy, spinal muscular atrophy, transverse myelitis, Refsum's disease, and spinocerebellar ataxia. Kit and Articles of Manufacture In another aspect, this disclosure provides a kit or an article of manufacture containing materials useful for the methods described above. The article of manufacture comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, solution bags, etc. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition which is by itself or combined with another composition effective (1) for improving delivery of a composition to a target site, (e.g., central nervous system interstitium, brain interstitium and/or a spinal cord interstitium of a subject) or (2) for treating, preventing and/or diagnosing one or more of the conditions mentioned above. The container may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The label or package insert indicates that the composition is used for treating the condition of choice. Moreover, the article of manufacture may comprise (a) a first container with a composition contained therein, wherein the composition comprises an agent that enhances glymphatic system efflux and (b) a second container with a composition contained therein, wherein the composition comprises an agent that enhances glymphatic system influx. The article of manufacture may comprise a third container with a composition contained therein, wherein the composition comprises a therapeutic agent or imaging agent. The article of manufacture in this embodiment of the invention may further comprise a package insert indicating that the compositions can be used to treat a particular condition. Alternatively, or additionally, the article of manufacture may further comprise a fourth container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may UR 6-23116 /FR: 161118.05100 further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes. In some embodiments, the kit or article of manufacture further comprises instructional materials containing directions (i.e., protocols) for the practice of the methods described herein (e.g., instructions for using the kit for administering a composition). While the instructional materials typically comprise written or printed materials, they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this invention. Such media include, but are not limited to, electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD-ROM), and the like. Such media may include addresses to internet sites that provide such instructional materials. Definitions A "prodrug" or "pharmaceutically acceptable prodrug" refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form any of the compounds of the present disclosure. The present disclosure includes within its scope, prodrugs of the compounds described herein. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds described herein may be preferred. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodrugs" Ed. H. Bundgaard, Elsevier, 1985. As used herein, "prodrug" may also refer to a naturally occurring precursor of a drug. UR 6-23116 /FR: 161118.05100 The term "biologically active metabolite" means a pharmacologically active product produced through metabolism in the body of a specified compound as disclosed herein or salt thereof. The term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4 alkyl)4- salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. The term "effective amount" as used herein refers to the amount of an agent needed to alleviate at least one or more symptom of the disease or disorder, and relates to a sufficient amount of pharmacological composition to provide the desired effect. The term UR 6-23116 /FR: 161118.05100 "therapeutically effective amount" therefore refers to an amount of the agent that is sufficient to provide a beneficial effect when administered to a typical subject. An effective amount as used herein, in various contexts, would also include an amount sufficient to delay the development of a symptom of the disease, alter the course of a symptom disease (for example but not limited to, slowing the progression of a symptom of the disease), or reverse a symptom of the disease. Thus, it is not generally practicable to specify an exact "effective amount". However, for any given case, an appropriate "effective amount" can be determined by one of ordinary skill in the art using only routine experimentation. Effective amounts, toxicity, and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dosage can vary depending upon the dosage form employed and the route of administration utilized. The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50/ED50. Compositions and methods that exhibit large therapeutic indices are preferred. A therapeutically effective dose can be estimated initially from cell culture assays. Also, a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 as determined in cell culture, or in an appropriate animal model. Levels in plasma can be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay. The dosage can be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment. The terms “decrease,” "reduced", "reduction", and "inhibit" are all used herein to mean a decrease by a statistically significant amount. In some embodiments, "reduce," "reduction" or "decrease" or "inhibit" typically means a decrease by at least 10% as compared to a reference level (e.g. the absence of a given treatment) and can include, for example, a decrease by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or more. A decrease can be preferably down to a level accepted as within the range of normal for an individual without a given disorder. UR 6-23116 /FR: 161118.05100 The terms “improve,” "increased", "increase", "enhance", or "activate" are all used herein to mean an increase by a statically significant amount. In some embodiments, the terms “improve,” "increased," "increase", "enhance", or "activate" can mean an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level. In the context of a marker or symptom, an "increase" is a statistically significant increase in such level. As used herein, a "subject" or "individual" means a human or animal. Usually the animal is a vertebrate such as a primate, rodent, domestic animal or game animal. Primates include chimpanzees, cynomologous monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters. Domestic and game animals include cows, horses, pigs, sheep, goats, deer, bison, buffalo, feline species, e.g., domestic cat, canine species, e.g., dog, fox, wolf, avian species, e.g., chicken, emu, ostrich, and fish, e.g., trout, catfish and salmon. In some embodiments, the subject is a mammal, e.g., a human or a non-human mammal. The mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but is not limited to these examples. Mammals other than humans can be advantageously used as subjects that represent animal models of disorders. The terms, "individual," "patient" and "subject" are used interchangeably herein. A subject can be male or female. A subject can be one who has been previously diagnosed with or identified as suffering from or having a condition or disorder in need of treatment or one or more complications related to such a condition or disorder, and optionally, have already undergone treatment for such a condition or disorder or the one or more complications related to the condition or disorder. Alternatively, a subject can also be one who has not been previously diagnosed as having a condition or disorder or one or more complications related to the condition or disorder. For example, a subject can be one who exhibits one or more risk factors for the condition or disorder or one or more complications related to the condition or disorder or a subject who does not exhibit risk factors. UR 6-23116 /FR: 161118.05100 A "subject in need" of treatment for a particular condition or disorder can be a subject having that condition or disorder, diagnosed as having that condition or disorder, or at risk of developing that condition or disorder. As used herein, the term "administering," refers to the placement of an agent as disclosed herein into a subject by a method or route which results in at least partial delivery of the agent at a desired site. Pharmaceutical compositions comprising the agents disclosed herein can be administered by any appropriate route which results in an effective treatment in the subject. The terms "administering" and "administration" refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, ophthalmic administration, intraaural administration, intracerebral administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition. As used herein, the terms “parenteral administration” and “administered parenterally” refers to modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. As used herein, “unit dosage” formulations are those containing a dose or sub-dose of the administered ingredient adapted for a particular timed delivery. For example, exemplary “unit dosage” formulations are those containing a daily dose or unit or daily sub-dose or a weekly dose or unit or weekly sub-dose and the like. As used herein, the terms "treat," "treatment," "treating," or "amelioration" refer to therapeutic treatments, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a condition associated with a disease or disorder. The term "treating" includes reducing or alleviating at least one adverse effect or symptom of UR 6-23116 /FR: 161118.05100 a condition, disease or disorder associated with a disorder. Treatment is generally "effective" if one or more symptoms or clinical markers are reduced. Alternatively, treatment is "effective" if the progression of a disease is reduced. That is, "treatment" includes not just the improvement of symptoms or markers, but also a slowing of, progress or worsening of symptoms compared to what would be expected in the absence of treatment. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptom(s), diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, remission (whether partial or total), and/or decreased mortality, whether detectable or undetectable. The term "treatment" of a disease also includes providing relief from the symptoms or side-effects of the disease (including palliative treatment). A "therapeutically effective amount" is an amount sufficient to remedy a disease state or symptoms, particularly a state or symptoms associated with the disease state, or otherwise prevent, hinder, retard or reverse the progression of the disease state or any other undesirable symptom associated with the disease in any way whatsoever. The terms “prevent”, “preventing”, “prevention” and the like are used interchangeably herein to mean inhibit, hinder, retard, reduce or otherwise delay the development of and/or progression of a condition or disorder (such as TBI) or a symptom thereof, in a subject. In the context of the present disclosure, the term “prevent” and variations thereof does not necessarily imply the complete prevention of the specified event. Rather, the prevention may be to an extent, and/or for a time, sufficient to produce the desired effect. Prevention may be inhibition, retardation, reduction or otherwise hindrance of the event, activity or function. Such preventative effects may be in magnitude and/or be temporal in nature. A "prophylactically effective amount" is an amount of a pharmaceutical composition that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of the disease state, or reducing the likelihood of the onset (or reoccurrence) of the disease state or associated symptoms. The full therapeutic or prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically or prophylactically effective amount may be administered in one or more administrations. As used herein, the term "pharmaceutical composition" refers to the active agent in combination with a pharmaceutically acceptable carrier e.g. a carrier commonly used in the pharmaceutical industry. The phrase "pharmaceutically acceptable" is employed herein to UR 6-23116 /FR: 161118.05100 refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. As used herein, the term “pharmaceutically acceptable carrier or excipient” refers to a carrier medium or an excipient which does not interfere with the effectiveness of the biological activity of the active ingredient(s) of the composition and which is not excessively toxic to the host at the concentrations at which it is administered. In the context of the present invention, a pharmaceutically acceptable carrier or excipient is preferably suitable for topical formulation. The term includes, but is not limited to, a solvent, a stabilizer, a solubilizer, a tonicity enhancing agent, a structure-forming agent, a suspending agent, a dispersing agent, a chelating agent, an emulsifying agent, an anti-foaming agent, an ointment base, an emollient, a skin protecting agent, a gel-forming agent, a thickening agent, a pH adjusting agent, a preservative, a penetration enhancer, a complexing agent, a lubricant, a demulcent, a viscosity enhancer, a bioadhesive polymer, or a combination thereof. The use of such agents for the formulation of pharmaceutically active substances is well known in the art (see, for example, "Remington 's Pharmaceutical Sciences", E. W. Martin, 18th Ed., 1990, Mack Publishing Co.: Easton, PA, which is incorporated herein by reference in its entirety). A "neurological disorder" refers to a disease or disorder which affects the CNS and/or which has an etiology in the CNS. Exemplary CNS diseases or disorders include, but are not limited to, neuropathy, amyloidosis, cancer, an ocular disease or disorder, viral or microbial infection, inflammation, ischemia, neurodegenerative disease, seizure, behavioral disorders, and a lysosomal storage disease. Specific examples of neurological disorders include, but are not limited to, neurodegenerative diseases (including, but not limited to, Lewy body disease, postpoliomyelitis syndrome, Shy-Draeger syndrome, olivopontocerebellar atrophy, Parkinson's disease, multiple system atrophy, striatonigral degeneration, tauopathies (including, but not limited to, Alzheimer disease and supranuclear palsy), prion diseases (including, but not limited to, bovine spongiform encephalopathy, scrapie, Creutzfeldt-Jakob syndrome, kuru, Gerstmann-Straussler-Scheinker disease, chronic wasting disease, and fatal familial insomnia), bulbar palsy, motor neuron disease, and nervous system heterodegenerative disorders (including, but not limited to, Canavan disease, Huntington's disease, neuronal ceroid-lipofuscinosis, Alexander's disease, Tourette's syndrome, Menkes kinky hair syndrome, Cockayne syndrome, Halervorden-Spatz syndrome, lafora disease, Rett UR 6-23116 /FR: 161118.05100 syndrome, hepatolenticular degeneration, Lesch-Nyhan syndrome, and Unverricht-Lundborg syndrome), dementia (including, but not limited to, Pick's disease, and spinocerebellar ataxia), cancer (e.g. of the CNS, including brain metastases resulting from cancer elsewhere in the body). As used herein, the term “a,” “an,” “the” and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention. As disclosed herein, a number of ranges of values are provided. It is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither, or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. The term “about” refers to within 10%, preferably within 5%, and more preferably within 1% of a given value or range. Alternatively, the term "about" refers to within an acceptable standard error of the mean, when considered by one of ordinary skill in the art. As used herein the term "comprising" or "comprises" is used in reference to compositions, methods, and respective component(s) thereof, that are essential to the method or composition, yet open to the inclusion of unspecified elements, whether essential or not. The term "consisting of" refers to compositions, methods, and respective components thereof UR 6-23116 /FR: 161118.05100 as described herein, which are exclusive of any element not recited in that description of the embodiment. As used herein the term "consisting essentially of" refers to those elements required for a given embodiment. The term permits the presence of elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment. EXAMPLES Example 1 This example descibes material and methods used in Examples 2-12 bellow. Animals Wild type C57BL/6 male and female mice, aged 8-12 weeks, were purchased from Charles River Laboratories (Wilmington, MA, USA). C57BL/6-Tg; Slc1a2-G-CaMP7 mice were obtained from RIKEN Brain Science Institute56,57. All mice were housed under standard laboratory conditions with ad libitum access to food and water. All experiments were approved by the University Committee on Animal Resources (UCAR), University of Rochester Medical Center, or the Animal Care and Use Committee at the University of Missouri School of Medicine and followed standards of the Accreditation of Laboratory Animal Care (AAALAC). Traumatic brain injury “Hit-and-run” moderate to severe closed-skull TBI was induced in lightly anesthetized (3-5% isoflurane for 30-60 s) mice using a cortical impact device (Pittsburgh Precision Instruments)58,19. The device was modified/angled such that the metal rod was positioned horizontally to better serve the hit-and-run injury purpose. A polished stainless- steel tip (3 mm diameter) struck the mouse head with a speed of 5.2 mm/s and 0.1 s of contact time. The mouse (mildly anesthetized) was hung head up vertically from its incisors by a metal ring. The impactor was positioned perpendicular to the skull at the loading point between the ipsilateral eye and midline on the horizontal side and the eye with bregma on the vertical side. Following the impact, the animal fell onto a soft pad underneath. The above- described hit-and-run model was adopted from Ren et al. (2013)58 and can be configured to induce mild, moderate, or severe injury. This study is based on the moderate injury paradigm due to the focus on TBI-induced cerebral edema. TBI is variable in the clinic and so is the outcome of the “hit-and-run” TBI model, thus replicating real-life occurrences59-61. The inventors are overcoming the variability by including a fairly large number of mice in each group. UR 6-23116 /FR: 161118.05100 After TBI, the mice were injected i.p. with saline or a cocktail of noradrenergic receptor inhibitors/antagonists (PPA): prazosin hydrochloride (10 µg/gm, P7791, Sigma Aldrich), propranolol hydrochloride (10 µg/gm, P8688, Sigma Aldrich), and atipamezole (1 µg/gm, A9611, Sigma Aldrich) followed by 2 subsequent doses with 24 h interval. The non- injury control groups received a sham hit and saline injection (i.p.). Brain Edema Measurement Groups of mice were killed by decapitation at different time points after injury (10 min, 20 min, 30 min, 1 h, and 3 h) and the brains were quickly removed. The olfactory bulb and cerebellum were discarded while the ipsilateral and contralateral hemispheres were placed on pre-weighed slides for determination of wet weight and then dried in an oven at 85 ºC for 48-72 h. Dry weight was measured on the same digital balance and the two weights were used to calculate the fractional water content of tissue per gram of dry weight62. Behavior Tests Mice were assessed with a battery of behavior tests, including neurological severity score, rota rod, wire grip, open field, novel object, and Morris water maze. Testing was done on day two and twelve weeks post-injury. IVIS Spectrum IR imaging Mice were implanted with an intra-striatal cannula as described above45, subjected to TBI or sham hit, treated with PPA or saline i.p. injection, and maintained under anesthesia (1.5-2% isoflurane, administered through nose cones fitting within the imaging apparatus), and the IR signals were recorded/imaged (excitation/emission; 640/690 nm) through the intact skull and femoral region using the IVIS Spectrum IR imager (PerkinElmer Inc.). Radiant efficiency was calculated using the formula: p/sec/cm2/Sr/µW/cm2; p=photon, Sr=surface area (cm2). Blood Plasma Collection for NA Estimation Mice subjected to TBI were either injected with saline or PPA immediately after injury, and blood samples were withdrawn within 10 min post-injury, taking into account the time needed for blood withdrawal in a fairly big cohort of mice and maintaining temporal consistency. Briefly, a 25G needle was inserted in the heart of mildly anesthetized (2.5-3% isoflurane) mice, and 0.5-0.8ml blood was withdrawn. The syringe was emptied into the UR 6-23116 /FR: 161118.05100 heparinized vial (1.5ml, Eppendorf) before the plasma was separated by centrifugation (1000rpm, 10 min, 4 °C) and frozen at -80°C for further processing. Cerebral Microdialysis and Analysis of Extracellular Concentration of Noradrenaline A dialysis guide cannula was positioned at the prefrontal cortex. The coordinates were AP + 2.1 mm, ML + 0.3 mm from bregma, and DV -0.7 mm from dura. The guide cannula was secured to the skull with dental cement. After implantation, mice were allowed to recover for 2-3 days as described previously12. On the day of recording, TBI was induced and sampling of extracellular fluid was started immediately by infusion of filtered artificial cerebrospinal fluid (aCSF) (155 mM NaCl, 4 mM KCl, 1.25 mM CaCl2, 2mM Na2HPO4, and 0.85 mM MgCl2, adjusted to pH 7.30-7.35) at a rate of 1 µl/min. Dialysates (30 µl, twice an hour) were collected in 0.5 ml Eppendorf tubes (placed on ice) from freely moving animals in their home cage, with or without TBI and PPA treatment up to 12 h post-injury. Concentrations of noradrenaline were determined in 10 µl samples by HPLC with electrochemical detection as per an established protocol12,31. The stationary phase was a Prodigy C18 column (100 x 2 mm I.D., 3 µm particle size, YMC Europe, Schermbeck, Germany). The mobile phase consisted of 55 mM sodium acetate, 1 mM octane sulfonic acid, 0.1 mM Na2EDTA, and 7% acetonitrile, adjusted to pH 3.7 with 0.1 M acetic acid, and with degassing using an online degasser, with isocratic flow at 0.55 ml/min. The electrochemical detection was accomplished using an amperometric detector (Antec Decade from Antec, Leiden, The Netherlands) with a glass carbon electrode set at +0.7 V, with an Ag+/AgCl reference electrode. The output was recorded using the CSW system (Data Apex, Prague, The Czech Republic), which was used to calculate the electrochemical peak areas. Influx of Radiolabeled 22Na The influx of radionuclide was estimated as described previously56. Briefly, the radionuclide 22Na (NaCl, Perkin Elmer) diluted either in aCSF or normal saline (final radioactivity concentrations 0.1 µCi/µl) were infused (10 µl, 2 µl/min) via CM in pre- canulated mice. For intravenous injection, PE10 tubing was inserted surgically into the femoral artery, and the 22Na was infused at the same rate as in the CM. Mice received TBI or sham hit followed immediately by i.p. injection of saline or PPA, administered less than 2 min before the start of the 22Na infusion. The cerebral hemispheres were harvested 30 min after the start of 22Na infusion, homogenized by Solvable (Perkin Elmer) overnight, followed by addition of scintillation cocktail (5 ml/vial). The radioactivity content (Max beta energy: UR 6-23116 /FR: 161118.05100 0.546 MeV (89.8%), annihilation photons: 0.511 MeV (180%)) was measured using a liquid scintillation counter (LS6500 Multipurpose Scintillation Counter, Beckman)56. Data were background-subtracted and calculated as a percentage of the total 22Na dose administered (CPMbrain-CPMblank)/CPMctrl x100% and compared statistically across the groups using GraphPad Prism. Cervical Lymphatic Vessel Isolation and Pressure Myography Mice were anesthetized and the superficial CLVs were exposed by retraction of the skin from the tip of the lower jaw toward the top of the thoracic cavity. Both pairs of vessels were removed and transferred to a Sylgard dissection dish with Krebs buffer containing albumin. After pinning and cleaning, a vessel was cannulated using two glass micropipettes, pressurized to 3 cmH2O and further cleaned of remaining tissue to enable accurate diameter tracking. The cannulated vessel, with chamber and pipette holder assembly, was transferred to the stage of an inverted microscope and connected through polyethylene tubing to a 2- channel microfluidic device (Elveflow OB1 MK3, Paris) for pressure control. The inner diameter was tracked at 30-60 fps from brightfield images of the vessel as described previously34. Pressures were transiently set to 10 cmH2O immediately after setup and the vessel was stretched axially to remove slack, which minimized longitudinal bowing and associated diameter-tracking artifacts. Spontaneous contractions typically began within 15-30 min of warm-up at a pressure of 2 or 3 cmH2O, and the vessel was allowed to stabilize at 37 °C for 30-60 min before beginning an experimental protocol. A suffusion line connected to a peristaltic pump exchanged the chamber contents with Krebs buffer at a rate of 0.5 ml/min. Assessment of Basal Contractile Function and Concentration-response of Drugs Spontaneous contractions were recorded at equal input and output pressures to prevent a pressure gradient for forward flow through the vessel during the experiments. When pressure was set at 3 cmH2O, contraction frequency averaged ~15 min-1, which was a much higher rate than recorded in vivo. When pressure was lowered to 1 or 0.5 cmH2O, contraction frequency fell into a range (5-10 min-1) closer to that recorded in vivo, so all subsequent protocols were performed at a pressure of 1 or 0.5 cmH2O. After the contraction pattern stabilized, a concentration-response curve to NA was performed over the range 1×10-9 M to 3×10-5 M. During that time the bath was stopped, and each concentration of NA was given in 2 min intervals in a cumulative manner. The total concentration-response curve was UR 6-23116 /FR: 161118.05100 completed within 20 min to prevent changes in bath osmolality from evaporation. In a separate protocol to evaluate the effects of pharmacological blockade of NA, PPA (10 ng/ml) was added to the Krebs perfusion solution for 20 min prior to and during assessment of the concentration-response curve to NA. For contraction wave experiments, the vessel was exposed to a single dose of NA (3 µM), in either the absence or presence of 10 ng/ml PPA, and contraction waves were assessed for 2-5 min. At the end of every experiment, each vessel was perfused with Ca2+-free Krebs buffer containing 3 mM EGTA for 20 min, and the passive diameter was recorded at the pressure used in the protocol. Contractile Function parameters After an experiment, custom-written analysis programs (LabVIEW) were used to detect peak end-diastolic diameter (EDD), end-systolic diameter (ESD), and contraction frequency (FREQ) on a contraction-by-contraction basis. These data were used to calculate parameters that characterize lymphatic vessel contractile function. Each of the parameters represents the average of the respective values from all the recorded contractions at a given NE concentration during a 2 min period. From concentration-response protocols, the following parameters were calculated and graphed: (1)
Figure imgf000048_0001
(2)
Figure imgf000048_0002
(3)
Figure imgf000048_0003
avg (4), where EDDavg and FREQavg represent the average EDD and frequency during the baseline period before the addition of a drug to the bath. DMAX represents the maximum passive diameter obtained under Ca2+ free Krebs buffer. Solutions and Chemicals Krebs buffer contained (in mM) 146.9 NaCl, 4.7 KCl, 2 CaCl2·2H2O, 1.2 MgSO4, 1.2 NaH2PO4·H2O, 3 NaHCO3, 1.5 NaHEPES, and 5 D-glucose (pH = 7.4). Krebs-BSA buffer was prepared with the addition of 0.5% bovine serum albumin. During cannulation, Krebs- BSA buffer was present both luminally and abluminally, but during the experiment, the bath solution was constantly exchanged with Krebs solution without albumin. All chemicals and drugs were purchased from Sigma-Aldrich (St. Louis, MO), with the exception of BSA UR 6-23116 /FR: 161118.05100 (United States Biochemicals; Cleveland, OH), MgSO4, and Na-HEPES (ThermoFisher Scientific; Pittsburgh, PA). Assessment of Contraction Wave Speed and Entrainment Brightfield videos of contractions were acquired for 1-2 min at video rates ranging from 30 to 60 fps. Recorded videos were then stored for offline processing, analysis, and quantification of the conduction speed. Videos of contractions were processed frame by frame to generate two-dimensional (2D) spatiotemporal maps (STMs) representing the measurement of the outside diameter (encoded in 8-bit grayscale) over time (horizontal axis) at every position along the vessel (vertical axis), as described previously34. All video processing and 2D analyzes were performed using a set of custom-written Python-based programs. High-Speed Two-Photon Microscopy Mice were operated on to expose lymphatic vessels in the neck region as described above and then imaged for the flow of particles (polystyrene microspheres, 1.0 µm, 580/605 nm, Fisher Scientific) and FITC-Dextran (2000 kDa, Invitrogen) using a two-photon microscope (resonant scanner Bergamo scope, Thorlabs) with imaging frequency 29.9-58.6 Hz using one/two-way scans. GCaMP7 mice were injected with BSA647 (66 kDa, Invitrogen) to visualize CLVs; further image processing and contrast adjustment enabled the inventors to identify the dark particle efflux as cells and debris, with possible colocalization with GCaMP7 cells. Vital signs (ECG and respiration) were recorded synchronously (3 kHz, ThorSync software) with the acquisition. Images were processed and analyzed using ImageJ and customized MATLAB scripts30,56. Lymphatic Vessel Contraction Measurements Measurements of the in vivo CLV contraction amplitude and frequency (Fig.4b) were obtained by analyzing imaging time series using ImageJ and custom MATLAB scripts. The vessel diameter (Fig. 3i) was measured in each frame at one location near the center of a lymphangion and averaged per recording and per mouse. Particle Tracking Velocimetry and Volume Flow Rate Estimate Time series of two-photon imaging were registered as described previously30,63, using the green (intraluminal dextran) channel. Contiguous intervals, manually selected to ensure the stability of the field of view and registration accuracy, were used for estimating the UR 6-23116 /FR: 161118.05100 average flow speed and median vessel diameter. Spatially and temporally resolved velocities were obtained via automated particle tracking velocimetry (PTV) as described previously30,63. Mean flow speeds were computed by time-averaging all velocity measurements (in 10-pixel bins), and then flow speeds were spatially averaged. The inventors required at least 30 separate measurements in space to ensure reliable estimate of the mean. The inventors recorded up to three independent mean flow speed measurements per mouse which were averaged; if more than three were obtained, The inventors kept the three with the largest number of speed measurements throughout space. The median vessel diameter was measured (using a custom MATLAB code) for the same temporal segments used for speed measurements. Images were first averaged in groups of 30 (about 1 s) to reduce noise and accelerate analysis. Then 3-5 transverse profiles were interpolated onto a 10-fold finer grid and the vessel diameter was measured with subpixel accuracy by identifying locations where pixel intensity dropped to 20% the maximum value. Finally, the median in space and time was computed. The volume flow rate was estimated as the average flow speed multiplied by the approximate cross-sectional area of the vessel, , where D is the median vessel diameter. The retrograde flow percentage was computed by identifying the fraction of each time series in which fluid was flowing in the direction opposite the net transport, as in prior work56,64. Cell and Cellular Debris Efflux Two-photon image time series were analyzed to estimate size distributions and volumetric efflux rates of cells/cellular debris, which appeared as dark objects in the intraluminal dextran (green) channel. For each image, a dynamic background image (average of the adjacent 15 frames in time) was added then a Gaussian blur was computed and subtracted to improve lighting uniformity. Each image was slightly smoothed by applying a 3x3 pixel moving average and a region of interest (ROI) was selected for analysis. The ROI was binarized using the MATLAB function “imbinarize” with an adaptive threshold and the particles inside the ROI were fit to ellipses using the MATLAB function “regionprops”. The particle volume was estimated as , where is the semimajor axis length, is the semiminor axis length, and The inventors estimated
Figure imgf000050_0001
. Average particle distributions per unit volume were estimated (based on the ROI size), then multiplied by the estimated volume flow rate. UR 6-23116 /FR: 161118.05100 Lumped Parameter Lymphatic Vessel Simulations Flow through cervical lymphatic vessels was simulated using a lumped parameter model based on previous studies65-67. A series of four lymphangions was simulated with a lymphangion length of 0.2 cm, minimum valve resistance of 0.0375 mmHg⋅min/µl, maximum valve resistance of 12.5 mmHg⋅min/µl, active tension ranging from 7.5x10-4 to 2.25x10-3 mmHg⋅cm, contraction frequency ranging from 0.5 to 10 min-1, inlet pressure 1.58 mmHg, outlet pressure 1.73 mmHg, and external pressure of 1.50 mmHg; all other parameters matched those of Bertram et al. (2011)65. The inventors solved a system of algebraic constraint equations using MATLAB’s nonlinear equation solvers (fzero and fsolve), and then The inventors integrated a system of ODEs in time using a fourth-order Runge-Kutta method. The inventors modeled conditions of different contraction amplitude by varying the active tension from 7.5x10-4 to 2.25x10-3 mmHg⋅cm with the contraction frequency fixed at 10 min-1. The inventors modeled conditions of variable contraction frequency by varying the frequency from 0.5 to 10 min-1 with the active tension fixed at 1.4x10-3 mmHg⋅cm. Presented results come from the fourth (final) lymphangion in the simulation. Image Averaging and Analyzes Images were acquired using the following microscopes: wide field fluorescent/epifluorescent microscope (MVX 10, Olympus), M205 FA fluorescence stereomicroscope equipped with an Xcite 200DC light source, and A12801-01 W-View GEMINI (Leica Inc.), Montage/slid scanning microscope (Olympus), FV 500 confocal microscope (IX81, Olympus), SP8 confocal microscope (Leica Microsystems), FV3000 confocal microscope (Olympus), and two/multiphoton galvoresonance scanner (Thorlabs Inc.). Field of view, regions of interest, resolution, and other acquisition factors were standardized, and fluorescence intensity was estimated using image processing plugins in ImageJ. Fluorescence stereomicroscopic images at relevant time points were co-registered according to the position of the bregma and lambda on each mouse, then averaged using a custom ImageJ macro39. Statistical Analysis Data (n=8-15 mice per group, each with multiple ROIs or replicates where applicable) were analyzed for mean and standard error and depicted as bar graphs, box plots, or line graphs. Specific statistical tests used for each figure are presented in the corresponding figure UR 6-23116 /FR: 161118.05100 legends. Numerical values (used as mean/mouse in the analysis in case of repeated measures) were compared using student t-test (unpaired), correlation matrix, regression analysis, one- way or two-way analysis of variance (ANOVA) followed by post hoc Tukey’s test, Bonferroni’s multiple comparison test, or non-parametric Kruskal-Wallis test using Prism GraphPad software with 95% confidence interval. Neurological severity score (NSS) A composite clinical score consisting of ten individual clinical parameters including motor function and alertness was obtained according to the methodology described by Flierl et al. (2009) Nat Protoc 4, 1328-1337. The score was calculated for each mouse (12- 15/group) on the day of injury, at two weeks, and at 12 weeks post-injury. Mice were assessed independently three times consecutively on each measurement day. Data are presented graphically for beam walk, round stick balance, and overall NSS. Wire grip testing Vestibulomotor function, as described by Petraglia et al. (2014) J Neurotrauma 31, 1211-1224, was assessed using wire grip testing immediately after injury and again at two weeks post-TBI. In brief, mice (8-10/group) were suspended by the tail and placed on a metallic wire hanging between two upright bars, 50 cm above the lab bench. The time and manner in which the mouse retained ahold of the wire were noted and blindly scored on a 0-5 scale. The average score of three consecutive trials at intervals of 5 min was used in the analysis. Rota-rod The motor function was assessed by placing each mouse on a circular rotating rod (Rota Rod Device, Ugo Basile) with speed gradually increasing from 5-40 rpm over 15 min, which provides a sensitive and efficient index for assessing motor impairment after TBI (Hamm, R. J., et al. Journal of neurotrauma 11, 187-196, (1994)). Mice (12-18/group) were trained in the rota-rod 24 h prior to the actual trial. Each experimental trial consisted of three consecutive mountings at intervals of 30 min. A composite mean group score was then calculated for the different treatment groups. Spontaneous Locomotor Activity Mice (12/group) were evaluated for their spontaneous locomotor activity, speed of movement, and anxiety-like behavior after placement in an uncovered rectangular open field UR 6-23116 /FR: 161118.05100 measuring 60 x 40 cm2. In brief, mice were placed in the box for 10 min, and their movements were recorded with an overhead video camera and analyzed later for total distance traveled, the velocity of movement, number and length of freezing episodes, and percentage time spent in the center of the open field using Anymaze software (San Diego Instruments). Spatial Learning and Memory Deficits Spatial learning and memory deficits were evaluated using the Morris water maze test as described by Vorhees and Williams (2010) Nature protocols 1, 848-858. The key concept here is that the mouse must memorize distal visual cues to navigate a direct path to a hidden platform just under the water surface, starting from different quadrants at the perimeter of the tank. In brief, the mice were placed in a circular pool of diameter 120 cm and filled to a depth of 30 cm with water (made opaque with skim milk), 22ºC, equipped with a 10 x 10 cm2 hidden platform submerged 5 mm below the surface. Visual cues were pasted at distinct places along the inner sides of the tub. Mice were introduced into the pool at four different points and allowed to swim until they found the hidden platform or until 60 s elapsed; the platform location remained constant. Mice that failed to locate the platform within the time limit were guided to it and allowed to rest and orient themselves for 15 s. An HD camera was fitted above the tub to record movements, with analysis using the AnyMaze software (San Diego Instruments). Mice were evaluated for five consecutive days, starting at two weeks post-injury. Blood Pressure Measurements: Arterial blood pressure was measured using a catheter in the femoral artery connected to a pressure transducer and digitizer (DigiData 1550A, World Precision Instruments) for continuous recording of pressure in mmHg using Axoscope software (Axon Instruments) (Min Rivas, F. et al. J R Soc Interface 17, 20200593, (2020)). Intracranial Pressure (ICP): Mice were implanted with a custom-made 30G needle cannula fitted with PE10 tubing into the CM. The outlet end of the PE10 tubing, which was filled with aCSF, was connected to a pressure transducer (World Precision Instruments) (Min Rivas, F. et al. J R Soc Interface 17, 20200593, (2020)). UR 6-23116 /FR: 161118.05100 Cerebral Blood Flow (CBF): Anesthetized mice were placed in a stereotaxic apparatus, the scalp was incised, the skin flap was removed, the skull surface was disinfected with isopropanol wipes, and a fiber optic probe was fixed to the skull at a point directly above the middle cerebral artery (AP 1 mm, ML 5.0 mm) using cyanoacrylate glue. The optical fiber was connected to the laser Doppler flowmetry apparatus (PF5010 Laser Doppler Perfusion Module, PR 418-2, Perimed) and signals were read and recorded by Axoscope (Min Rivas, F. et al. J R Soc Interface 17, 20200593, (2020)). ECG and Respiration The respiratory and cardiac rhythms of mice anesthetized with a mixture of ketamine/xylazine (100 mg/kg, 10 mg/kg) were recorded using a small animal physiological monitoring system (Harvard Apparatus). The recording duration was synchronized with the Thorlabs 2P imager while performing lymphatic vessel imaging experiments (Min Rivas, F. et al. J R Soc Interface 17, 20200593, (2020)). Cisterna Magna Tracer Injections Mice were anesthetized with ketamine/xylazine (100 mg/kg, 10 mg/kg), the day before tracer injection. A cannula (30 gauge) was implanted in the cisterna magna (CM) and connected to PE10 tubing. The cranial opening was sealed using superglue mixed with dental cement (Hablitz, L. M. et al. Nature communications 11, 4411 (2020) and Plog, B. A. et al. The Journal of neuroscience: the official journal of the Society for Neuroscience 35, 518-526, (2015)). The day following the TBI, with or without PPA treatment, the mice received 10 µl of bovine serum albumin (BSA) conjugated Alexa flour 647 (A34785, Invitrogen) infused into the CM at a rate of 2 µl/min using a Harvard Instrument Syringe Pump (Series 11 Elite). After 1 h, mice were decapitated, and the brains were removed and immersion-fixed in 4% paraformaldehyde (PFA) in phosphate-buffered saline (PBS; Sigma) overnight at 4 ºC. The next day, 100 µm thick coronal sections of brains were cut using a vibratome (VTS1000, Leica), mounted on a glass slide, and imaged for tracer penetration using a fluorescent microscope (MVX10, Olympus) or confocal microscope (SP8, Leica Microsystems). Intrastriatal Tracer Injections Mice were placed on a stereotaxic frame under ketamine/xylazine anesthesia (100 mg/kg, 10 mg/kg), the scalp flap was removed, and the exposed area was disinfected with UR 6-23116 /FR: 161118.05100 isopropanol wipes. A burr hole was drilled over the target coordinates relative to bregma (AP -0.6 mm, ML -2.0 mm, DV -3.25 mm), and a cannula with removable cap (C315DC/SP, 0.1 mm projection, Plastic One Inc) was fitted through the hole and secured in place using cyanoacrylate/dental cement mixture (NC9991371, Fisher Scientific). The cap was replaced 24 h later with PE10 tubing connected to a 10 µl Hamilton syringe pump, and the tracer (4% Direct Blue 53, DB53, MW 960 Da, 1 µl) was delivered into the left striatum at a flow rate of 0.2 µl/min. The tubing was then sealed using an arterial cauterizer (Hablitz, L. M. et al. Nature communications 11, 4411 (2020)). The TBI or sham injury had been applied 30 min prior to tracer injection, with either PPA cocktail or vehicle (saline) administered i.p. during the tracer infusion. Immunohistochemistry While deeply anesthetized, mice were perfused trans-cardially with 4% PFA in PBS and the brain was removed and post-fixed in the same medium overnight. The next morning, the brain was either sliced into coronal sections (50 µm thick) using a vibratome (Leica Biosystems) or placed in cryoprotectant (30% w/v sucrose solution in PBS) for 42-72 h, until sinking. Brains were then frozen in Tissue-Tek OCT (Sakura Finetek) and stored at -80 ºC until further use. Frozen brains were sliced (30µm) using Cryostat and immunostaining was performed on brain slices as described previously in Hussain, R. et al. J Neurosci 37, 397- 412, (2017). The following primary antibodies were used: rabbit anti-GFAP (1:300, AB5804, Millipore), mouse anti-GFAP (1:300, ab10062, Abcam), rabbit anti-Iba1 (1:500, 019-19741, Wako Chemicals), mouse anti-Tau5 (1:300, MA5-12808, Thermo Fisher Scientific), rabbit anti-pTau-Thr212 (1:300, 44-740G, Thermo Fisher Scientific), rabbit anti-pTau-Ser262 (1:300, 44-750G, Thermo Fisher Scientific), rabbit anti-pTau-Thr205 (1:300, 44738G, Thermo Fisher Scientific), and rabbit anti-pTau-Ser404 (1:300, 44-758G, Thermo Fisher Scientific). Cell nuclei were counterstained with DAPI (2.5 µg/mL, Invitrogen). Western Blot Mice (C57bl6, n=3-5/group, 6-months post-TBI) were decapitated while deeply anesthetized, and brain tissue from the side ipsilateral and contralateral to the injury were collected using a 4.8 mm diameter cork borer (470019-716, VWR). Tissue was immediately homogenized in RIPA lysis and extraction buffer (89901, Fisher Scientific) supplemented with protease inhibitor (complete mini, 04693124001; Roche) and phosphatase inhibitor (524625; Calbiochem). Protein concentration was measured by the Pierce bicinchoninic acid UR 6-23116 /FR: 161118.05100 protein assay (BCA, 23227; Thermo Scientific) and adjusted as 2 µg/µl for blotting. Samples were prepared in 4x Laemmli buffer (1610747, BioRad) supplemented with 5% β- mercaptoethanol and heated to 95 ºC for 5 min. Proteins were separated using a standard SDS PAGE protocol with Mini-PROTEAN TGX (4-20% pre-cast stain-free gels, 456-8049, BioRad) (Hussain, R. et al. J Neurosci 37, 397-412, (2017)). Separated proteins were transferred onto a polyvinylidene fluoride membrane (1620174, BioRad), blocked for 1 h with 5% BSA in Tris-buffered saline containing 0.1% Tween 20, and incubated with primary antibodies overnight. Near-infrared fluorescent secondary antibodies, 680 RD Donkey Anti- rabbit (NC0883607, LiCOR) and IR dye 800CW Donkey anti-mouse (NC0987647, LiCOR), were used to visualize the primary antibodies/protein of interest using the Odyssey Infrared Imaging System (LI-COR). Primary antibodies used were: mouse anti-β-Actin (1:5000, #3700S; Cell Signaling Technology), rabbit anti-GAPDH (1:5000, #5174S; Cell Signaling Technology), mouse anti-Tau (1:700, MA5-12808, Thermo Fisher Scientific), rabbit anti- pTau-Thr212 (1:700, 44-740G, Thermo Fisher Scientific), rabbit anti-pTau-Ser262 (1:700, 44-750G, Thermo Fisher Scientific), rabbit anti-pTau-Thr205 (1:700, 44738G, Thermo Fisher Scientific), and rabbit anti-pTau-Ser404 (1:700, 44-758G, Thermo Fisher Scientific). Epi-fluorescence Optical Microscopy Mice implanted with a CM cannula were infused with a mixture of FITC-Dextran (2000 kDa, Invitrogen) and Texas red Fluospheres (Polystyrene microspheres, 1.0 µm, 580/605 nm, Fisher Scientific), to a total volume of 10 µl (2 µl/min) (Min Rivas, F. et al. J R Soc Interface 17, 20200593, (2020) and Plog, B. A. et al. JCI Insight 3, (2018). Neck skin (ventral) was shaved and removed surgically to expose the cervical lymph vessel and nodes within the neck region. Time-lapse imaging was performed both for FITC (excitation/emission 480/510 nm) and Tx-red (excitation/emission, 560/630 nm) channels using an Olympus MVX10 microscope equipped with a PRIOR Lumen LED and Hamamatsu ORCA-Flash4.0 V2 Digital CMOS camera, or a Leica M205 FA fluorescence stereomicroscope, equipped with an Xcite 200DC light source and a Hamamatsu ORCA- Flash4.0 V2 Digital CMOS camera. Images were acquired using the Cell Sense (Olympus) and LAS X software (Leica) and exported in TIFF format for further analysis. Example 2 Adrenergic inhibition eliminates post-TBI edema The inventors first assessed the dynamics of cerebral edema and CSF influx in the “Hit-and-Run” TBI model in mice19. A significant increase in brain water content was UR 6-23116 /FR: 161118.05100 evident 30 min after injury in the ipsilateral hemisphere, and at 180 min in the contralateral hemisphere (Fig. 1a). TBI suppresses glial-dependent CSF flow through the perivascular spaces, which defines glymphatic flow19. To improve brain fluid transport, the inventors broadly inhibited adrenergic receptors. The pharmacological cocktail included prazosin (an α1 receptor antagonist), atipamezole (an α2 antagonist), and propranolol (a broad β receptor antagonist); as such, it was designated as PPA, and was administered12 intraperitoneally (i.p.) to mice shortly after exposing them to “Hit-and-Run” head injury19. Strikingly, PPA treatment virtually eliminated cerebral edema (Fig. 1a). Among the separate components of PPA, prazosin and propranolol individually reduced edema to some extent, but the beneficial effect was sharply potentiated by combining the three NA receptor antagonists (Fig.7a). PPA administration 24 h post-injury also reduced cerebral edema significantly (Fig.7b). Example 3 Adrenergic inhibition improves functional outcome Suppression of post-TBI edema by PPA had long-term behavioral benefits; the scores for neurological function (Fig. 1c-e), rotarod performance, and string suspension (Fig. 1f-g) all significantly improved in the mice treated with PPA, which was administered daily for three days (Fig.1b). Spatial learning and memory, as assessed by the Morris water maze test, were significantly enhanced during post-traumatic recovery of the PPA-treated mice, compared with vehicle-injected TBI mice (Fig. 1h). Similarly, the locomotor function of PPA-treated injured animals was significantly improved two weeks after injury. In addition, anxiety-like behaviors, characterized by the number and duration of freezing episodes during undisturbed ambulation, were reduced (Fig. 8a-b). A twelve-week post-TBI assessment revealed spontaneous recovery of locomotor function with or without PPA treatment, but anxiety-like behaviors persisted in the injured mice unless treated with PPA (Fig.8c). Example 4 TBI-induced suppression of glymphatic transport contributes to cerebral edema On the basis of these data, the inventors next considered whether post-TBI edema was a consequence of increased fluid influx from the vascular or CSF compartments, or alternatively, whether TBI might yield edema via the suppression of brain fluid efflux. The inventors first confirmed that TBI was associated with an acute reduction of CSF tracer transport20 (Fig. 2a-d). PPA treatment administered shortly after injury partly rescued CSF influx (Fig. 2b-c and Fig. 9a). The inventors also assessed glymphatic function six months after the head injury, which revealed a persistent reduction relative to that of age-matched UR 6-23116 /FR: 161118.05100 controls (Fig.2d, right and Fig.9a, d-f). Both transcranial macroscopic imaging in vivo (Fig. 2b-c) and ex vivo analysis of CSF tracer distribution in the whole brain (Fig. 9a, d-f) or in brain slices (Fig.2d), suggested that TBI was linked to a long-lasting reduction in glymphatic flow. The analysis quantified fluorescence intensities of in vivo transcranial vs. ex vivo dorsal images, and in vivo transcranial vs. ex vivo brain slices (Fig. 9b). Glymphatic impairment as the result of TBI was global rather than unilateral in accordance with unilateral insertion of a small glass canula20,21 or irradiating deeper brain regions, which decrease CSF inflow brain- wide22. Nonetheless, regional differences in CSF flow were identified, with the relative largest suppression of CSF influx in the dorsal cortex, lateral cortex, and hypothalamus, (Fig. 9g). In addition, high-resolution confocal microscopy confirmed that TBI reduced tracer distribution within the perivascular spaces (Fig.9c). Example 5 Adrenergic inhibition attenuated post-traumatic inflammation and pTau accumulation The inventors next conducted a detailed analysis of the cytokine/chemokine parenchymal profile to map both the impact of TBI, and the protective effects of PPA treatment. TBI induced a significant increase in the concentrations of several interleukins (IL- 1β, IL-4, IL6, and IL-12p70), as well as chemokines (CXCL1 (KC), CXCL10, MCP-1, and MIP-2) in the ipsilateral hemisphere within 24 hours (Fig. 10d-i, k, m). Yet a single dose of PPA proved sufficient to significantly reduce the levels of IL-4, IL-6, and CXCL10 (Fig.10). The inventors further extended the study to investigate the long-term effects (6 months) of TBI (Fig. 11). PPA treatment after TBI resulted in a marked decrease in astrogliosis and microglial activation (Fig.11a-d), as well as a downregulation of Caspase 3, 7, and 9 (Fig. 12). In addition, Western blot analysis showed that post-TBI PPA treatment suppressed the accumulation of hyperphosphorylated tau, in particular at sites T404, Th205, and Ser262 (Fig. 11e). Immunohistochemistry also revealed an overall higher accumulation of total (Tau5) and phosphorylated tau (Ser262, T212, Thr205) in the TBI group, which was broadly decreased in PPA-treated mice (Fig.11f-j). Example 6 Neither transudation nor CSF over-production underlies post-traumatic edema CSF is a major contributor to post-stroke edema23. To assess the respective contributions of plasma transudation and CSF to post-traumatic edema, the two fluid compartments were separately tagged by intravenous (i.v.) or intracisternal CSF administration, respectively, of radioactive sodium (22Na) shortly (<5 min) after TBI (Fig.2e- UR 6-23116 /FR: 161118.05100 f). The brains were harvested 30 min later, and the 22Na content was quantified in each cerebral hemisphere. When blood was labeled with 22Na, no significant differences in 22Na content were noted in either hemisphere (Fig. 2e). In contrast, when 22Na-tagged CSF was injected into the cisterna magna (CM) (Fig.2f), significantly less 22Na uptake occurred in the ipsilateral injured hemisphere of the TBI-saline group. PPA treatment increased ipsilateral 22Na uptake, mirroring the glymphatic tracer analysis, showing that TBI suppressed CSF tracer inflow, confirming that PPA administration after TBI partially restored CSF influx (Fig. 2b-f). The experiment depicted in Fig. 2 was repeated using 14C-tagged mannitol (182 Da) as the vascular tracer. Mannitol cannot cross the intact BBB, but will enter the brain when there is a modest breach of BBB. It was found that, as in the 22Na experiments, BBB leakage and influx of vascular fluid did not contribute significantly to acute edema after TBI (Fig. 13). Thus, compartment-selective radiolabeling together with PPA administration demonstrated that neither plasma transudation nor excessive CSF transport was responsible for TBI-induced edema. Example 7 PPA rescues the post-traumatic production of CSF and enhances CSF efflux CSF is an essential component of the fluid compartment of the brain. Data characterizing the effect of TBI on CSF production is still lacking. Therefore, forebrain ventricular CSF production was quantified in injured and control mice24: it was found that TBI dramatically reduced ventricular CSF production by at least 90%, and that this drop was rescued by PPA (Fig. 2g-i). Yet this observation, that PPA-treatment increased and largely normalized CSF inflow and production after TBI, seemed puzzling since this same treatment efficiently reduced post-traumatic edema. To address this paradox, it was posited that the PPA might globally increase fluid transport and prevent edema formation by enhancing fluid drainage. To test this idea, the inventors assessed the clearance of a small intracortically-administered near-infrared (IR) tracer, Direct Blue 53 (DB53, 960 Da), which can be imaged through the mouse skull (Fig. 148a). DB53 dispersed from the site of injection into the surrounding brain parenchyma of uninjured control mice. In contrast, TBI mice exhibited little spread of the tracer over the duration of observation (60-90 min). Pan-adrenergic inhibition after TBI partially restored the spread and clearance of the tracer (Figs. 148b-c). To further validate this hypothesis, the inventors leveraged the fact that brain solutes ultimately are exported via glymphatic/lymphatic transport to the vascular compartment and then cleared by the liver and kidneys. DB53 diffuses freely in the brain but binds tightly to albumin when exported, and is UR 6-23116 /FR: 161118.05100 thereby retained within the vascular compartment for durations measured in days25,26. Thus, the DB53 signal within the femoral vein correlates directly to total DB53 glymphatic/lymphatic clearance from the brain. Continuous imaging over the femoral region (Fig. 15a) showed a steady increase in the DB53 fluorescence signal (Fig. 15b). Animals subjected to TBI exhibited a significantly slower increase in DB53 signal, which was partly restored by PPA treatment (Fig. 15c). Surgical exposure of the femoral artery and vein to enhance DB53 sensitivity revealed the same pattern of reduced tracer export after TBI, which was partly restored by PPA (Fig. 3a- c). Thus, pan-adrenergic antagonism by PPA treatment improved the glymphatic clearance of DB53, while eliminating post-traumatic edema (Figs. 1a and 3c), indicating that the adrenergic suppression of glymphatic clearance causally contributes to post-traumatic brain edema. PPA treatment resulted in enhanced efflux, which was further confirmed using a range of radiolabeled CSF tracers (mannitol, inulin, and 22Na) followed by the detection of tracer radioactivity in plasma in controls (Fig.16) and after injury (22Na, Fig.17). Example 8 Cervical lymphatic drainage is compromised by TBI and rescued by PPA Adrenergic signaling is not only a critical regulator of glymphatic function12 but also a dose-dependent modulator of activity of the peripheral lymphatic system, including that of the cervical lymph vessels (CLV). Low levels of adrenergic stimulation enhance the frequency of lymph vessel contraction, while excessive or prolonged noradrenaline has the opposite effect27,28. The inventors first confirmed that CLV drainage was suppressed after TBI29 by injecting a mixture of FITC-dextran (2 kDa) and Texas Red-microspheres (1 µm diameter) into CSF and quantifying their outflow in superficial and deep cervical lymph nodes (Fig. 3d-f). A detailed analysis of tracer intensity, lymph node size, and area of tracer distribution further confirmed these findings (Figs. 3e-f; Fig. 18). Time-lapse imaging revealed rhythmic contractions of the CLVs and the opening/closing of valves associated with active pumping that directed net transport of the CSF tracers. The inventors tracked the microspheres by analyzing high-speed two-photon in vivo recordings (Fig.3g-h) and noted a characteristic pulsatile pattern peaking every 7-10 s (Fig. 3h). The microsphere efflux frequency coincided with CLV contractions, but not with cardiac or respiratory cycles (Fig. 19). Furthermore, microsphere counts were greatly reduced after TBI, but PPA partially restored the particle efflux count (Fig.3h). Image analysis showed that TBI reduced lymphatic vessel diameter, while PPA treatment increased it (Fig. 3i, p=0.004). Automated particle tracking velocimetry30 showed UR 6-23116 /FR: 161118.05100 that the average speed was lower in the TBI group (Fig. 3j, mean±sem: 25.0±4.9 µm/s) compared to the control (60.8±7.8 µm/s), while subsequent PPA treatment restored the microsphere speed (62.5±15.7 µm/s). Based on mean speed and vessel diameter, The inventors calculated the volume flow rate for a single superficial lymph vessel. The analysis showed that lymph flow was significantly reduced in the TBI group, but restored by PPA treatment (Fig.3j). Next valve dysfunction was quantified by measuring retrograde flow. Under physiological conditions, retrograde flow is counteracted by contraction wave entrainment, the process by which the lymphangions contract in series, resulting in the consecutive opening and closing of valves which efficiently propels fluid forward. In non-injured mice, retrograde flow averaged 35.1±1.9% but rose to 43.2±2.2% after TBI, and remained elevated at 41.3±2.3% following PPA treatment (Fig. 3j). Furthermore, The inventors developed numerical simulations of fluid transport through lymph vessels and obtained predictions of volume flow rates that proved remarkably close to the experimental measurements (Fig.3k). Example 9 PPA eliminates the adrenergic storm after TBI It was next asked how pan-adrenergic inhibition might exert its neuroprotective effects. To this end, plasma NA levels were first quantified as a function of time after injury. It was found that plasma NA exhibited a sharp elevation immediately after TBI (Fig.4a). The inventors also monitored the temporal changes in the NA concentration of microdialysis samples after TBI31 collected in the contralateral hemisphere, which revealed multiple delayed peaks in NA, which rose to levels 5-8-fold higher than both baseline and in uninjured controls (Fig. 4a). These TBI-triggered increases in NA, both in the plasma and brain, were largely eliminated by PPA administration (Fig.4a; Fig. 24). It thus seems plausible that the excessive increases in NA observed in plasma and brain interstitial fluid (Fig. 4a) directly suppress fluid transport by the meningeal and cervical lymphatic vessels, which normally serve to return fluid from CNS to the systemic venous circulation14,32,33. Furthermore, since adrenergic signaling is a critical negative regulator of glymphatic activity12, these data suggested that PPA might rescue glymphatic flow (Fig.2a-d). However, the low volume transfer by cervical lymphatic vessels in the event of TBI raises various questions: 1) Is there less efflux and more retention of fluid due to the adrenergic spikes in the brain? 2) Can administration of PPA or its individual components to counteract noradrenergic spikes increase the pumping efficiency of cervical lymphatic UR 6-23116 /FR: 161118.05100 vessels? 3) How do lymphatic vessels respond to variable adrenergic stimulation ex vivo? These questions were addressed in a series of experiments. Example 10 PPA support of CSF clearance is attended by normalization of cardiovascular parameters To assess if the post-traumatic failure of lymphatic transport is a direct consequence of the adrenergic storm, different concentrations of NA were topically applied to exposed superficial cervical lymphatic vessels (Fig. 4b). NA reduced the contraction frequency and amplitude in a dose-dependent manner while the effect was partially restored by PPA administration (Fig.4b). To study the effect of NA in isolation, the inventors excised and cannulated the cervical lymphatic vessels and quantified contraction parameters under a constant internal pressure from 0.5-3 cm H2O with or without NA treatment (Fig. 4c). NA administration ex vivo disrupted contraction wave entrainment (Fig.4c), which is critical for lymph propulsion against an adverse pressure gradient34, as would be the case if central venous pressure were elevated after TBI. The inventors tracked the vessel's outer diameter pixel by pixel and generated spatiotemporal and Fast Fourier Transform maps (Fig. 20 and Fig. 4c), which revealed fully entrained contraction waves at conduction speeds ~10 mm/sec, as well as a single, predominant frequency component at ~10 min-1 in the absence of NA. The addition of NA resulted in lower conduction speeds, shorter conduction lengths, and multiple pacemaker sites (Fig. 4d), indicative of a loss of entrainment (Fig. 4c); these effects were all prevented by PPA treatment. Additionally, the inventors performed a thorough assessment of cardiovascular parameters and noted decreases in both mean arterial pressure and cerebral blood flow, which were prevented by PPA (Fig.4e). Dramatic increases in both intracranial pressure and central venous pressure were noted after TBI; both reverted to control levels in response to PPA (Fig. 4e-f). An increase in central venous pressure is associated with the retention of fluid/lymph in peripheral tissues as well as in the brain, as the pressure gradient between the large lymphatic vessels and the central veins into which they drain regulates the rate of fluid transfer35. PPA treatment in non-injured mice did not significantly change cardiac or respiratory rhythms, or cerebral blood flow, but resulted in a decrease in intracranial and mean arterial pressure (Fig. 21). Conversely, PPA administration increased the high amplitude contraction frequency of cervical lymphatic vessels (Fig.22). UR 6-23116 /FR: 161118.05100 Example 11 Cervical lymphatic vessels export neuronal debris after TBI While imaging the superficial cervical lymphatic vessels (Fig. 3), the inventors observed the presence of dark, unevenly sized particles that were detectable against the bright fluorescent signal from the lymph and which were most frequently observed in the TBI+PPA group (Fig. 5a-b). These particles were identified as cortical debris (Fig. 5c) by use of a transgenic mouse line expressing the calcium indicator GCaMP7 in both cortical astrocytes and neurons (Fig.5d)36. Through high-speed two-photon imaging, the inventors were able to quantify the temporal and volumetric variations in the debris/cells. Subsequent histological analysis showed that GCaMP7 signal was increased in cervical lymph nodes harvested 60-90 min post-TBI in the PPA-treated mice, consistent with the real-time imaging (Fig.5e-g, h, j). A higher fluorescence signal of the CSF tracer was also noted in the lymph nodes of the PPA- treated TBI mice, compared with controls and untreated TBI (Fig.5e-g, i, k). Example 12 Meningeal lymphatics direct glymphatic outflow to the cervical lymphatics Several studies have reported that meningeal lymphatic vessels are chiefly responsible for collecting brain waste before emptying into cervical lymphatic vessels13,32. 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E., Jr. Development of a model of a multi-lymphangion lymphatic vessel incorporating realistic and measured parameter values. Biomech Model Mechanobiol 13, 401-416, doi:10.1007/s10237- 013-0505-0 (2014). The foregoing examples and description of the preferred embodiments should be taken as illustrating, rather than as limiting the present disclosure as defined by the claims. UR 6-23116 /FR: 161118.05100 As will be readily appreciated, numerous variations and combinations of the features set forth above can be utilized without departing from the present disclosure as set forth in the claims. Such variations are not regarded as a departure from the scope of the disclosure, and all such variations are intended to be included within the scope of the following claims. All references cited herein are incorporated by reference in their entireties.

Claims

UR 6-23116 /FR: 161118.05100 CLAIMS WHAT IS CLAIMED IS: 1. A method for treating a cerebral edema or a brain injury, comprising administering to a subject in need thereof an effective amount of one or more adrenergic antagonists. 2. A method for improving glymphatic-lymphatic efflux from the central nervous system (CNS) of a subject, comprising administering to a subject in need thereof an effective amount of one or more adrenergic antagonists. 3. A method for promoting clearance of a substance from the CNS interstitium, brain interstitium and/or spinal cord interstitium of a subject, comprising administering to a subject in need thereof an effective amount of one or more adrenergic antagonists. 4. The method of claim 3, wherein the substance comprises a fluid or a solute. 5. The method of claim 4, wherein the substance comprises amyloid β (Aβ), tau, or alpha synuclein. 6. The method of claim 4, wherein the substance comprises a drug or a metabolite thereof. 7. The method of any one of the preceding claims, wherein the one or more adrenergic antagonists are administered systemically. 8. The method of any one of the preceding claims, wherein said administering comprises administering to the subject (A) one or more α adrenergic antagonists and (B) one or more β adrenergic antagonists. 9. The method of claim 8, wherein the α adrenergic antagonists are selected from the group consisting of an α1 adrenergic antagonist and an α2 adrenergic antagonist. 10. The method of claim 8, wherein the β adrenergic antagonists are selected from the group consisting of a β1 adrenergic antagonist, a β2 adrenergic antagonist, and a β3 adrenergic antagonist. 11. The method of any one of the preceding claims, wherein said administering comprises administering to the subject (i) an α1 adrenergic antagonist, (ii) an α2 adrenergic antagonist, and (iii) a β adrenergic antagonist. 12. The method of claim 9 or 11, wherein the α1 adrenergic antagonist is selected from the group consisting of Acepromazine, Alfuzosin, Doxazosin, Phenoxybenzamine, Phentolamine, Prazosin, Tamsulosin, Terazosin, Trazodone, Clomipramine, Doxepin, Trimipramine, Antihistamines, Hydroxyzine, 5-methyl urapidil, chloroethylclonidine, UR 6-23116 /FR: 161118.05100 bunazosin, RS17053, L-765,314, nicergoline, ABT-866, cyclazosin, A322312, A 119637, fiduxosin, JTH-601, WB4101, niguldipine, KMD3213, and UIC 14304. 13. The method of claim 9 or 11, wherein the α2 adrenergic antagonist is selected from the group consisting of Phenoxybenzamine, Phentolamine, Yohimbine, Idazoxan, Atipamezole, and Trazodone. 14. The method of claim 10 or 11, wherein the β1 adrenergic antagonist is selected from the group consisting of Metoprolol, Atenolol, Bisoprolol, Propranolol, Timolol, Nebivolol, and Vortioxetine. 15. The method of claim 10 or 11, wherein the β2 adrenergic antagonist is selected from the group consisting of Butoxamine, Timolol, Propranolol, ICI-118,551, H35/25, prenaterol, 4- and 5-[2-hydroxy-3-(isopropylamino)propoxy]benzimidazoles, 1-(t-butyl-amino-3-ol-2- propyl)oximino-9 fluorene, and 2-(α-hydroxyarylmethyl)-3,3-dimethylaziridines. 16. The method of claim 10 or 11, wherein the β3 adrenergic antagonist is selected from the group consisting of L-748,328, L-748,337 and SR 59230A. 17. The method of any one of the preceding claims, wherein the brain injury is a traumatic brain injury or an acute brain injury. 18. The method of claim 17, wherein the traumatic brain injury is an acute traumatic brain injury. 19. The method of claim 18, wherein the acute traumatic brain injury results from closed head trauma. 20. The method of claim 18, wherein the acute traumatic brain injury results from open head and/or penetrating injury-induced trauma. 21. The method of any one of the preceding claims, wherein the subject is a mammal. 22. The method of claim 21, wherein the mammal is a human.
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