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WO2025034510A1 - Antagonistes adrénergiques destinés à être utilisés dans une méthode de traitement d'un œdème cérébral ou d'une lésion cérébrale - Google Patents

Antagonistes adrénergiques destinés à être utilisés dans une méthode de traitement d'un œdème cérébral ou d'une lésion cérébrale Download PDF

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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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tbi
adrenergic
brain
ppa
injury
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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

La présente divulgation concerne le traitement de lésions cérébrales et d'états ou de troubles associés.
PCT/US2024/040536 2023-08-04 2024-08-01 Antagonistes adrénergiques destinés à être utilisés dans une méthode de traitement d'un œdème cérébral ou d'une lésion cérébrale Pending WO2025034510A1 (fr)

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Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4110449A (en) 1977-05-23 1978-08-29 E. R. Squibb & Sons, Inc. 2-substituted benzisothiazol-3-ones
US4760071A (en) 1984-02-27 1988-07-26 Merck & Co., Inc. 17β-N-monosubstituted carbamoyl-4-aza-5α-androst-1-en-3-ones which are active as testosterone 5α-reductase inhibitors
US4908387A (en) 1988-06-06 1990-03-13 The Regents Of The University Of California Use of beta2 antagonists in the treatment of inflammatory diseases, in particular, rheumatoid arthritis
US5403847A (en) 1992-11-13 1995-04-04 Synaptic Pharmaceutical Corporation Use of α1C specific compounds to treat benign prostatic hyperlasia
US5620993A (en) 1995-06-07 1997-04-15 Merck & Co., Inc. Alpha-1a adrenergic receptor antagonists
US5661163A (en) 1995-06-07 1997-08-26 Merck & Co., Inc. Alpha-1a adrenergic receptor antagonists
US5807856A (en) 1995-11-15 1998-09-15 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonist
US6071915A (en) 1997-05-12 2000-06-06 Ortho-Mcneil Pharmaceutical, Inc. Arylsubstituted piperazines useful in the treatment of benign prostatic hyperplasia
US6124319A (en) 1997-01-21 2000-09-26 Merck & Co., Inc. 3,3-disubstituted piperidines as modulators of chemokine receptor activity
US6358959B1 (en) 1999-01-26 2002-03-19 Merck & Co., Inc. Polyazanaphthalenone derivatives useful as alpha 1a adrenoceptor antagonists
US6399614B1 (en) 1997-08-01 2002-06-04 Recordati S.A. Chemical And Pharmaceutical Company 1-(N-phenylaminoalkyl)piperazine derivatives substituted at position 2 of the phenyl ring
US6468798B1 (en) 1991-12-17 2002-10-22 The Regents Of The University Of California Expression of cloned genes in the lung by aerosol and liposome-based delivery
US6894052B1 (en) 1997-08-01 2005-05-17 Recordati S.A. Chemical And Pharmaceutical Company Diarylalkylpiperazines active on the lower urinary tract
WO2010099546A1 (fr) * 2006-08-23 2010-09-02 The University Of Montana Procédé de réduction de dommages ou de la mort de cellules cérébrales
US20110195974A1 (en) 2007-08-24 2011-08-11 Rekha Bansal Methods of treating inflammatory conditions with adrenergic antagonists
US20220049306A1 (en) 2011-08-05 2022-02-17 Genincode Uk, Ltd. Cardiovascular disease
US20220117921A1 (en) 2018-11-01 2022-04-21 Imuneks Farma Ilac Sanayi Ve Ticaret A.S. Pharmaceutical combinations for the treatment of pain
US20220218630A1 (en) 2019-06-10 2022-07-14 Jenivision Inc. Methods and formulations for treating vision disorders
US20220267269A1 (en) 2019-06-14 2022-08-25 Srx Cardio, Llc Compounds for the modulation of proprotein convertase subtilisin/kexin type 9 (pcsk9)
US20220362055A1 (en) 2021-05-14 2022-11-17 Glaukos Corporation Materials and methods for punctal plugs
US20220364184A1 (en) 2019-09-27 2022-11-17 Dana-Farber Cancer Institute, Inc. Compositions and methods for treatment of a poor prognosis subtype of colorectal cancer

Patent Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4110449A (en) 1977-05-23 1978-08-29 E. R. Squibb & Sons, Inc. 2-substituted benzisothiazol-3-ones
US4760071A (en) 1984-02-27 1988-07-26 Merck & Co., Inc. 17β-N-monosubstituted carbamoyl-4-aza-5α-androst-1-en-3-ones which are active as testosterone 5α-reductase inhibitors
US4908387A (en) 1988-06-06 1990-03-13 The Regents Of The University Of California Use of beta2 antagonists in the treatment of inflammatory diseases, in particular, rheumatoid arthritis
US6468798B1 (en) 1991-12-17 2002-10-22 The Regents Of The University Of California Expression of cloned genes in the lung by aerosol and liposome-based delivery
US5403847A (en) 1992-11-13 1995-04-04 Synaptic Pharmaceutical Corporation Use of α1C specific compounds to treat benign prostatic hyperlasia
US5620993A (en) 1995-06-07 1997-04-15 Merck & Co., Inc. Alpha-1a adrenergic receptor antagonists
US5661163A (en) 1995-06-07 1997-08-26 Merck & Co., Inc. Alpha-1a adrenergic receptor antagonists
US5807856A (en) 1995-11-15 1998-09-15 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonist
US6124319A (en) 1997-01-21 2000-09-26 Merck & Co., Inc. 3,3-disubstituted piperidines as modulators of chemokine receptor activity
US6593474B1 (en) 1997-05-12 2003-07-15 Ortho-Mcneil Pharmaceutical, Inc. Arylsubstituted piperazines useful in the treatment of benign prostatic hyperplasia
US6071915A (en) 1997-05-12 2000-06-06 Ortho-Mcneil Pharmaceutical, Inc. Arylsubstituted piperazines useful in the treatment of benign prostatic hyperplasia
US6890921B1 (en) 1997-05-12 2005-05-10 Ortho-Mcneil Pharmaceutical, Inc. Arylsubstituted piperazines useful in the treatment of benign prostatic hyperplasia
US6399614B1 (en) 1997-08-01 2002-06-04 Recordati S.A. Chemical And Pharmaceutical Company 1-(N-phenylaminoalkyl)piperazine derivatives substituted at position 2 of the phenyl ring
US6894052B1 (en) 1997-08-01 2005-05-17 Recordati S.A. Chemical And Pharmaceutical Company Diarylalkylpiperazines active on the lower urinary tract
US6358959B1 (en) 1999-01-26 2002-03-19 Merck & Co., Inc. Polyazanaphthalenone derivatives useful as alpha 1a adrenoceptor antagonists
WO2010099546A1 (fr) * 2006-08-23 2010-09-02 The University Of Montana Procédé de réduction de dommages ou de la mort de cellules cérébrales
US20110195974A1 (en) 2007-08-24 2011-08-11 Rekha Bansal Methods of treating inflammatory conditions with adrenergic antagonists
US20220049306A1 (en) 2011-08-05 2022-02-17 Genincode Uk, Ltd. Cardiovascular disease
US20220117921A1 (en) 2018-11-01 2022-04-21 Imuneks Farma Ilac Sanayi Ve Ticaret A.S. Pharmaceutical combinations for the treatment of pain
US20220218630A1 (en) 2019-06-10 2022-07-14 Jenivision Inc. Methods and formulations for treating vision disorders
US20220267269A1 (en) 2019-06-14 2022-08-25 Srx Cardio, Llc Compounds for the modulation of proprotein convertase subtilisin/kexin type 9 (pcsk9)
US20220364184A1 (en) 2019-09-27 2022-11-17 Dana-Farber Cancer Institute, Inc. Compositions and methods for treatment of a poor prognosis subtype of colorectal cancer
US20220362055A1 (en) 2021-05-14 2022-11-17 Glaukos Corporation Materials and methods for punctal plugs

Non-Patent Citations (84)

* Cited by examiner, † Cited by third party
Title
"Global Burden of Disease Study", LANCET NEURAL, vol. 18, 2016, pages 56 - 87
AHN, J. H. ET AL.: "Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid", NATURE, vol. 572, 2019, pages 62 - 66, XP036848584, DOI: 10.1038/s41586-019-1419-5
AZUMA, M.LEE, H.SHINZAKI, K.YAMANE, R.MORITA, M.: "Cortical-wide impairment of ''The Glymphatic system'' after focal brain injury", BIORXIV, 2022
BERGE ET AL.: "describe pharmaceutically acceptable salts in detail in", J. PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19
BERTRAM, C. D.MACASKILL, C.DAVIS, M. J.MOORE, J. E., JR.: "Development of a model of a multi-lymphangion lymphatic vessel incorporating realistic and measured parameter values", BIOMECH MODEL MECHANOBIOL, vol. 13, 2014, pages 401 - 416
BERTRAM, C. D.MACASKILL, C.MOORE, J. E., JR.: "Simulation of a chain of collapsible contracting lymphangions with progressive valve closure", J BIOMECH ENG, vol. 133, 2011
BOLTE, A. C. ET AL.: "Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis", NATURE COMMUNICATIONS, vol. 11, 2020, pages 4524
BRASSARD, P.SEIFERT, T.SECHER, N. H.: "Is cerebral oxygenation negatively affected by infusion of norepinephrine in healthy subjects?", BR J ANAESTH, vol. 102, 2009, pages 800 - 805
CASTORENA-GONZALEZ, J. A. ET AL.: "Mechanisms of Connexin-Related Lymphedema", CIRC RES, vol. 123, 2018, pages 964 - 985
CHERIAN, I. ET AL.: "Introducing the concept of ''CSF-shift edema'' in traumatic brain injury", J NEUROSCI RES, vol. 96, 2018, pages 744 - 752
CLIFTON, G. L.ZIEGLER, M. G.GROSSMAN, R. G.: "Circulating catecholamines and sympathetic activity after head injury", NEUROSURGERY, vol. 8, 1981, pages 10 - 14
CORTES, D.PERA, M. F.: "The genetic basis of inter-individual variation in recovery from traumatic brain injury", NPJ REGENERATIVE MEDICINE, vol. 6, 2021, pages 5
DA MESQUITA, S. ET AL.: "Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease", NATURE, vol. 560, 2018, pages 185 - 191, XP036629657, DOI: 10.1038/s41586-018-0368-8
DEWAN, M. C. ET AL.: "Estimating the global incidence of traumatic brain injury", J NEUROSURG, 2018, pages 1 - 18
FLIERL ET AL., NAT PROTOC, vol. 4, 2009, pages 1328 - 1337
GEORGE, K. C.KEBEJIAN, L.RUTH, L. J.MILLER, C. W.HIMELHOCH, S.: "Meta-analysis of the efficacy and safety of prazosin versus placebo for the treatment of nightmares and sleep disturbances in adults with posttraumatic stress disorder", J TRAUMA DISSOCIATION, vol. 17, 2016, pages 494 - 510
GOLDMAN-RAKIC, P. S.LIDOW, M. S.GALLAGER, D. W.: "Overlap of dopaminergic, adrenergic, and serotoninergic receptors and complementarity of their subtypes in primate prefrontal cortex", THE JOURNAL OF NEUROSCIENCE : THE OFFICIAL JOURNAL OF THE SOCIETY FOR NEUROSCIENCE, vol. 10, 1990, pages 2125 - 2138
GOLDSTEIN, D. S. ET AL.: "Effect of ganglion blockade on cerebrospinal fluid norepinephrine", J NEUROCHEM, vol. 49, 1987, pages 1484 - 1490
HABLITZ, L. M. ET AL.: "Circadian control of brain glymphatic and lymphatic fluid flow", NATURE COMMUNICATIONS, vol. 11, 2020, pages 4411
HABLITZ, L. M. ET AL.: "Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia", SCI ADV, vol. 5, 2019, pages eaav5447, XP055664019, DOI: 10.1126/sciadv.aav5447
HAMILL, R. W.WOOLF, P. D.MCDONALD, J. V.LEE, L. A.KELLY, M.: "Catecholamines predict outcome in traumatic brain injury", ANNALS OF NEUROLOGY, vol. 21, 1987, pages 438 - 443
HAMM, R. J. ET AL., JOURNAL OF NEUROTRAUMA, vol. 11, 1994, pages 187 - 196
HUSSAIN RASHAD ET AL: "Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema", NATURE, vol. 623, no. 7989, 15 November 2023 (2023-11-15), pages 992 - 1000, XP093217028, ISSN: 0028-0836, Retrieved from the Internet <URL:https://www.nature.com/articles/s41586-023-06737-7> DOI: 10.1038/s41586-023-06737-7 *
HUSSAIN, R. ET AL., J NEUROSCI, vol. 37, 2017, pages 397 - 412
ILIFF JEFFREY J. ET AL: "Impairment of Glymphatic Pathway Function Promotes Tau Pathology after Traumatic Brain Injury", THE JOURNAL OF NEUROSCIENCE, vol. 34, no. 49, 3 December 2014 (2014-12-03), US, pages 16180 - 16193, XP093217030, ISSN: 0270-6474, Retrieved from the Internet <URL:https://www.jneurosci.org/content/jneuro/34/49/16180.full.pdf> DOI: 10.1523/JNEUROSCI.3020-14.2014 *
ILIFF, J. J. ET AL.: "A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta", SCIENCE TRANSLATIONAL MEDICINE, vol. 4, 2012, pages 147ra111, XP055290916, DOI: 10.1126/scitranslmed.3003748
ILIFF, J. J. ET AL.: "Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury", THE JOURNAL OF NEUROSCIENCE : THE OFFICIAL JOURNAL OF THE SOCIETY FOR NEUROSCIENCE, vol. 34, 2014, pages 16180 - 16193
JAMALIAN, S.BERTRAM, C. D.RICHARDSON, W. J.MOORE, J. E., JR.: "Parameter sensitivity analysis of a lumped-parameter model of a chain of lymphangions in series", AM J PHYSIOLHEART CIRC PHYSIOL, vol. 305, 2013, pages H1709 - H1717
JOHANSSON, P. I. ET AL.: "Elderly trauma patients have high circulating noradrenaline levels but attenuated release of adrenaline, platelets, and leukocytes in response to increasing injury severity", CRIT CARE MED, vol. 40, 2012, pages 1844 - 1850
KANG, R. ET AL.: "Intraoperative dexmedetomidine attenuates norepinephrine levels in patients undergoing transsphenoidal surgery: a randomized, placebo-controlled trial", BMC ANESTHESIOLOGY, vol. 20, 2020, pages 100
KELLEY, D. H.OUELLETTE, N. T.: "Using particle tracking to measure flow instabilities in an undergraduate laboratory experiment", AMERICAN JOURNAL OF PHYSICS, vol. 79, 2011, pages 267 - 273
KO, A. ET AL.: "Early propranolol after traumatic brain injury is associated with lower mortality", J TRAUMA ACUTE CARE SURG, vol. 80, 2016, pages 637 - 642
LAINE, G. A.ALLEN, S. J.KATZ, J.GABEL, J. C.DRAKE, R. E.: "Effect of systemic venous pressure elevation on lymph flow and lung edema formation", J APPLPHYSIOL, vol. 61, 1985, pages 1634 - 1638
LEANDOER, L.LEWIS, D. H.: "The effect of L-norepinephrine on lymph flow in man", ANN SURG, vol. 171, 1970, pages 257 - 260
LEY, E. J. ET AL.: "The in vivo effect of propranolol on cerebral perfusion and hypoxia after traumatic brain injury", J TRAUMA, vol. 66, 2009, pages 154 - 159
LIEBE, T. ET AL.: "Ketamine influences the locus coeruleus norepinephrine network, with a dependency on norepinephrine transporter genotype - a placebo controlled fMRI study", NEUROIMAGE CLIN, vol. 20, 2018, pages 715 - 723
LIU, G. ET AL.: "Direct Measurement of Cerebrospinal Fluid Production in Mice", CELL REPORTS, vol. 33, 2020, pages 108524
LIU, X. ET AL.: "Subdural haematomas drain into the extracranial lymphatic system through the meningeal lymphatic vessels", ACTA NEUROPATHOL COMMUN, vol. 8, 2020, pages 16, XP021273817, DOI: 10.1186/s40478-020-0888-y
LLOYD-DONALD, P. ET AL.: "In adult patients with severe traumatic brain injury, does the use of norepinephrine for augmenting cerebral perfusion pressure improve neurological outcome? A systematic review", INJURY, vol. 51, 2020, pages 2129 - 2134, XP086259466, DOI: 10.1016/j.injury.2020.07.054
LOUVEAU, A. ET AL.: "CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature", NATURE NEUROSCIENCE, vol. 21, 2018, pages 1380 - 1391, XP036929121, DOI: 10.1038/s41593-018-0227-9
MANNIX, R. ET AL.: "Clinical correlates in an experimental model of repetitive mild brain injury", ANNALS OF NEUROLOGY, vol. 74, 2013, pages 65 - 75, XP071641050, DOI: 10.1002/ana.23858
MANTYH, P. ET AL.: "Beta 2-adrenergic receptors are expressed by glia in vivo in the normal and injured central nervous system in the rat, rabbit, and human", THE JOURNAL OF NEUROSCIENCE, vol. 15, 1995, pages 152 - 164
MAWHINNEY, H. J.RODDIE, I. C.: "Spontaneous activity in isolated bovine mesenteric lymphatics", JPHYSIOL, vol. 229, 1973, pages 339 - 348
MAYUR B PATEL ET AL: "Decreasing adrenergic or sympathetic hyperactivity after severe traumatic brain injury using propranolol and clonidine (DASH After TBI Study): study protocol for a randomized controlled trial", TRIALS, BIOMED CENTRAL, LONDON, GB, vol. 13, no. 1, 26 September 2012 (2012-09-26), pages 177, XP021129511, ISSN: 1745-6215, DOI: 10.1186/1745-6215-13-177 *
MCKEE, A. C.: "The spectrum of disease in chronic traumatic encephalopathy.", BRAIN, vol. 136, 2013, pages 43 - 64, XP055422672, DOI: 10.1093/brain/aws307
MESTRE, H. ET AL.: "Cerebrospinal fluid influx drives acute ischemic tissue swelling", SCIENCE, 2020
MESTRE, H. ET AL.: "Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension", NATURE COMMUNICATIONS, vol. 9, 2018, pages 4878
MIN RIVAS, F. ET AL., JR SAC INTERFACE, vol. 17, 2020, pages 20200593
MIN RIVAS, F. ET AL., JR SOC INTERFACE, vol. 17, 2020, pages 20200593
MIN RIVAS, F. ET AL.: "Surface periarterial spaces of the mouse brain are open, not porous", J R SAC INTERFACE, vol. 17, 2020, pages 20200593
MONAI HIROMU ET AL: "Adrenergic receptor antagonism induces neuroprotection and facilitates recovery from acute ischemic stroke", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 116, no. 22, 28 May 2019 (2019-05-28), pages 11010 - 11019, XP055930708, ISSN: 0027-8424, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561179/pdf/pnas.201817347.pdf> DOI: 10.1073/pnas.1817347116 *
MONAI, H. ET AL.: "Adrenergic receptor antagonism induces neuroprotection and facilitates recovery from acute ischemic stroke", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 116, 2019, pages 11010 - 11019, XP055930708, DOI: 10.1073/pnas.1817347116
NEMOTO, E. M.: "Dynamics of cerebral venous and intracranial pressures", ACTA NEUROCHIR SUPPL, vol. 96, 2006, pages 435 - 437
NEUMANN, H.KOTTER, M. R.FRANKLIN, R. J.: "Debris clearance by microglia: an essential link between degeneration and regeneration", BRAIN, vol. 132, 2009, pages 288 - 295
NISSINEN JARI ET AL: "Disease-modifying effect of atipamezole in a model of post-traumatic epilepsy", EPILEPSY RESEARCH, ELSEVIER SCIENCE PUBLISHERS , AMSTERDAM, NL, vol. 136, 12 July 2017 (2017-07-12), pages 18 - 34, XP085194637, ISSN: 0920-1211, DOI: 10.1016/J.EPLEPSYRES.2017.07.005 *
NISSINEN, J. ET AL.: "Disease-modifying effect of atipamezole in a model of post-traumatic epilepsy", EPILEPSY RES, vol. 136, 2017, pages 18 - 34, XP085194637, DOI: 10.1016/j.eplepsyres.2017.07.005
NORDNESS MINA F. ET AL: "Effect of propranolol and clonidine after severe traumatic brain injury: a pilot randomized clinical trial", CRITICAL CARE, vol. 27, no. 1, 9 June 2023 (2023-06-09), GB, XP093217126, ISSN: 1364-8535, Retrieved from the Internet <URL:https://link.springer.com/article/10.1186/s13054-023-04479-6/fulltext.html> DOI: 10.1186/s13054-023-04479-6 *
OHKURA, M. ET AL.: "Genetically encoded green fluorescent Ca2+ indicators with improved detectability for neuronal Ca2+ signals", PLOS ONE, vol. 7, 2012, pages e51286
PASHKOV, V. N.HEMMINGS, H. C., JR.: "The effects of general anesthetics on norepinephrine release from isolated rat cortical nerve terminals", ANESTH ANALG, vol. 95, 2002, pages 1274 - 1281
PATEL, M. B.: "Decreasing adrenergic or sympathetic hyperactivity after severe traumatic brain injury using propranolol and clonidine (DASH After TBI Study): study protocol for a randomized controlled trial.", TRIALS, vol. 13, 2012, pages 177, XP021129511, DOI: 10.1186/1745-6215-13-177
PETRAGLIA ET AL., J NEUROTRAUMA, vol. 31, 2014, pages 1211 - 1224
PITKANEN, A.NARKILAHTI, S.BEZVENYUK, Z.HAAPALINNA, A.NISSINEN, J.: "Atipamezole, an alpha(2)-adrenoceptor antagonist, has disease modifying effects on epileptogenesis in rats", EPILEPSY RES, vol. 61, 2004, pages 119 - 140, XP027185986
PLA, V. ET AL.: "A real-time in vivo clearance assay for quantification of glymphatic efflux", CELL REPORTS, vol. 40, 2022, pages 111320
PLOG, B. A. ET AL., JCI INSIGHT, vol. 3, 2018
PLOG, B. A. ET AL., THE JOURNAL OF NEUROSCIENCE: THE OFFICIAL JOURNAL OF THE SOCIETY FOR NEUROSCIENCE, vol. 35, 2015, pages 518 - 526
PLOG, B. A. ET AL.: "Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system", THE JOURNAL OF NEUROSCIENCE : THE OFFICIAL JOURNAL OF THE SOCIETY FOR NEUROSCIENCE, vol. 35, 2015, pages 518 - 526
PLOG, B. A. ET AL.: "Transcranial optical imaging reveals a pathway for optimizing the delivery of immunotherapeutics to the brain", JCIINSIGHT, vol. 3, 2018, XP055664423, DOI: 10.1172/jci.insight.120922
RAUCH, S. ET AL.: "Severe traumatic brain injury and hypotension is a frequent and lethal combination in multiple trauma patients in mountain areas - an analysis of the prospective international Alpine Trauma Registry", SCAND J TRAUMA RESUSC EMERG MED, vol. 29, 2021, pages 61
REN, Z. ET AL.: "Hit & Run' model of closed-skull traumatic brain injury (TBI) reveals complex patterns of post-traumatic AQP4 dysregulation", JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM : OFFICIAL JOURNAL OF THE INTERNATIONAL SOCIETY OF CEREBRAL BLOOD FLOW AND METABOLISM, vol. 33, 2013, pages 834 - 845
RIZOLI, S. B. ET AL.: "Catecholamines as outcome markers in isolated traumatic brain injury: the COMA-TBI study", CRITICAL CARE, vol. 21, 2017, pages 37
SELLAPPAN, P. ET AL.: "Variability and uncertainty in the rodent controlled cortical impact model of traumatic brain injury", JOURNAL OF NEUROSCIENCE METHODS, vol. 312, 2019, pages 37 - 42, XP085565294, DOI: 10.1016/j.jneumeth.2018.10.027
SI, J.CHEN, L.XIA, Z.: "Effects of cervical-lymphatic blockade on brain edema and infarction volume in cerebral ischemic rats", CHIN J PHYSIOL, vol. 49, 2006, pages 258 - 265
TSCHUOR, C. ET AL.: "In vitro norepinephrine significantly activates isolated platelets from healthy volunteers and critically ill patients following severe traumatic brain injury", CRIT CARE, vol. 12, 2008, pages R80, XP021041457
TUCKER, B. ET AL.: "Early Brain Edema is a Predictor of In-Hospital Mortality in Traumatic Brain Injury", J EMERG MED, vol. 53, 2017, pages 18 - 29, XP085154471, DOI: 10.1016/j.jemermed.2017.02.010
URSANO, R. J. ET AL.: "Practice guideline for the treatment of patients with acute stress disorder and posttraumatic stress disorder", AM J PSYCHIATRY, vol. 161, 2004, pages 3 - 31
VORHEESWILLIAMS, NATURE PROTOCOLS, vol. 1, 2010, pages 848 - 858
WALSH J CLIN SLEEP MED., vol. 5, no. 2, 15 April 2009 (2009-04-15), pages S27 - S32
WANG, L. ET AL.: "Deep cervical lymph node ligation aggravates AD-like pathology of APP/PS1 mice", BRAIN PATHOL, vol. 29, 2019, pages 176 - 192
WEIKOP, P.KEHR, J.SCHEEL-KRUGER, J.: "Reciprocal effects of combined administration of serotonin, noradrenaline and dopamine reuptake inhibitors on serotonin and dopamine levels in the rat prefrontal cortex: the role of 5-HT1A receptors", J PSYCHOPHARMACOL, vol. 21, 2007, pages 795 - 804
WOLMAN, M. ET AL.: "Evaluation of the dye-protein tracers in pathophysiology of the blood-brain barrier", ACTA NEUROPATHOL, vol. 54, 1981, pages 55 - 61
WOOLF, P. D.HAMILL, R. W.LEE, L. A.COX, C.MCDONALD, J. V.: "The predictive value of catecholamines in assessing outcome in traumatic brain injury", J NEUROSURG, vol. 66, 1987, pages 875 - 882
XIE, L. ET AL.: "Sleep drives metabolite clearance from the adult brain", SCIENCE, vol. 342, 2013, pages 373 - 377, XP055312252, DOI: 10.1126/science.1241224
XIONG, Y.MAHMOOD, A.CHOPP, M.: "Animal models of traumatic brain injury", NAT REV NEUROSCI, vol. 14, 2013, pages 128 - 142
ZOU, W. ET AL.: "Blocking meningeal lymphatic drainage aggravates Parkinson's disease-like pathology in mice overexpressing mutated α-synuclein", TRANSL NEURODEGENER, vol. 8, 2019, pages 7

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