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WO2021225349A1 - Composition pour prévenir ou traiter un traumatisme crânien - Google Patents

Composition pour prévenir ou traiter un traumatisme crânien Download PDF

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Publication number
WO2021225349A1
WO2021225349A1 PCT/KR2021/005583 KR2021005583W WO2021225349A1 WO 2021225349 A1 WO2021225349 A1 WO 2021225349A1 KR 2021005583 W KR2021005583 W KR 2021005583W WO 2021225349 A1 WO2021225349 A1 WO 2021225349A1
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Prior art keywords
head trauma
pharmaceutical composition
treatment
preventing
nlrp3
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Korean (ko)
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양승호
이정은
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Industry Academic Cooperation Foundation of Catholic University of Korea
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Industry Academic Cooperation Foundation of Catholic University of Korea
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)

Definitions

  • the present invention relates to a composition for preventing or treating head trauma.
  • TBI head trauma or traumatic brain injury
  • TBI is an injury caused by an external physical force applied to the head, which causes a decrease or change in consciousness, thereby causing impairment of cognitive or physical function. It can also cause behavioral problems or emotional damage. These impairments or disorders may be temporary or permanent, and may result in damage to parts of the body or impairment of all functions or psycho-psychological problems.
  • TBI is classified into mild, moderate, and severe according to the severity of the injury. People with mild TBI may remain conscious, or may experience loss of consciousness for seconds or minutes. or headache, confusion, lightheadedness, dizziness, blurred vision, eye strain, ringing in the ears, changes in behavior or mood, difficulty remembering, concentrating, paying attention, or thinking. People with moderate or severe TBI may have these same symptoms.
  • TBI can be divided into primary damage caused by shock and damage to the scalp, skull and brain, and secondary damage resulting from pathophysiological processes in the body.
  • Primary damage is invasive TBI (penetrating, open TBI) and non Invasive TBI (nonpenetrating, closed-TBI) can be divided, and invasive TBI is more severe than non-invasive TBI.
  • secondary damage after TBI is divided into acute and chronic phases.
  • TBI cerebral edema
  • the impairments caused by TBI may vary depending on the severity of the injury, the location of the injury, and the age and health of the patient. , touch, taste and smell), communication disorders (expression and understanding), and behavioral or mental health disorders (depression, anxiety, personality transformation, aggression and social inadequacy).
  • TBI patients receive rehabilitation treatment such as physical therapy, occupational therapy, and speech therapy.
  • the rehabilitation treatment has a disadvantage in that the rate of improvement of the disability is slow. Therefore, there is a need for a technology that can more effectively treat TBI.
  • Cerebral edema an acute disease caused by invasive TBI, is a phenomenon in which water flows into cells or tissues and enlarges the brain tissue, which increases intracranial pressure. Due to the increased pressure, the pressure on the brain damage area increases, and in severe cases, brain herniation occurs, leading to death. Cerebral edema is a phenomenon that has received general attention in the study of vascular targets, has little to do with nerve cells, and can be recognized as a result of pathological mechanisms closely related to blood vessels. According to a previous report, it is known that brain damage can be reduced by 50% just by lowering the intracranial pressure induced by cerebral edema (Gerriets T et al., 2009, Walberer M et al., 2008).
  • the treatment for brain edema is a hyperosmolar solution using osmotic pressure, craniectomy as a surgical treatment, and an osmotic regulator such as mannitol are used (Papadopoulos et al., 2002, Hutchinson et al.) al., 2007).
  • an osmotic regulator such as mannitol
  • nucleic acid-binding oligomerization domain-like receptors are generally flanked by a C-terminal goleucine repeat (LRR) domain and an N-terminal effector pyrin domain (PYD) or caspase recruitment domain (CARD), It is an evolutionarily conserved family of cytosolic receptors with tripartite structures that share a common central nucleic acid binding and oligomerization (NACHT) domain.
  • LRR goleucine repeat
  • PYD N-terminal effector pyrin domain
  • CARD caspase recruitment domain
  • NSRs form inflammasome complexes (inflammasomes) by oligomerizing and recruiting the adapter protein ASC and the cysteine protease propaspase-1, and are self-catalyzed. action and induce the activity of caspase-1. Active caspase-1 ultimately cleaves the precursor pro-inflammatory cytokines pro-IL-1 ⁇ and pro-IL-18 to a mature secreted form.
  • Another object of the present invention is to provide a pharmaceutical composition for the prevention and treatment of cerebral edema.
  • Another object of the present invention is to provide a method for screening a candidate for treatment of head trauma.
  • another object of the present invention is to provide a method for preventing or treating head trauma, comprising administering to an individual a pharmaceutically effective amount of the pharmaceutical composition.
  • another object of the present invention is to provide a method for preventing or treating cerebral edema, comprising administering to an individual a pharmaceutically effective amount of the pharmaceutical composition.
  • the present invention provides a pharmaceutical composition for preventing and treating head trauma containing pioglitazone as an active ingredient.
  • the present invention provides a pharmaceutical composition for the prevention and treatment of cerebral edema containing pioglitazone as an active ingredient.
  • the present invention also provides a method of reducing or inhibiting NLRP3 expression in vitro comprising treating pioglitazone.
  • the present invention provides a method for screening a candidate for treatment of head trauma.
  • the present invention provides a method for assaying the effect of a therapeutic agent for head trauma.
  • the present invention provides a method for preventing or treating head trauma, comprising administering to an individual a pharmaceutically effective amount of the pharmaceutical composition.
  • the present invention provides a method for preventing or treating cerebral edema, comprising administering to a subject a pharmaceutically effective amount of the pharmaceutical composition.
  • pioglitazone reduces inflammasome activity and modulates the inflammatory response in astrocytes and microglia.
  • TBI head trauma
  • Figure 2a is a diagram showing the comparison data of the water content of the damaged brain (right hemisphere) and uninjured brain (left hemisphere) in the sham group according to the date after TBI:
  • 2b is a diagram comparing brain water content in the sham group, the NLRP3 K/O group and the pioglitazone-treated group.
  • Figure 3a is a diagram showing the results of Western blot analysis of IL-1 ⁇ , caspase-1, NLRP3, NF- ⁇ B and ERK expression in the NLRP3 K/O group and the pioglitazone-treated group after TBI induction.
  • 3b is a diagram illustrating quantification of the expression level of IL-1 ⁇ in the NLRP3 K/O group and the pioglitazone-treated group after TBI induction.
  • 3c is a diagram illustrating quantification of the expression level of caspase-1 in the NLRP3 K/O group and the pioglitazone-treated group after TBI induction.
  • 3D is a diagram illustrating quantification of the expression level of NLRP3 in the NLRP3 K/O group and the pioglitazone-treated group after TBI induction.
  • 3e is a diagram illustrating quantification of the expression level of NF- ⁇ B in the NLRP3 K/O group and the pioglitazone-treated group after TBI induction.
  • 3f is a diagram illustrating the quantification of the expression level of ERK in the NLRP3 K/O group and the pioglitazone-treated group after TBI induction.
  • FIG. 4 is a view confirming the level of NLRP3 expression after TBI induction in NLRP3 K/O mice treated with pioglitazone.
  • FIG. 5 is a diagram showing the results of immunohistochemical analysis for GFAP and Iba1 in brain tissue on the 3rd day after TBI induction.
  • 6A is a diagram showing the results of immunofluorescence analysis for NLRP3, GFAP and Iba1 in TBI-induced model brain tissue after TBI induction.
  • Figure 6b is a diagram analyzed with a confocal microscope showing the location of NLRP3 3 days after TBI induction.
  • Figure 6c is a diagram confirming the activity of GFAP-positive astrocytes after TBI induction.
  • the present invention relates to a pharmaceutical composition for preventing and treating head trauma containing pioglitazone as an active ingredient.
  • the pharmaceutical composition of the present invention can prevent or treat cerebral edema, which is an acute stage disease (symptom) caused by invasive head trauma.
  • the pharmaceutical composition of the present invention can reduce the intracranial pressure caused by invasive head trauma.
  • the pharmaceutical composition of the present invention can inhibit or reduce the expression of leucine-rich repeat family pyrin domain-containing 3 protein (NLRP3) or the activity of the inflammasome.
  • NLRP3 leucine-rich repeat family pyrin domain-containing 3 protein
  • the pharmaceutical composition of the present invention may further comprise an NLRP3 expression inhibitor.
  • the present invention relates to a pharmaceutical composition for preventing and treating cerebral edema containing pioglitazone as an active ingredient.
  • the pharmaceutical composition of the present invention may further comprise an NLRP3 expression inhibitor.
  • the cerebral edema may be cerebral edema caused by invasive head trauma.
  • beneficial or desirable clinical outcomes include, but are not limited to, alleviation of symptoms, reduction of the extent of the disease, stabilization of the disease state (i.e., not worsening), delay or reduction in rate of disease progression, disease state improvement or temporary alleviation and alleviation (partial or total), detectable or undetectable.
  • Treatment may also mean increasing survival as compared to the expected survival rate if not receiving treatment. “Treatment” refers to both therapeutic treatment and prophylactic or prophylactic methods. Such treatments include the treatment required for the disorder being prevented as well as the disorder that has already occurred. “Palliating” a disease means that the extent and/or undesirable clinical signs of the disease state are reduced and/or the time course of progression is delayed or prolonged, compared to no treatment. means to lose
  • treatment unless otherwise stated, is meant reversing, ameliorating, inhibiting the progression of, or preventing the disease or condition to which the term applies, or one or more symptoms of the disease or condition;
  • treatment as used herein refers to the act of treating when treating is defined as above. Accordingly, treatment or therapy for head trauma in a mammal may include one or more of the following:
  • a composition is indicated to be "pharmaceutically or physiologically acceptable” if the recipient animal can tolerate administration of the composition, or if administration of the composition to that animal is suitable.
  • the agent can be said to have been administered in a "therapeutically effective amount”.
  • An agent is physiologically meaningful if the presence of the agent results in a physiologically detectable change in the recipient patient.
  • an “effective amount” is an amount appropriate to effect beneficial or desirable clinical or biochemical results.
  • An effective amount may be administered one or more times.
  • an effective amount of a promoter is an amount suitable to temporarily alleviate, ameliorate, stabilize, reverse, slow down or delay the progression of the associated disease state.
  • prevention refers to any action that inhibits or delays the occurrence, spread, and recurrence of head trauma or brain edema by administration of the protein or fragment thereof according to the present invention, or a composition comprising the same.
  • the therapeutically effective amount of the composition of the present invention may vary depending on several factors, for example, the administration method, the target site, the condition of the patient, and the like. Therefore, when used in the human body, the dosage should be determined as an appropriate amount in consideration of both safety and efficiency. It is also possible to estimate the amount used in humans from the effective amount determined through animal experiments. These considerations in determining effective amounts are found, for example, in Hardman and Limbird, eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. (2001), Pergamon Press; and E.W. Martin ed., Remington's Pharmaceutical Sciences, 18th ed. (1990), Mack Publishing Co.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level is determined by the patient's Health status, disease type, severity, drug activity, sensitivity to drug, administration method, administration time, administration route and excretion rate, treatment period, factors including drugs used in combination or concurrently, and other factors well-known in the medical field can be determined according to
  • the composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.
  • the pharmaceutical composition of the present invention may include a carrier, diluent, excipient, or a combination of two or more commonly used in biological agents.
  • pharmaceutically acceptable refers to exhibiting non-toxic properties to cells or humans exposed to the composition.
  • the carrier is not particularly limited as long as it is suitable for in vivo delivery of the composition, for example, Merck Index, 13th ed., Merck & Co. Inc.
  • Compounds described in , saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components can be mixed and used as needed. Conventional additives may be added.
  • diluents such as aqueous solutions, suspensions, emulsions, pills, capsules, granules or tablets.
  • injectable formulations such as aqueous solutions, suspensions, emulsions, pills, capsules, granules or tablets.
  • injectable formulations such as aqueous solutions, suspensions, emulsions, pills, capsules, granules or tablets.
  • it can be preferably formulated according to each disease or component using an appropriate method in the art or a method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA, 18th, 1990).
  • the pharmaceutical composition may be one or more formulations selected from the group comprising oral formulations, topical formulations, suppositories, sterile injection solutions and sprays.
  • compositions of the present invention may also include carriers, diluents, excipients or combinations of two or more commonly used in biological agents.
  • the pharmaceutically acceptable carrier is not particularly limited as long as it is suitable for in vivo delivery of the composition, for example, Merck Index, 13th ed., Merck & Co. Inc.
  • Compounds described in , saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components can be mixed and used as needed. Conventional additives may be added.
  • diluents such as aqueous solutions, suspensions, emulsions, pills, capsules, granules or tablets.
  • injectable formulations such as aqueous solutions, suspensions, emulsions, pills, capsules, granules or tablets.
  • injectable formulations such as aqueous solutions, suspensions, emulsions, pills, capsules, granules or tablets.
  • it can be preferably formulated according to each disease or component using an appropriate method in the art or a method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA, 18th, 1990).
  • composition of the present invention may further contain one or more active ingredients exhibiting the same or similar function.
  • the composition of the present invention comprises 0.0001 to 10% by weight of the protein, preferably 0.001 to 1% by weight, based on the total weight of the composition.
  • the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additive includes starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, Lactose, mannitol, syrup, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, Opadry, sodium starch glycolate, lead carnauba, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, stearic acid Calcium, sucrose, dextrose, sorbitol, talc and the like can be used.
  • the pharmaceutically acceptable additive according to the present invention is preferably included in an amount of 0.1 to 90 parts by weight based on the composition, but is not limited thereto.
  • composition of the present invention may be administered parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) or orally according to a desired method, and the dosage may vary depending on the patient's weight, age, sex, health status, The range varies depending on the diet, administration time, administration method, excretion rate, and the severity of the disease.
  • the daily dose of the composition according to the present invention is 0.0001 to 10 mg/ml, preferably 0.0001 to 5 mg/ml, and it is more preferable to divide and administer once to several times a day.
  • Liquid preparations for oral administration of the composition of the present invention include suspensions, internal solutions, emulsions, syrups, etc., and various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. and the like may be included.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories, and the like.
  • the present invention relates to a method of reducing or inhibiting NLRP3 expression in vitro, comprising the step of treating pioglitazone.
  • the present invention comprises the steps of: injecting a target head trauma treatment candidate material to the head trauma animal model; measuring the NLRP3 expression level or inflammasome activity of the experimental group animals injected with the target head trauma treatment candidate substance and the control animals not administered with the same; And when the NLRP3 expression level or inflammasome activity of the experimental group animals is reduced or inhibited compared to the control animals, it relates to a method for screening a head trauma treatment candidate, comprising determining a head trauma treatment agent.
  • the head trauma may be brain edema caused by invasive head trauma.
  • the present invention comprises the steps of: injecting a therapeutic agent for head trauma to the head trauma animal model; measuring the NLRP3 expression level or inflammasome activity of the experimental group animals injected with the head trauma treatment for the purpose of the assay and the positive control animals administered with the existing head trauma treatment; And it relates to a method for assaying the effect of a therapeutic agent for head trauma, comprising comparing the reduction or inhibition of NLRP3 expression level or inflammasome activity of the experimental group animal with a positive control animal.
  • the term “detection” or “measurement” means to quantify the concentration of a detected or measured object.
  • the present invention provides a method for preventing or treating head trauma, comprising administering to an individual a pharmaceutically effective amount of the pharmaceutical composition.
  • the pharmaceutical composition of the present invention is administered in a therapeutically effective amount or a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level depends on the subject type and severity, age, sex, activity of the drug, and the drug. It can be determined according to factors including sensitivity, administration time, administration route and excretion rate, duration of treatment, concurrent drugs, and other factors well known in the medical field.
  • the present invention provides a method for preventing or treating cerebral edema, comprising administering to a subject a pharmaceutically effective amount of the pharmaceutical composition.
  • mice were used as male C57BL/6 mice (6-8 weeks old) and NLRP3 knockout (K/O) male mice (provided by KU Lee), and mice were treated with C57BL/6 (Siamese group), NLRP3 K/O ( K/O group) and pioglitazone-treated mice (treatment group) (10, 20 or 40 mg/kg) (16 mice in each group), head immobilization of the central fall mechanism to induce traumatic brain injury (TBI) Invasive TBI was induced by placing the mouse in the system and dropping 2 g of flat-tipped steel onto the skull from a height of 18 cm (Fig. 1). The sham group performed only right parietal craniotomy without central fall.
  • TBI traumatic brain injury
  • mice were sacrificed on days 1, 3, 7 and 14 of TBI induction. All these procedures were approved by the Animal Care Committee of St. Vincent Hospital, Catholic University of Korea (approval number 16-15).
  • mice in each group were measured after transcardial blood sampling (AccuChek; Roche) for all experimental periods.
  • cerebral edema a major symptom of the acute phase induced by TBI, was evaluated based on water content. Specifically, after euthanizing mice with CO 2 , the brain was removed and the cerebrum was dissected from the brain stem to measure the brain water content in the right (injured) and left (uninjured) hemispheres to function their function. Wet weight was measured. Thereafter, it was dried in an oven at 100° C. and the dry weight was measured. Accordingly, the water content of the brain was calculated by Equation 1 below.
  • Moisture content [(water weight - dry weight)/water weight] ⁇ 100%
  • proteins from each mouse sample were separated through SDS-PAGE gel, transferred to a nitrocellulose membrane, and antibodies against NLRP3, caspase-1, IL-1 ⁇ , ERK and NF- ⁇ (Cell Signaling Technology) and control antibody ⁇ It was detected with -actin (Sigma-Aldrich), and immunoreactivity was detected by ELC (enhanced chemiluminescence), and then analyzed using an imaging densitometer. The density of each band was measured using Quantity One software (Bio-Rad).
  • IL-1 ⁇ and NLRP3 in the sham group increased on the 3rd day of TBI induction, and the expression levels of caspase-1, NF- ⁇ and ERK were higher on the 1st day than on the 3rd, 7th and 14th days (Fig. 3a).
  • NLRP3 expression did not appear in NLRP3 K/O mice treated with pioglitazone ( FIG. 4 ), suggesting that pioglitazone exerts its therapeutic effect on brain edema through NLRP3.
  • glial fibrillary acidic protein GFAP
  • Iba1 1:1000, Cell Signaling) Technology
  • ⁇ -actin 1:2000, Sigma-Aldrich
  • NLRP3 and GFAP were immunofluorescently analyzed using tyramide signal amplification fluorescence (Perkin Elmer), observed with a confocal microscope (CarlZeiss LSM 700), and samples were analyzed using Image ZEN 2009 Light Edition software (version 1.0). did.
  • GFAP expression was also lower in the pioglitazone-treated group.
  • GFAP-positive astrocytes appeared as stellate, branched bipolar or large cytoplasmic cells, but in the NLRP3 K/O mouse group, GFAP-stained astrocytes were hardly detected ( FIG. 6c ).
  • pioglitazone administration reduced NLRP3 expression by regulating the inflammatory response in astrocytes and microglia.

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Abstract

La présente invention concerne une composition pour prévenir ou traiter un traumatisme crânien, et la composition comprenant de la pioglitazone de la présente invention réduit l'activité de l'inflammasome. De plus, il a été confirmé que la composition régule les réponses inflammatoires dans les astrocytes et la microglie, et inhibe un œdème cérébral aigu après une lésion cérébrale traumatique ouverte par inhibition de l'expression de NLRP3. Par conséquent, la composition peut être efficacement utilisée pour la prévention ou le traitement d'un traumatisme crânien et d'un œdème cérébral consécutif à un traumatisme crânien.
PCT/KR2021/005583 2020-05-07 2021-05-04 Composition pour prévenir ou traiter un traumatisme crânien Ceased WO2021225349A1 (fr)

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KR20130020949A (ko) * 2011-08-18 2013-03-04 한국과학기술연구원 퇴행성 뇌질환의 예방 또는 치료용 약학적 조성물 및 이의 스크리닝 방법

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20130020949A (ko) * 2011-08-18 2013-03-04 한국과학기술연구원 퇴행성 뇌질환의 예방 또는 치료용 약학적 조성물 및 이의 스크리닝 방법

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
DENG YONGBING, JIANG XUE, DENG XIAOYAN, CHEN HONG, XU JIE, ZHANG ZHAOSI, LIU GELI, YONG ZHU, YUAN CHENGFU, SUN XIAOCHUAN, WANG CHA: "Pioglitazone ameliorates neuronal damage after traumatic brain injury via the PPARγ/NF-κB/IL-6 signaling pathway", GENES & DISEASES, vol. 7, no. 2, 1 June 2020 (2020-06-01), pages 253 - 265, XP055863882, ISSN: 2352-3042, DOI: 10.1016/j.gendis.2019.05.002 *
HO JUN YI , JUNG EUN LEE , DONG HOON LEE , YOUNG IL KIM , CHUL BUM CHO , IL SUP KIM , JAE HOON SUNG ,SEUNG HO YANG: "The role of NLRP3 in traumatic brain injury and its regulation by pioglitazone", JOURNAL OF NEUROSURGERY, vol. 133, no. 4, 1 January 2019 (2019-01-01), pages 1 - 9, XP009531543, ISSN: 0022-3085, DOI: 10.3171/2019.6.JNS1954 *
KIM HOON, LEE JUNG EUN, YOO HYUN JU, SUNG JAE HOON, YANG SEUNG HO: "Effect of Pioglitazone on Perihematomal Edema in Intracerebral Hemorrhage Mouse Model by Regulating NLRP3 Expression and Energy Metabolism", JOURNAL OF KOREAN NEUROSURGICAL SOCIETY, vol. 63, no. 6, 1 November 2020 (2020-11-01), pages 689 - 697, XP055863909, ISSN: 2005-3711, DOI: 10.3340/jkns.2020.0056 *
KUWAR RAM; ROLFE ANDREW; DI LONG; XU HONGYU; HE LIU; JIANG YUQI; ZHANG SHIJUN; SUN DONG: "A novel small molecular NLRP3 inflammasome inhibitor alleviates neuroinflammatory response following traumatic brain injury", JOURNAL OF NEUROINFLAMMATION, vol. 16, no. 1, 81, 1 December 2019 (2019-12-01), pages 1 - 14, XP055741724, DOI: 10.1186/s12974-019-1471-y *
PILIPOVIĆ KRISTINA, ŽUPAN ŽELJKO, DOLENEC PETRA, MRŠIĆ-PELČIĆ JASENKA, ŽUPAN GORDANA: "A single dose of PPARγ agonist pioglitazone reduces cortical oxidative damage and microglial reaction following lateral fluid percussion brain injury in rats", PROGRESS IN NEURO-PSYCHOPHARMACOLOGY AND BIOLOGICAL PSYCHIATRY, vol. 59, 1 June 2015 (2015-06-01), GB, pages 8 - 20, XP055863901, ISSN: 0278-5846, DOI: 10.1016/j.pnpbp.2015.01.003 *
SERGE C. THAL, MARIUS HEINEMANN, CLARA LUH, DANA PIETER, CHRISTIAN WERNER,, KRISTIN ENGELHARD: "Pioglitazone Reduces Secondary Brain Damage after Experimental Brain Trauma by PPAR-γ-Independent Mechanisms", JOURNAL OF NEUROTRAUMA, vol. 28, no. 6, 1 June 2011 (2011-06-01), US, pages 983, XP055863905, ISSN: 0897-7151, DOI: 10.1089/neu.2010.1685 *

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