WO2011065480A1 - Inhibiteur de l'apoptose des cellules nerveuses - Google Patents

Inhibiteur de l'apoptose des cellules nerveuses Download PDF

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WO2011065480A1
WO2011065480A1 PCT/JP2010/071127 JP2010071127W WO2011065480A1 WO 2011065480 A1 WO2011065480 A1 WO 2011065480A1 JP 2010071127 W JP2010071127 W JP 2010071127W WO 2011065480 A1 WO2011065480 A1 WO 2011065480A1
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group
phosphatidic acid
carbon atoms
linear
cell death
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PCT/JP2010/071127
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Japanese (ja)
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きみ子 室伏
晴美 金敷
擴 室伏
真里 後藤
康孝 垣内
進 小林
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国立大学法人お茶の水女子大学
Ｓａｎｓｈｏ株式会社
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Priority to JP2011543320A priority Critical patent/JP5747263B2/ja
Publication of WO2011065480A1 publication Critical patent/WO2011065480A1/fr

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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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
    • C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems

Definitions

  • the present invention relates to a drug for suppressing delayed neuronal cell death due to transient cerebral ischemia, comprising cyclic phosphatidic acid or carbcyclic phosphatidic acid as an active ingredient.
  • Cerebral vascular disease includes some brain abnormalities caused by vascular pathological processes.
  • Vascular pathological processes are considered to include any one or more of the following. There are changes due to occlusion of the lumen of blood vessels due to thrombus or embolism, rupture of blood vessels, change in permeability of blood vessel wall, increase in blood quality viscosity and the like.
  • Cerebrovascular diseases typically present as seizures, which can be characterized as brain tissue death caused by lack of blood flow and insufficient oxygen to the brain. In the West, seizures are the main cause of death following heart disease and cancer. In Japan, the mortality rate of cerebrovascular disorders is decreasing, but the incidence is increasing, accounting for about 40% of the bedridden causes of the elderly.
  • Seizures are ischemic or hemorrhagic.
  • an ischemic stroke the blood supply to a part of the brain is reduced or stopped by a blood clot that occludes a blood vessel or by atherosclerosis. Reduced or stopped blood flow to the brain is known as cerebral ischemia. Cerebral ischemia can last from a few seconds to several minutes, and if the ischemia occurs for more than a few minutes, an infarction of the brain tissue occurs.
  • cerebral ischemia can also result from circulatory and hypotensive disorders resulting from severe and prolonged heart failure or shock.
  • Patent Document 1 a technique using lysophosphatidylethanolamine
  • Patent Document 2 a glutamate receptor agonist
  • Patent Document 3 a technique using lysophosphatidylethanolamine
  • Patent Document 4 a glutamate receptor agonist
  • Patent Document 5 preventive agent containing phosphatidylcholine and the like as an active ingredient
  • Patent Document 6 pharmaceutical composition containing dilinoleoylphosphatidylethanolamine as an active ingredient
  • Patent Document 6 Lysophosphatidic acid, lysophosphatidylinositol, etc.
  • an object of the present invention is to provide a novel neuronal cell death inhibitor having an action of suppressing delayed neuronal cell death caused by transient cerebral ischemia.
  • cyclic phosphatidic acid and its derivatives have neuronal differentiation induction, neuronal neurite outgrowth action, and suppress brain neuronal cell death.
  • Cyclic phosphatidic acid or carbacyclic phosphatidine The present inventors have found that acids and derivatives thereof suppress delayed neuronal cell death due to transient cerebral ischemia, and have completed the present invention.
  • medical agent for suppressing the delayed neuronal cell death by transient cerebral ischemia containing cyclic phosphatidic acid, carb cyclic phosphatidic acid, or its salt is provided.
  • the cyclic phosphatidic acid or the carbcyclic phosphatidic acid is a compound represented by the formula (1).
  • R is a linear or branched alkyl group having 1 to 30 carbon atoms, a linear or branched alkenyl group having 2 to 30 carbon atoms, or a linear or branched group having 2 to 30 carbon atoms.
  • An alkynyl group which may contain a cycloalkane ring or an aromatic ring, wherein X and Y each independently represent —O— or —CH 2 —, wherein X and Y are simultaneously —CH 2; (M is a hydrogen atom or a counter cation.)
  • X and Y are —O—.
  • X or Y is —CH 2 —.
  • R is C 15 H 29 or C 17 H 33 .
  • the transient cerebral ischemia further comprising administering cyclic phosphatidic acid or carbacyclic phosphatidic acid or a salt thereof to a patient with delayed neuronal cell death due to transient cerebral ischemia.
  • a method for inhibiting delayed neuronal cell death caused by is provided.
  • the present invention further provides use of cyclic phosphatidic acid, carbacyclic phosphatidic acid or a salt thereof for the manufacture of a medicament for suppressing delayed neuronal cell death due to transient cerebral ischemia. .
  • a drug for suppressing delayed neuronal cell death caused by transient cerebral ischemia with few side effects comprising cyclic phosphatidic acid or carbacyclic phosphatidic acid as an active ingredient.
  • FIG. 1 shows the effects of 2 ccPA (carbacyclic phosphatidic acid) and cPA (cyclic phosphatidic acid) on hippocampal CAI region delayed neuronal death associated with transient cerebral ischemia treatment.
  • FIG. 2 shows the results of observation of the hippocampal CAI region associated with transient cerebral ischemia treatment.
  • FIG. 3 shows the effects of 2 ccPA (carbacyclic phosphatidic acid) and cPA (cyclic phosphatidic acid) on hippocampal CAI region delayed neuronal death associated with transient cerebral ischemia treatment.
  • Delayed neuronal cell death caused by transient cerebral ischemia is a cause of hindering the therapeutic effect of diseases such as cerebral infarction.
  • the mechanism is not yet clear, but it is thought that after transient cerebral ischemia, a neuronal cell death-determining mechanism works, which eventually proceeds irreversibly to a common pathway of apoptosis. .
  • transient cerebral ischemia in the hippocampal CA1 region it is reported that the function of ubiquitin / proteasome is irreversibly decreased prior to delayed neuronal cell death, which causes neuronal cell death.
  • caspase 3 and p53 are indispensable (Yonekura, I., Takai, K., Asai, A., Kawahara, N., Kirino, T. P53 potentiates hippocampal neuronal death caused by global ischemia. J. Cereb. Blood Flow Metab., 26: 1332-1340 (2006); and Asai, A., Tanahashi, N., Qui, J.-H., Saito, N., Chi , S., Kawahara, N., Tanaka, K., Kirino, T. Selective proteasomal dysfunction in the hippocampal CA1 rregion after transient forebrain ischemia. J. Cereb. Blood Flow Metab., 22: 705-710 (2002).
  • oxidative stress due to free radical production from arachidonic acid metabolic system and nitric oxide synthase also promotes cell death (Love, S. Oxidative stress in brain ischemia. Brain Pathol. 9: 119-131 (1999)).
  • a free radical scavenger at the time of reperfusion may block or reduce the reperfusion injury by blocking the pathway to cell death.
  • Generic name: edaravone This is a substance that suppresses peroxidation of cell membrane lipids by scavenging free radicals and exhibits a brain-protecting action, and its mechanism of action is completely different from cPA in this study.
  • the agent of the present invention can be used for suppressing delayed neuronal cell death due to transient cerebral ischemia, and contains cyclic phosphatidic acid, carbacyclic phosphatidic acid or a salt thereof as an active ingredient.
  • the cyclic phosphatidic acid or the carbcyclic phosphatidic acid is not particularly limited as long as it exhibits the effects of the present invention, but a cyclic phosphatidic acid represented by the following formula (I) can be preferably used.
  • R is a linear or branched alkyl group having 1 to 30 carbon atoms, a linear or branched alkenyl group having 2 to 30 carbon atoms, or a linear or branched group having 2 to 30 carbon atoms.
  • An alkynyl group which may contain a cycloalkane ring or an aromatic ring, wherein X and Y each independently represent —O— or —CH 2 —, wherein X and Y are simultaneously —CH 2;
  • M is a hydrogen atom or a counter cation.
  • specific examples of the linear or branched alkyl group having 1 to 30 carbon atoms represented by the substituent R include, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group.
  • linear or branched alkenyl group having 2 to 30 carbon atoms represented by the substituent R include an allyl group, a butenyl group, an octenyl group, a decenyl group, a dodecadienyl group, a hexadecatrienyl group, and the like.
  • linear or branched alkynyl group having 2 to 30 carbon atoms represented by the substituent R include, for example, 8-decynyl group, 8-undecynyl group, 8-dodecynyl group, 8-tridecynyl group, and 8-tetradecynyl group.
  • cycloalkane ring that can be contained in the alkyl group, alkenyl group, or alkynyl group
  • a cyclopropane ring a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, and a cyclooctane ring.
  • the cycloalkane ring may contain one or more heteroatoms, and examples thereof include an oxirane ring, an oxetane ring, a tetrahydrofuran ring, and an N-methylprolysine ring.
  • aromatic ring that can be contained in the alkyl group, alkenyl group, or alkynyl group include a benzene ring, a naphthalene ring, a pyridine ring, a furan ring, and a thiophene ring.
  • substituent R is an alkyl group substituted by a cycloalkane ring
  • substituent R is an alkyl group substituted by a cycloalkane ring
  • specific examples in the case where the substituent R is an alkyl group substituted by a cycloalkane ring include a cyclopropylmethyl group, a cyclohexylethyl group, an 8,9-methanopentadecyl group, and the like.
  • substituent R is an alkyl group substituted by an aromatic ring
  • substituent R is an alkyl group substituted by an aromatic ring
  • R is preferably a linear or branched alkyl group having 9 to 17 carbon atoms, a linear or branched alkenyl group having 9 to 17 carbon atoms, or a linear or branched alkynyl group having 9 to 17 carbon atoms. It is a group. R is more preferably a linear or branched alkyl group having 9, 11, 13, 15 or 17 carbon atoms, or a linear or branched alkenyl group having 9, 11, 13, 15 or 17 carbon atoms. is there. R is particularly preferably a linear or branched alkenyl group having 9, 11, 13, 15 or 17 carbon atoms.
  • X and Y in the compound represented by the general formula (1) each independently represent —O— or —CH 2 —, but X and Y are not simultaneously —CH 2 —. That is, there are the following three combinations of X and Y. (1) X is —O— and Y is —O—. (2) X is —CH 2 — and Y is —O—. (3) X is —O— and Y is —CH 2 —.
  • M in the cyclic phosphatidic acid derivative represented by the formula (I) is a hydrogen atom or a counter cation.
  • M is a counter cation.
  • examples of the case where M is a counter cation include, for example, an alkali metal atom, an alkaline earth metal atom, and a substituted or unsubstituted ammonium group.
  • examples of the alkali metal atom include lithium, sodium, and potassium
  • examples of the alkaline earth metal atom include magnesium and calcium.
  • the substituted ammonium group include a butyl ammonium group, a triethyl ammonium group, and a tetramethyl ammonium group.
  • the compounds of formula (I) may have isomers such as positional isomers, geometric isomers, tautomers, or optical isomers depending on the type of substituent, but all possible Isomers and mixtures containing two or more of these isomers in any ratio are also within the scope of the present invention.
  • the compound of formula (I) may exist in the form of an adduct (hydrate or solvate) with water or various solvents, and these adducts are also within the scope of the present invention. is there. Furthermore, any crystalline form of the compound of formula (I) and salts thereof is within the scope of the invention.
  • compounds in which X and Y are —O— are, for example, JP-A-5-230088, JP-A-7-149772, JP-A-7-258278, It can be chemically synthesized according to the method described in Kaihei 9-25235.
  • a compound in which X and Y are —O— causes phospholipase D to act on lyso-type phospholipid according to the method described in JP-A-2001-178589.
  • the lyso-type phospholipid used here is not particularly limited as long as it is a lyso-type phospholipid capable of acting on phospholipase D.
  • Many types of lyso-type phospholipids are known, those having different fatty acid species, and molecular species having an ether or vinyl ether bond are known, and these are available as commercial products.
  • phospholipase D those derived from higher plants such as cabbage and peanuts, and those derived from microorganisms such as Streptomyces chromofuscus and Actinomadula sp. Are available as commercially available reagents .
  • CPA is synthesized (Japanese Patent Application Laid-Open No. 11-367032).
  • the reaction between lyso-type phospholipid and phospholipase D is not particularly limited as long as the enzyme can exhibit its activity. For example, it is heated from room temperature in an acetic acid buffer solution (about pH 5 to 6) containing calcium chloride. (Preferably at about 37 ° C.) for about 1 to 5 hours.
  • the produced cPA derivative can be purified by extraction, column chromatography, thin layer chromatography (TLC) or the like according to a conventional method.
  • Cyclic phosphatidic acid or carbacyclic phosphatidic acid used as an active ingredient in the present invention can suppress delayed neuronal cell death due to transient cerebral ischemia.
  • the drug of the present invention can be used as a drug for suppressing delayed neuronal cell death due to transient cerebral ischemia.
  • the drug of the present invention comprises one or more pharmaceutically acceptable pharmaceutical additives and an active ingredient, cyclic phosphatidic acid or carbacyclic phosphatidic acid (preferably a compound represented by the formula (1)). It is preferably provided in the form of a pharmaceutical composition comprising.
  • the drug of the present invention can be administered in various forms. Suitable administration forms include oral administration and parenteral administration (for example, intravenous, intramuscular, subcutaneous or intradermal injection, rectal administration, etc. Administration, transmucosal administration, etc.).
  • Examples of the pharmaceutical composition suitable for oral administration include tablets, granules, capsules, powders, solutions, suspensions, syrups, etc.
  • Examples of the pharmaceutical composition suitable for parenteral administration include , Injections, drops, suppositories, transdermal absorption agents, and the like, but the dosage form of the drug of the present invention is not limited thereto. Furthermore, it can be made into a sustained-release preparation by a known technique.
  • the type of formulation additive used for the production of the drug of the present invention is not particularly limited, and can be appropriately selected by those skilled in the art.
  • excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, bases, solubilizers or solubilizers, dispersants, suspending agents, emulsifiers, buffers, antioxidants, antiseptics Agents, isotonic agents, pH adjusters, solubilizers, stabilizers, and the like can be used, and the specific components used for these purposes are well known to those skilled in the art.
  • compositions for oral administration include, for example, excipients such as glucose, lactose, D-mannitol, starch, or crystalline cellulose; carboxymethylcellulose, starch, carboxymethylcellulose calcium, etc.
  • Disintegrating agents or disintegrating aids include binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin; lubricants such as magnesium stearate or talc; coatings such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol, or titanium oxide
  • Bases such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, or hard fat can be used.
  • Examples of pharmaceutical additives that can be used for the preparation of pharmaceutical preparations for injection or infusion include aqueous solutions such as distilled water for injection, physiological saline, propylene glycol, surfactants, etc. Agents or solubilizers; isotonic agents such as glucose, sodium chloride, D-mannitol, glycerin, etc .; use of pharmaceutical additives such as pH regulators such as inorganic acids, organic acids, inorganic bases or organic bases it can.
  • the agent of the present invention can be administered to mammals such as humans.
  • the dose of the drug of the present invention should be appropriately increased or decreased according to conditions such as the patient's age, sex, body weight, symptom, and route of administration.
  • the amount of the active ingredient per adult day In the range of about 1 ⁇ g / kg to 1,000 mg / kg, preferably in the range of about 10 ⁇ g / kg to 100 mg / kg.
  • the above dose of the drug may be administered once a day, or may be divided into several times (for example, about 2 to 4 times).
  • Example 1 Method of Effect of cPA on Delayed Neuronal Cell Death After Transient Cerebral Ischemia in Rat Hippocampus
  • the method of cerebral ischemia and histological analysis is basically Kagitani, F., Uchida, S., Hotta, H, and Sato, A (2000) Effects fo nicotine on blood flow and delayed neuronal death fllowing internittent transient ischemia.
  • rat hippocampus Jpn. J. Physiol. 50, 585-595, some modifications were made as described below.
  • the animals were anesthetized with halothane (3.5% at the induction of anesthesia: 1.5% during surgery and ischemia).
  • Antibiotics were administered (viccillin 50 mg / kg IM), and an osmotic pump for cyclic phosphatidic acid was implanted subcutaneously in the abdomen. Subsequently, tracheal intubation was performed and breathing was maintained using a ventilator (SN-480-7, Shinano, Tokyo). Rectal temperature and temporal muscle temperature were monitored, and both were maintained at about 37.5 ° C. using a heat pad and lamp (ATB-1100, Nihon Kohden, Tokyo). Bilateral vertebral arteries were permanently ligated and bilateral common carotid arteries were temporarily occluded for 8 minutes. Havante was cut immediately after the end of transient cerebral ischemia, and the ventilator was removed 15 minutes later.
  • cPA18: 1 The structure of cPA18: 1 is as follows.
  • a section of 3.3 mm behind Bregma was stained with hematoxylin and eosin, and the left and right hippocampal CAI region pyramidal cells were observed histologically. Calculate the number of viable pyramidal cells per CAI unit length by measuring the number of viable pyramidal cells in the cone cells in the CAI region that show nuclear enrichment and the cell bodies are not atrophied and divide by the CAI length Further, the value of the CI group was set to 1, and the value of each group was represented relatively.
  • Example 2 Effect of cPA on delayed neuronal cell death after transient cerebral ischemia in rat hippocampus Using the same compounds (2ccPA16: 1 and cPA18: 1) as in Example 1, In a similar experimental system, the effect of cPA on delayed neuronal cell death after transient cerebral ischemia in the rat hippocampus was examined.
  • FIG. 2 The result of histological observation of the pyramidal cells in the hippocampal CAI region is shown in FIG.
  • a in A Vehicle administration group
  • B in B cPA administration group
  • CA1 range where the arrowhead is sandwiched
  • hippocampus Bregma -3.3 mm
  • FIG. 2A (Vehicle administration group) b and B (cPA administration group) b in FIG. 2 show the state of cells in the CA1 region.
  • Small and darkly stained cells are cells that have aggregated the nucleus, that is, nerve cells that have undergone delayed cell death. Large round cells are living cells, and the nucleus is small in the center of the cell.
  • a (Vehicle administration group) b the number of dead cells is large and almost no living neurons are found, whereas in B (cPA administration group) b, living cells are mainly used. Only a few cells are dead. It can be seen that the survival rate of neurons in the CA1 region is significantly increased by cPA treatment.
  • c of A (vehicle administration group) and B (cPA administration group) of c show stained images of GFAP (glial-fibrillary acidic protein).
  • GFAP is a protein constituting an intermediate filament localized in astroglia, and expression of GFAP is increased in neurological diseases such as brain injury and dementia, and is considered to be involved in the severity of cases.
  • c of A (Vehicle administration group) there are some dark brown cells (anti-GFAP, DAB staining) around dead cells, but in c of B (cPA administration group) around the cells. The darkly stained sites were not found as much as A's c. That is, it is considered that the production of GFAP was suppressed by cPA administration.

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Abstract

La présente invention concerne un inhibiteur de l'apoptose des cellules nerveuses qui a un effet d'inhibition de l'apoptose des cellules nerveuses causée par une ischémique transitoire. La présente invention concerne spécifiquement un médicament destiné à inhiber l'apoptose des cellules nerveuses causée par une ischémie transitoire, qui contient de l'acide phosphatidique cyclique ou de l'acide phosphatidique carbacyclique ou un sel de ceux-ci.
PCT/JP2010/071127 2009-11-26 2010-11-26 Inhibiteur de l'apoptose des cellules nerveuses WO2011065480A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013161978A1 (fr) * 2012-04-27 2013-10-31 Ｓａｎｓｈｏ株式会社 Agent pour la pousse des cheveux
WO2014115885A1 (fr) * 2013-01-28 2014-07-31 国立大学法人お茶の水女子大学 Agent thérapeutique pour maladies démyélinisantes
US10385081B2 (en) 2014-08-12 2019-08-20 Otsuka Chemical Co., Ltd. Crystal of cyclic phosphonic acid sodium salt and method for manufacturing same

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US10385081B2 (en) 2014-08-12 2019-08-20 Otsuka Chemical Co., Ltd. Crystal of cyclic phosphonic acid sodium salt and method for manufacturing same
EP3492479A3 (fr) * 2014-08-12 2019-10-02 Otsuka Chemical Co., Ltd. Cristal de sel de sodium d'acide phosphonique cyclique et son procédé de fabrication
US10774100B2 (en) 2014-08-12 2020-09-15 Otsuka Checmial Co., Ltd. Crystal of cyclic phosphonic acid sodium salt and method for manufacturing same
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