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WO2008126932A2 - Régulation épigénétique de la plasticité du cerveau - Google Patents

Régulation épigénétique de la plasticité du cerveau Download PDF

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Publication number
WO2008126932A2
WO2008126932A2 PCT/JP2008/057375 JP2008057375W WO2008126932A2 WO 2008126932 A2 WO2008126932 A2 WO 2008126932A2 JP 2008057375 W JP2008057375 W JP 2008057375W WO 2008126932 A2 WO2008126932 A2 WO 2008126932A2
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WIPO (PCT)
Prior art keywords
histone
acid
plasticity
dna
group
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PCT/JP2008/057375
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English (en)
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WO2008126932A3 (fr
Inventor
Judy Sng
Takao Hensch
Michela Fagiolini
Piero Carninci
Andreas Lennartsson
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Riken
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Publication of WO2008126932A3 publication Critical patent/WO2008126932A3/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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/24—Antidepressants
    • 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

Definitions

  • the present invention relates to an agent for regulating brain plasticity, which comprises a substance affecting an epigenetic state including histone modification, such as histone acetylation or DNA methylation, especially a histone deacetylase (HDAC) inhibitor or a DNA methyltransferase (DNMT) inhibitor, as an active ingredient.
  • histone modification such as histone acetylation or DNA methylation
  • HDAC histone deacetylase
  • DNMT DNA methyltransferase
  • Neuronal circuits are shaped by experience during well-defined intervals of early postnatal brain development called critical periods. After the critical period (CP), the brain plasticity is reduced or absent.
  • critical period CP
  • the visual system has been used for the assessment of brain plasticity.
  • Hubel and Wiesel conducted a series of pioneering vision studies using cats and monkeys. In a set of experiments, they deprived kittens of visual stimulation for various periods of time after birth. From these landmark investigations, they deduced that a critical period exists for the proper development of vision. That is, even a brief period (e.g., a few days) of monocular deprivation (MD) at an early stage immediately after birth resulted in permanently impaired vision of the closed eye and a shift of ocular dominance (OD) of the cortical neurons in favor of the non-deprived eye. Thus, the brain has a high degree of plasticity during this period.
  • MD monocular deprivation
  • OD ocular dominance
  • HDAC inhibitors for example, patent documents 1-3
  • DNMT inhibitors for example, patent documents 4-5
  • valproic acid and salts thereof have been clinically used for the treatment of epilepsy and the like.
  • HDAC inhibitors for the treatment of CNS diseases. However, they disclose only a neuroprotective effect and the like of HDAC inhibitors, and does not disclose or suggest that HDAC and DNMT inhibitors can be used to regulate brain plasticity.
  • the present inventors focused on the effects of epigenetic on critical period of brain development and investigated global changes that alter the chromatin status, and found that histone hyperacetylation occurs in the pre- critical period of the developing visual cortex. It was also observed that DNA demethylation peaked during the
  • an agent for regulating brain plasticity which comprises a substance affecting an epigenetic state selected from the group consisting of histone acetylation and DNA methylation;
  • a method for regulating brain plasticity in a mammal which comprises regulating an epigenetic state selected from the group consisting of histone acetylation and DNA methylation in said mammal;
  • a method for regulating brain plasticity in a mammal which comprises administrating an effective amount of the agent according to any one of above [I]- [6] to the mammal;
  • a substance affecting an epigenetic state selected from the group consisting of histone acetylation and DNA methylation, for use as an agent for regulating brain plasticity;
  • a commercial package comprising the agent according to any one of above [I]- [6] and a written matter which states that the agent can or should be used for regulating brain plasticity.
  • the present invention demonstrates that epigenetic state is responsible for the CP of brain development for the first time.
  • a substance regulating histone acetylation or DNA methylation can alter the chromatin status in a mammal, thereby regulate brain plasticity even after the CP.
  • Figure 1 shows quantitative analysis of western blot results.
  • the dashed line represents histones extracted from hippocampus and the solid line represents histones extracted from visual cortex.
  • Figure 2 shows comparison of acetylated H3 and H4 histones western blot results.
  • the dashed line represents acetylated histones H4 and the solid line represents acetylated H3 histones.
  • Figure 3 shows result of immunohistochemistry staining for acetylated histones H3 in the visual cortex.
  • Figure 4 shows proportion of demethylated CpG islands which represents the status of DNA demethylation.
  • Figure 5 shows representative blot and the quantitative analysis of western blot results obtained from wild type adult mice aged P56, dark reared mice (DR) and Gad65 knockout mice (GAD KO) .
  • Figure 6 shows quantitative analysis of histone deacetylase activity results after injecting wild type adult mice with either vehicle, valproic acid (VPA) or Trichostatin A (TSA) .
  • VPA valproic acid
  • TSA Trichostatin A
  • Figure 7 shows shift in ocular dominance and change in CBI values in adult wild-type mice treated daily (>P60) with vehicle (left) or valproic acid (right) during brief monocular deprivation initiated on P60. Black circle indicates deprived eye and white circle indicates undeprived eye.
  • Figure 8 shows that balance between histone acetylation and DNA demethylation predicts transient critical period in visual cortex.
  • Histone H3 acetylation was observed in the pre- critical period (CP) ( ⁇ P21) of developing visual cortex, diminished by the peak of the CP (P27) and throughout to adulthood (>P55) .
  • Immunofluorescence photomicrographs of AcH3 expressed in different layers of developing visual cortex. Sections of visual cortex obtained from wild-type mice between postnatal ages P11-P56 (n 4-6 per group) were double-stained with AcH3 (green) and DAPI (blue) .
  • Cortical layers (I-VI, WM-white matter) are indicated on the left on DAPI staining. Scale bar, 200 ⁇ m.
  • Histone acetylation prepares visual cortex during pre- CP and DNA demethylation peaked during CP.
  • AcH3 was normalized to H3 histones.
  • DNA demethylation is expressed as percentage of CpG islands that were demethylated.
  • the upward dashed arrow indicates day of eye opening.
  • Figure 9 shows that inverted DNA demethylation / histone acetylation balance persists throughout life in the hippocampus. Downregulation of histone acetylation in developing visual cortex compared to a transient activation of AcH3 during hippocampal development. Immunoblot comparing AcH3 levels in (a) visual cortex and (b) hippocampus during development. Anti-H3 and ⁇ -actin antibodies reveal equal amount of protein loaded.
  • Figure 10 shows that sensory experience regulates the balance between histone acetylation and DNA demethylation.
  • DR dark reared
  • LR light-reared adult mice
  • DR dark-reared adult mice
  • DR dark-reared adult mice exposed to light for 2-days (+2d) or 7-days (+7d) .
  • Cortical layers I-VI, WM-white matter
  • Scale bar 200 ⁇ m.
  • Figure 11 shows that histone hyperacetylation by valproic acid induces DNA ⁇ iethylation and reignite histone acetylation in parvalbumin-positive cells.
  • HDAC histone deacetylase
  • VPA valproic acid
  • TSA trichostatin A
  • HDAC activity was normalized to vehicle.
  • VPA valproic acid
  • TSA trichostatin A
  • HDAC activity was normalized to vehicle.
  • VPA valproic acid
  • TSA trichostatin A
  • Increased levels of histone acetylation after VPA administration Immunoblot comparing AcH3 levels in adult visual cortex after time of vehicle (Veh) and VPA administration. Anti-H3 and ⁇ -actin antibodies revealed equal amount of protein loaded.
  • AcH3 level was normalized to H3 histones in adult visual cortex after vehicle (red dashed line) or VPA administration (red solid line) .
  • DNA demethylation was expressed as percentage of CpG islands that were demethylated (black dashed line for vehicle, black solid line for VPA) .
  • VPA treatment reignites high acetylation levels in PV cells to recreate pre-CP in adulthood.
  • Figure 12 shows that histone hyperacetylation by valproic acid reactivates ocular dominance plasticity in adulthood.
  • Brief MD induces a significant CBI reduction after VPA administration.
  • CBI indicates distribution bias in favor of the contralateral eye (closed circle) .
  • Orientation selectivity remained the same for both vehicle- and VPA-treated mice.
  • VPA and diazepam are both anti-epileptic drugs.
  • Figure 13 shows that valproic acid administration reactivates adult plasticity by induction of non-coding genes and nucleus-localized DNA-binding genes.
  • the number of non-coding genes was 214 in 796 up-regulated genes (red) and 9 in 480 down-regulated genes (green) .
  • the present invention provides an agent for regulating brain plasticity, which comprises a substance affecting an epigenetic state selected from the group consisting of histone acetylation and DNA methylation.
  • regulating brain plasticity generally means positively regulating (controlling, altering and the like) brain plasticity, and more specifically means, for example, promoting, enhancing, reactivating.
  • Epigenetics refers to reversible, heritable changes in gene expression without changing DNA sequence, and also contributes to individual variation in normal biology and in disease states. Epigenetics is based on modification of histone and/or DNA. Thus, “epigenetic state” means modification (e.g. acetylation, methylation and phosphorylation) pattern of histone, DNA methylation and the like. Particularly, as used herein, “epigenetic state” refers to degree of histone acetylation or DNA methylation.
  • Histone acetylation/deacetylation is regulated by histone acetyltransferases (HAT) and histone deacetylases (HDAC) . It is believed that HAT/HDAC activity is normally in equilibrium, and upon stimulation, histone is acetylated by HAT, activating transcription and the gene expression is induced.
  • Substance affecting histone acetylation may be any substance which can affect (e.g., modulate, control, alter, manipulate) the degree of histone acetylation.
  • the substance includes but not limited to HDAC inhibitor, HAT or activator thereof.
  • Substance affecting DNA methylation may be any substance which can affect (e.g., modulate, control, alter, manipulate) the degree of DNA methylation.
  • DNA methyltransferase (DNMT) inhibitor enzymes involved in demethylation of DNA (e.g., 5-methylcitosine DNA glycosylase and DNA repairing enzyme) or activator thereof, and the like can be mentioned.
  • DNMT DNA methyltransferase
  • enzymes involved in demethylation of DNA e.g., 5-methylcitosine DNA glycosylase and DNA repairing enzyme
  • activator thereof e.g., 5-methylcitosine DNA glycosylase and DNA repairing enzyme
  • HDAC inhibitor refers any inhibitor which can eventually lead the inhibition of HDAC, whether directly or indirectly.
  • histone deacetylases e.g., HDACl-9
  • HDAC targeted by the HDAC inhibitor of the present invention may be any HDAC, and not limited to specific one. Examples of HDAC inhibitor used for the purpose of the present invention include, but not limited to the followings:
  • SCFA short chain fatty acids
  • valproic acid valproate sodium butyrate
  • isovalerate McBain et al .
  • Biochem. Pharm. 53: 1357-1368 valerate
  • valerate McBain et al., supra
  • 4-phenylbutyrate 4-phenylbutyrate
  • hydroxamic acid derivatives such as trichostatin analogues such as trichostatin A (TSA) and trichostatin C (Koghe et al . , Biochem. Pharmacol., 56: 1359-1364 (1998)), suberoylanilide hydroxamic acid (SAHA) (Richon et al . , Proc. Natl. Acad. Sci. USA, 95: 3003-3007 (1998)), m- carboxycinnamic acid bishydroxamide (CBHA) (Richon et al., supra) , pyroxamide, salicylbishydroxamic acid (Andrews et al., International J.
  • SBHA suberoyl bishydroxamic acid
  • ABHA azelaic bishydroxamic acid
  • AAHA azelaic-l-hydroxamate-9-anilide
  • cyclic tetrapeptides such as trapoxin A (TPX) -cyclic tetrapeptide (cyclo- (L-phenylalanyl-L-phenylalanyl-D- pipecolinyl-L-2-amino-8-oxo-9, 10-epoxy decanoyl) ) (Kijima et al., J. Biol. Chem., 268: 22429-22435 (1993)), FR901228 (FK 228, depsipeptide) (Nakajima et al., Ex. Cell Res., 241: 126-133 (1998)), FR225497 cyclic tetrapeptide (H. Mori et al . , PCT Application WO 00/08048 (17 February
  • apicidin cyclic tetrapeptide [cyclo (N-O-methyl-L- tryptophanyl-L-isoleucinyl-D-pipecolinyl-L-2-amino-8- oxodecanoyl) ] (Darkin-Rattray et al., Proc. Natl. Acad. Sci. USA, 93: 13143-13147 (1996)), apicidin Ia, apicidin Ib, apicidin Ic, apicidin Ha, and apicidin Hb (P.
  • the above-mentioned HDAC inhibitor may be a free form or a pharmacologically acceptable salt thereof.
  • the salt for example, when a compound has an acidic functional group therein such as carboxyl group, inorganic salts such as alkali metal salt (e.g., sodium salt, potassium salt, lithium salt and the like) , alkaline earth metal salt (e.g., calcium salt, magnesium salt, barium salt and the like) , ammonium salt and the like can be mentioned, and when a compound has a basic functional group therein such as amino group, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p- toluenesulfonic acid and the like can
  • the HDAC inhibitor is valproic acid shown by the following formula:
  • Valproic acid was released in 1967 in Europe and in 1978 in the United States to treat epilepsy.
  • Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy and bipolar disorder. It is also used to treat migraine headaches and schizophrenia.
  • valproic acid is used to control absence seizures, tonic-clonic seizures (grand mal), complex partial seizures, juvenile myoclonic epilepsy and the seizures associated with Lennox-Gastaut syndrome. It is also used in treatment of myoclonus.
  • parenteral (administered intravenously) preparations of valproate are used also as second-line treatment of status epilepticus, alternatively to phenytoin.
  • Related drugs include the sodium salts sodium valproate, used as an anticonvulsant, and a combined formulation, valproate semisodium, used as a mood stabilizer and additionally in U.S. also as an anticonvulsant.
  • valproic acid include, for example, Depakene (Abbott Laboratories in U.S.
  • Valpro (Alphapharm in Australia)
  • Epilim (Sanofi-Aventis in the UK)
  • Convulex (Pfizer in the UK and Byk Madaus in South Africa)
  • Depakine and MicropakineLP by Sanofi-Aventis and Orfiril by Desitin Arzneistoff GmbH in Europe.
  • HDAC inhibitor Another preferable HDAC inhibitor is trichostatin A shown by the following formula:
  • Trichostatin A is an organic compound that serves as an antifungal antibiotic and selectively inhibits the mammalian histone deacetylases enzyme. TSA inhibits the eukaryotic cell cycle during the beginning of the growth stage. TSA can be used to alter gene expression by interfering with the removal of acetyl groups from histones and therefore altering the ability of DNA transcription factors to access the DNA molecules inside chromatin. Thus, TSA has some uses as an anti-cancer drug, By promoting the expression of apoptosis-related genes, it may lead to cancerous cells surviving at lower rates, thus slowing the progression of cancer.
  • MS-275 Another preferable HDAC inhibitor is MS-275 shown by the following formula:
  • the substance affecting DNA methylation is a DNMT inhibitor.
  • DNMT inhibitor refers any inhibitor which can eventually lead the inhibition of DNA methyltransferase, i.e. inhibition of DNA methylation, whether directly or indirectly.
  • four DNA methyltransferases (DNMTl, 2, 3A and 3B) are known in mammals, DNMT targeted by the DNMT inhibitor of the present invention may be any DNMT, and not limited to specific one.
  • Examples of DNMT inhibitor used for the purpose of the present invention include, but not limited to the followings: RG108, DNMTI 5-azacytidine, DNMTI zebularine (these compounds can be available from Calbiochem) and the like.
  • the above-mentioned DNMT inhibitor may be a free form or a pharmacologically acceptable salt thereof.
  • the salt for example, when a compound has an acidic functional group therein such as carboxyl group, inorganic salts such as alkali metal salt (e.g., sodium salt, potassium salt, lithium salt and the like) , alkaline earth metal salt (e.g., calcium salt, magnesium salt, barium salt and the like) , ammonium salt and the like can be mentioned, and when a compound has a basic functional group therein such as amino group, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p- toluenesulfonic acid and the like
  • HDAC and DNMT inhibitors can be produced by methods known in the art or described in the references cited above.
  • the substance affecting histone acetylation or DNA methylation can alter the epigenetic state (chromatin status) in a mammal, thereby regulating brain plasticity of the mammal. More specifically, the substance bringing about histone hyperacetylation or DNA hypermethylation in chromatin, preferably HDAC or DNMT inhibitor, can reactivate brain plasticity even after the CP. Therefore, the agent for regulating brain plasticity of the present invention can be used for the remedy or prevention of diseases, disorders or conditions wherein the regulation (preferably promotion (reactivation) ) of brain plasticity is necessary or suitable for the remedy or prevention thereof.
  • Such diseases, disorders or conditions include, but not limited to, amblyopia, autism spectrum disorders, fragile X syndrome, Rubinstein-Taybi syndrome, mental retardation, Rett's syndrome, schizophrenia, bipolar disorder, Alzheimer's disease, depression, stroke, spinal muscular atrophy, brain lesion and ischemia.
  • the active ingredient when used as a pharmaceutical, the active ingredient, substance affecting histone acetylation or DNA methylation, can be safely administered orally or parenterally (e.g., topically, intravenously, intracerebrally, intraperitoneally and the like) as it is or as a preparation containing a pharmaceutical composition containing a pharmacologically acceptable carrier admixed according to a method known per se, such as tablets (including sugar-coated tablets and film-coated tablets) , powder, granule, capsule (including soft capsule) , orally disintegrating tablet, liquid, injectables, suppository, sustained-release preparation, 5 plaster and the like.
  • parenterally e.g., topically, intravenously, intracerebrally, intraperitoneally and the like
  • a pharmaceutical composition containing a pharmacologically acceptable carrier admixed according to a method known per se, such as tablets (including sugar-coated tablets and film-coated tablets) , powder, granul
  • the content of an active ingredient in the pharmaceutical composition of the present invention is about 0.01 to 100% by weight relative to the entire composition.
  • the pharmacologically acceptable carrier that may be used to produce the pharmaceutical composition of the present invention includes various organic or inorganic carrier substances in common use as pharmaceutical materials, including excipients, lubricants, binders,5 disintegrants, water-soluble polymers and basic inorganic salts for solid preparations; and solvents, dissolution aids, suspending agents, isotonizing agents, buffers and soothing agents for liquid preparations and the like. Other conventional additives such as ° preservatives, anti-oxidants, coloring agents, sweetening agents, souring agents, bubbling agents and flavorings may also be used as necessary.
  • excipients include, for example, lactose, sucrose, D-mannitol, starch, cornstarch, crystalline ⁇ cellulose, light anhydrous silicic acid, titanium oxide and the like.
  • Such “lubricants” include, for example, magnesium stearate, sucrose fatty acid esters, polyethylene glycol, talc, stearic acid and the like.
  • Such "binders” include, for example, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, crystalline cellulose, starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan, low-substituted hydroxypropyl cellulose and the like.
  • Such “disintegrants” include (1) crosspovidone, (2) what is called super-disintegrants such as crosscarmellose sodium (FMC-Asahi Chemical) and carmellose calcium (Gotoku Yakuhin) etc, (3) carboxymethyl starch sodium (e.g., product of Matsutani Chemical), (4) low-substituted hydroxypropyl cellulose 5 (e.g., product of Shin-Etsu Chemical), (5) corn starch, and so forth.
  • super-disintegrants such as crosscarmellose sodium (FMC-Asahi Chemical) and carmellose calcium (Gotoku Yakuhin) etc
  • carboxymethyl starch sodium e.g., product of Matsutani Chemical
  • low-substituted hydroxypropyl cellulose 5 e.g., product of Shin-Etsu Chemical
  • corn starch e.g., corn starch, and so forth.
  • Said "crosspovidone” may be any crosslinked polymer having the chemical name 1-ethenyl- 2-pyrrolidinone homopolymer, including polyvinylpyrrolidone (PVPP) and l-vinyl-2-pyrrolidinone° homopolymer, and is exemplified by Colidon CL (produced by BASF) , Polyplasdon XL (produced by ISP) , Polyplasdon XL-IO (produced by ISP) , Polyplasdon INF-IO (produced by ISP) and the like.
  • PVPP polyvinylpyrrolidone
  • Colidon CL produced by BASF
  • Polyplasdon XL produced by ISP
  • Polyplasdon XL-IO produced by ISP
  • Polyplasdon INF-IO produced by ISP
  • water-soluble polymers include, for example,5 ethanol-soluble water-soluble polymers [e.g., cellulose derivatives such as hydroxypropyl cellulose (hereinafter also referred to as HPC) etc., polyvinylpyrrolidone and the like] , ethanol-insoluble water-soluble polymers [e.g., cellulose derivatives such as hydroxypropylmethyl0 cellulose (hereinafter also referred to as HPMC) etc., methyl cellulose, carboxymethyl cellulose sodium and the like, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum and the like] and the like.
  • HPC hydroxypropyl cellulose
  • HPMC hydroxypropylmethyl0 cellulose
  • Such “basic inorganic salts” include, for example, ⁇ basic inorganic salts of sodium, potassium, magnesium and/or calcium. Preferred are basic inorganic salts of magnesium and/or calcium. More preferred are basic inorganic salts of magnesium. Such basic inorganic salts of sodium include, for example, sodium carbonate,0 sodium hydrogencarbonate, disodium hydrogenphosphate and the like. Such basic inorganic salts of potassium include, for example, potassium carbonate, potassium hydrogencarbonate and the like.
  • Such basic inorganic salts of magnesium include, for example, heavy magnesium ⁇ carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium aluminometasilicate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg 6 Al 2 (OH) 16 ⁇ CO 3 MH 2 O], and aluminum magnesium hydroxide.
  • Preferred are heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide and the like.
  • Such basic inorganic salts of calcium include, for example, precipitated calcium carbonate, calcium hydroxide, etc.
  • solvents include, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • dissolution aids include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • Such “suspending agents” include, for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate etc; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose etc., and the like.
  • Such “isotonizing agents” include, for example, glucose, D-sorbitol, sodium chloride, glycerol, D- mannitol and the like.
  • buffers include, for example, buffer solutions of phosphates, acetates, carbonates, citrates etc., and the like.
  • Such “soothing agents” include, for example, benzyl alcohol and the like.
  • Such “preservatives” include, for example, p- oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Such “antioxidants” include, for example, sulfites, ascorbic acid, ⁇ tocopherol and the like.
  • Such “coloring agents” include, for example, food colors such as Food Color Yellow No. 5, Food Color Red No. 2, Food Color Blue No. 2 etc.; food lake colors, red ferric oxide and the like.
  • sweetening agents include, for example, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin and the like.
  • sweetening agents include, for example, citric acid (citric anhydride) , tartaric acid, malic acid and the like.
  • Such “bubbling agents” include, for example, sodium bicarbonate and the like.
  • Such “flavorings” may be synthetic substances or naturally occurring substances, and include, for example, lemon, lime, orange, menthol, strawberry and the like.
  • the active ingredient may be prepared as a preparation for oral administration in accordance with a commonly-known method, for example, by compression- shaping with a carrier such as an excipient, a disintegrant, a binder, a lubricant, or the like, and subsequently coating the preparation as necessary by a commonly known method for the purpose of taste masking, enteric dissolution or sustained release.
  • a carrier such as an excipient, a disintegrant, a binder, a lubricant, or the like
  • an intermediate layer may be provided by a commonly known method between the enteric layer and the drug-containing layer for the purpose of separation of the two layers.
  • available methods include, for example, a method in which a core containing crystalline cellulose and lactose is coated with the active ingredient and, where necessary, a basic inorganic salt, and then further coated with a coating layer containing a water-soluble polymer to give a composition, which is coated with an enteric coating layer containing polyethylene glycol, further coated with an enteric coating layer containing triethyl citrate, still further coated with an enteric coating layer containing polyethylene glycol, and finally coated with mannitol to give fine granules, which are mixed with additives and shaped.
  • enteric coating layer includes, for example, a layer consisting of a mixture of one or more kinds from aqueous enteric polymer substrates such as cellulose acetate phthalate (CAP) , hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, methacrylic acid copolymers (e.g., Eudragit L30D-55 (trade name; produced by Rohm), Colicoat MAE30DP (trade name; produced by BASF),
  • aqueous enteric polymer substrates such as cellulose acetate phthalate (CAP) , hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, methacrylic acid copolymers (e.g., Eudragit L30D-55 (trade name; produced by Rohm), Colicoat MAE30DP (trade name; produced by BASF),
  • Polyquid PA30 (trade name; produced by San-yo Chemical) etc.), carboxymethylethyl cellulose, shellac and the like; sustained-release substrates such as methacrylic acid copolymers (e.g., Eudragit NE30D (trade name), Eudragit RL30D (trade name), Eudragit RS30D (trade name), etc.) and the like; water-soluble polymers; plasticizers such as triethyl citrate, polyethylene glycol, acetylated monoglycerides, triacetin, castor oil and the like; and the like, and the like.
  • methacrylic acid copolymers e.g., Eudragit NE30D (trade name), Eudragit RL30D (trade name), Eudragit RS30D (trade name), etc.
  • water-soluble polymers plasticizers such as triethyl citrate, polyethylene glycol, acetylated monoglycerides, triacetin, castor oil and the
  • additive includes, for example, water-soluble sugar alcohols (e.g., sorbitol, mannitol, maltitol, reduced starch saccharides, xylitol, reduced palatinose, erythritol, etc.), crystalline cellulose (e.g., Ceolas KG 801, Avicel PH 101, Avicel PH 102, Avicel PH 301, Avicel PH 302, Avicel RC-591
  • water-soluble sugar alcohols e.g., sorbitol, mannitol, maltitol, reduced starch saccharides, xylitol, reduced palatinose, erythritol, etc.
  • crystalline cellulose e.g., Ceolas KG 801, Avicel PH 101, Avicel PH 102, Avicel PH 301, Avicel PH 302, Avicel RC-591
  • cellulose carmellose sodium etc.
  • low- substituted hydroxypropyl cellulose e.g., LH-22, LH-32, LH-23, LH-33 (Shin-Etsu Chemical), mixtures thereof etc.
  • binders souring agents, bubbling agents, sweetening agents, flavorings, lubricants, coloring agents, stabilizers, excipients, disintegrants etc. are also used.
  • the active ingredient may be used in combination with one or more (preferably 1 to 3) other pharmaceutically active ingredients at a suitable ratio.
  • Such “other active ingredients” include, for example, cebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, alprazolam, alfacalcidol, allantoin, allopurinol, ambroxol, amikacin, amiloride, aminoacetic acid, amiodarone, amitriptyline, amlodipine, amoxicillin, ampicillin, ascorbic acid, aspartame, astemizole, atenolol, beclomethasone, benserazide, benzalkoniumhydrochloride, benzocaine, benzoic acid, betamethasone, bezafibrate, biotin, biperiden, bisoprolol, bromazepam, bromhexine, bromocriptine, budesonide, bufexamac, buflomedil, buspirone, caffeine, camphor, captopril, carbamaze
  • the agent of the present invention can be administered to any mammal (e.g., mouse, rat, hamster, guinea pig, rabbit, cat, dog, bovine, sheep, monkey, human, etc.), and more preferably human. While the dose of the agent varies depending on subject of administration, administration route, target disease, symptoms and the like, it is generally about 10 to about 1000 mg/kg/day, and preferably about 100 to about 500 mg/kg/day, based on the active ingredient, which is administered once or several times a day.
  • mammal e.g., mouse, rat, hamster, guinea pig, rabbit, cat, dog, bovine, sheep, monkey, human, etc.
  • the dose of the agent varies depending on subject of administration, administration route, target disease, symptoms and the like, it is generally about 10 to about 1000 mg/kg/day, and preferably about 100 to about 500 mg/kg/day, based on the active ingredient, which is administered once or several times a day.
  • the agent of the present invention can also be used as a reagent for controlling the timing of the onset of critical period in brain research and the like.
  • METHODS AND MATERIALS Animals C57BL/6 mice were used during the WT development period postnatal day 11 (PIl) to adulthood P56. During dark rearing (DR) , animals were kept in a darkroom till P56 and feeding or cage cleaning was performed wearing an infrared visor. Some animals were exposed to light at P56 for a 2 (DR to 2d) or 7-day (DR to 7d) period. Fast photographic film was exposed in the darkroom for several days to monitor effectiveness of the light seal before use.
  • mice carrying a functional disruption of GAD65 were generated as described previously (Asada et al., 1996). Animals were maintained on a 12 hr light/dark (LD) cycle (except when noted for dark- adaptation experiments) and had access to food and water ad libtum.
  • LD light/dark
  • Images were captured using Fluoview ver 1.3a and processed with Adobe Photoshop 7.0.
  • the number of acetylated histones localized in the nucleus was quantified using Image Pro Plus 5.0 software.
  • the binocular area of the visual cortex was selected and separated into the supragranular layer (layers I, II and III) and the infragranular layer (layers IV, V and VI) first on the DAPI image detected at 408 nm to count the number of outlined nuclei of each layer. The same area of interest was then used to count the number of acetylated histones.
  • the percentage of acetylated histones was measured as the number of acetylated histones over the number of nuclei in each layer.
  • the percentage of parvalbumin-positive (PV) interneurons colocalized with AcH3 was expressed against total number of PV cells.
  • Histone protein (5 ⁇ g) was loaded and separated by 15% SDS-PAGE followed by electrophoretic transfer onto polyvinylidene difluoride membrane (Millipore, MA, USA) .
  • the membranes were probed with rabbit polyclonal anti-AcH3 (1:1000), anti-histone H4 acetylated at lysines K5, K8, K12 and K16 (anti-AcH4, 1:1000, Upstate), anti-H3 (1:500, Upstate) and anti-H4
  • Valproic acid (VPA; 200mgkg “1 , i.p; Sigma-Aldrich) was dissolved in sterile saline.
  • Trichostatin A (TSA; lmgkg '1 ; Wako) was dissolved in vehicle solution (25% DMSO, 5% propylene glycol in saline) . Both solutions were freshly prepared and administered to WT P56 mice every 12 hr for 2 or 6 days. The same volume of vehicle solution was injected into control animals. Mice were anesthetized with halothane and killed by cervical dislocation at 2h for VPA and 5h for TSA for HDAC activity. VPA or vehicle solution (Veh) was injected into WT P56 adult mice and the mice were sacrificed at 2h or 12h after 2 nd day or 6 th day of injection for DNA methylation or AcH3 immunoblot assay.
  • HDAC and HAT activity HDAC activity was measured using HDAC Fluorometric Assay/Drug Discovery kit (BIOMOL research Laboratories Inc.), according to manufacturer's instructions. Briefly, nuclear proteins were extracted from visual cortex (Kawabata H, et al. 2002). Nuclear extract containing 75 ⁇ g proteins was incubated with acetylated substrate for 1 hour at room temperature. The reaction was stopped by addition of developer solution, which produces a fluorophore .
  • HAT activity was analyzed using a non-radioactive HAT assay kit (Upstate) according to manufacturer's protocol, without or with the modification that 100 ⁇ l H3 or H4 (4 ⁇ g/ml) were immobilized in each well. The acetylation reaction occurred for 45 minutes with 100 ⁇ g protein lysate. HDAC and HAT activity was measured in a microtiter plate reader.
  • Cytosine-extension assay to detect alteration in DNA methylation was performed as previously described in Progribny and James (1999).
  • the isoschizomers HpaII (DNA methylation sensitive) and Mspl (DNA methylation unsensitive) were used to digest 2 ⁇ g gDNA.
  • the digested DNA was purified with QiaexII kit (Qiagen) and eluted with 25 ⁇ l EB buffer.
  • the single nucleotide extension reaction was performed on all elute, using Ex Taq polymerase (Takara BIO Inc.) and ⁇ P 32 labeled dCTP, in a 25 ⁇ l reaction mixture.
  • VPA Prior to monocular deprivation (MD) experiments, VPA was injected into wild-type adult mice every 12 hourly for 2 days. After the 2 nd day, eyelid margins were trimmed and sutured under halothane anaesthesia for 4 days (brief MD) . VPA was administered i.p. every 12 hourly over the 4 days. All recordings were obtained contralateral to the deprived eye and blind to drug treatment. 8) Electrophysiology
  • Electro-physiological recordings were performed under Nembutal (50 mg kg-1; Abbot) /chlorprothixene (0.2 mg; Sigma) anaesthesia using standard techniques. For each animal, 5 to 8 single units (> 75 ⁇ m apart) were recorded in each of 4 to 6 vertical penetrations spaced evenly (> 200 ⁇ m intervals) across the medio-lateral extent of primary visual cortex to map the monocular and binocular zones and avoid sampling bias. Cells were assigned ocular dominance scores using a 7-point classification scheme.
  • the quantity and size distribution of purified aRNA was assessed by Nanodrop and denaturing gel to ensure that the aRNA amplification was successful.
  • Target fragmentation was achieved by incubation at 94 0 C for 35 min in fragmentation buffer (40 mM Tris-acetate, pH 8.1/100 mM KOAc/30 mM MgOAc) .
  • the size distribution of the fragmented labeled transcripts was assessed by denaturing gel.
  • Affymetrix Test-2 Array After fragmentation and quality confirmation with the Affymetrix Test-2 Array, 20 ⁇ g of the biotinylated aRNA were hybridized to Affymetrix Murine Genome 430 GeneChips (45 101 probe sets) (Affymetrix, Inc., Santa Clara, CA, USA). The chips were washed, stained with streptavidin-phycoerythrin and scanned with a probe array scanner (HP GeneArray Scanner, Hewlett-Packard Company, Palo Alto, CA, USA) . 10) GeneChip data analysis
  • Affymetrix Microarray Suite 5.0 software (Affymetrix, Inc.) and GeneSpring 5.0 software (Silicon Genetics, Redwood City, CA, USA) .
  • the Suite 5.0 software normalized the values of expression levels using all probes. Statistical comparisons of expression levels between Veh and VPA mice were performed by using the Mann-Whitney U-test. After normalization, the software scaled the data for each chip and then generated a change P-value, a change call and a signal log ratio using Wilcoxon's signed-rank test. A pairwise analysis was performed using Affymetrix software. Genes that showed an appropriate absence or presence call in all 4 repeats of each sample were selected. Fold changes were calculated using the formula: 2 signal log ratio.
  • each probe set on the experiment array was compared with its counterpart on the Veh baseline array to calculate the change P-value that was used to generate the change call of increase (P ⁇ 0.0025), marginal increase (0.0025 ⁇ P ⁇ 0.003) , decrease (P>0.9975), marginal decrease (0.997 ⁇ P ⁇ 0.9975) or no change
  • Example 1 Quantitative analysis of acetylated histones In the hippocampus and visual cortex, the ratio of acetylated histone to non-acetylated histone was analyzed. The results are shown in Fig. 1. Although histone acetylation profiles somewhat differ between visual cortex and hippocampus, histone acetylation seems to prepare the visual cortex to enter the critical period.
  • the visual cortex was stained for the presence of acetylated histone H3. The results are shown in Fig. 3. Histone acetylation was observed at the early stages of development, strengthening the need of histone acetylation to prepare the visual cortex before entering the critical period.
  • HDAC histone deacetylase
  • Example 8 Balance between histone acetylation and DNA demethylation predicts transient critical period in visual cortex
  • Histone AcH3 staining was nucleated in neurons when double-stained with DAPI (Fig. 8b top panel) .
  • Histone acetyltransferase (HAT) activity is a direct measurement of histone acetylation level.
  • Histone acetyltransferease enzymes are responsible for acetylation of histones while histone deacetylases (HDACs) are for deacetylation of histones.
  • HATs and HDACs Equilibrium between HATs and HDACs is necessary for controlled levels of gene transcription. Nuclear extracts taken from early postnatal age at PIl have considerably higher HAT activity than adults (Fig. 8c) , further supporting our observation.
  • high histone acetylation and low DNA demethylation may prepare the visual cortex to enter the CP.
  • low histone acetylation and high DNA demethylation may drive the expression of the CP.
  • low histone acetylation and low DNA demethylation lead to no expression or plasticity in the visual cortex.
  • a balance between these two global epigenomic changes may be essential to create the critical period window in the visual cortex.
  • Example 9 Inverted DNA demethylation / histone acetylation balance persists throughout life in the hippocampus
  • Example 10 Sensory experience regulates the balance between histone acetylation and DNA demethylation
  • DR dark-rearing from birth to adulthood
  • GAD65 KO GAD 65 deletion
  • Example 11 Histone hyperacetylation by valproic acid reactivate plasticity in adulthood
  • HDAC histone deacetylase
  • VPA Valproic acid
  • TSA Trichostatin A
  • VPA did not affect the orientation bias preference of the mice (Fig. 12c) .
  • VPA and diazepam (DZ) are both anti-epileptic drugs. We wanted to show that both work on different mechanistic pathways to manipulate visual cortical plasticity.
  • Adult mice with either no MD or MD and treated with VPA or DZ were assessed by their CBI values. While DZ showed no change in CBI values as in adult with no MD, VPA showed a reduction in CBI value (Fig. 12d) .
  • Example 12 Histone hyperacetylation occurs in all cell types, including parvalbumin cells
  • GABAergic neurons contain high levels of parvalbumin, both in their soma and neurites.
  • Parvalbumin is a slow Ca 2+ buffer that may affect the amplitude and time course of intracellular Ca 2+ transients in terminals after an action potential, and in turn regulate short-term synaptic plasticity (Caillard et al, PNAS 2000) .
  • parvalbumin cells were focused on parvalbumin cells as they are known to be the trigger of critical period and GABA.
  • Histone H3 acetylation were observed in all laminar layers of the visual cortex after 2h of VPA administration but disappeared at 6d (Fig. Hd, top panel) . Under high magnification, many cell types, including parvalbumin cells were colocalized with AcH3 after 2h of VPA administration (Fig. Hd, bottom panel) but there was little or no colocalization in the parvalbumin cells at 6d. The number of colocalization of histone H3 hyperacetylation occurring in parvalbumin cells is higher in P18 than adults. After 2h of VPA administration, the number of colocalization of PV cells with AcH3 positive cells increased more than at P18 (Fig. He) . This indicates that the VPA treatment reignited the histone acetylation levels in parvalbumin cells in adulthood.
  • Example 13 Histone hyperacetylation upregulates non- coding genes and reactivates adult plasticity Taking a step further, we wanted to examine the mechanism behind reactivation of plasticity. We also wanted to confirm that the change in epigenetic status is a causal effect and not a consequence for the critical period plasticity. We were also able to identify whether VPA is truly working epigenetically on the gene expression states. We used commercial genechip analysis to see the changes in gene expression after 2h of VPA treatment. A total of 796 were up-regulated and 480 were down-regulated in VPA-treated mice compared to vehicle-treated mice. Interestingly, from the transcripts that were induced, 27% were non-coding genes and only 2% of the suppressed transcripts were non- coding.
  • chromatin remodeling such as histone acetyltransferases (N-myristoyltransferase 2), RNA II polymerase (TAF4A, Kruppel-like factor 13), SWI/SNF.
  • DNA-directed beta polymerase and upstream transcription factor 2 were upregulated indicative of transcriptional activation.
  • TAF4A histone acetyltransferase 2
  • TAF4A RNA II polymerase
  • SWI/SNF SWI/SNF.
  • DNA-directed beta polymerase and upstream transcription factor 2 were upregulated indicative of transcriptional activation.
  • DNA binding protein chromodomain helicase another family of SWI SNF and we see a reduction in CREB binding protein (which has known HAT activity) .
  • myelin-related expression myelin transcription factor, myelin basic protein and myelin-associated oligodendrocytic basic protein.
  • myelin transcription factor myelin transcription factor
  • myelin basic protein myelin basic protein
  • myelin-associated oligodendrocytic basic protein we also see a decrease in expression of an inhibitor of tissue protein metalloproteinase .
  • VPA reduce myelination and tissue process and allow plasticity and restructuring of the visual cortex to occur.
  • the present invention provides a novel use of HDAC inhibitor and DNMT inhibitor for regulating brain plasticity by altering the epigenetic state.
  • brain plasticity can be reactivated even in adulthood.
  • epigenetic modifications are general mechanisms that are generally conserved through evolution: therefore, modifications observed in mice represent modifications that are applicable to all mammals including human subjects. Therefore, the agent of the present invention is useful for the remedy or prevention of various diseases, disorders and/or conditions wherein the reactivation of brain plasticity is necessary or suitable for the remedy or prevention. Since some of the active ingredient of the present invention including valproic acid and the like has been clinically used as a medicament with safety for a long time, they have a high possibility to be put into practice.

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Abstract

La présente invention concerne un agent permettant la régulation de la plasticité du cerveau, qui comprend une substance affectant un état épigénétique sélectionnée parmi le groupe constitué de l'acétylation d'histone et de la méthylation d'ADN. De manière préférée, la substance est un inhibiteur de désacétylase d'histone ou un inhibiteur de méthyltransférase d'ADN. L'agent de la présente invention peut être utilisé pour le traitement ou la prévention de diverses maladies, divers troubles et/ou états, dans lesquels la régulation (en particulier une amélioration (réactivation)) de la plasticité du cerveau est souhaitée.
PCT/JP2008/057375 2007-04-09 2008-04-09 Régulation épigénétique de la plasticité du cerveau WO2008126932A2 (fr)

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WO2011047204A1 (fr) * 2009-10-14 2011-04-21 Mount Sinai School Of Medicine Procédé de traitement de troubles de la mémoire et d'activation de la mémoire à l'aide de composés à base d'igf-ii
EP4206319A1 (fr) 2009-10-16 2023-07-05 The Scripps Research Institute Induction de cellules pluripotentes
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EP3199623A1 (fr) 2010-03-31 2017-08-02 The Scripps Research Institute Nouvelle programmation de cellules
WO2011123572A1 (fr) 2010-03-31 2011-10-06 The Scripps Research Institute Nouvelle programmation de cellules
EP3936608A1 (fr) 2010-03-31 2022-01-12 The Scripps Research Institute Reprogrammation de cellules
US9732319B2 (en) 2010-12-22 2017-08-15 Fate Therapeutics, Inc. Cell culture platform for single cell sorting and enhanced reprogramming of iPSCs
US10844356B2 (en) 2010-12-22 2020-11-24 Fate Therapeutics, Inc. Cell culture platform for single cell sorting and enhanced reprogramming of iPSCs
WO2013049615A1 (fr) 2011-09-30 2013-04-04 Bluebird Bio, Inc. Composés améliorant la transduction virale
EP3269802A1 (fr) 2011-09-30 2018-01-17 Bluebird Bio, Inc. Composés permettant d'améliorer la transduction virale
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US11268069B2 (en) 2014-03-04 2022-03-08 Fate Therapeutics, Inc. Reprogramming methods and cell culture platforms
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US10961532B2 (en) 2015-04-07 2021-03-30 The General Hospital Corporation Methods for reactivating genes on the inactive X chromosome
US11912994B2 (en) 2015-04-07 2024-02-27 The General Hospital Corporation Methods for reactivating genes on the inactive X chromosome
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