Valproate ameliorates the survival and the motor performance in a transgenic mouse model of Huntington's disease
Huntington's disease (HD) is one of the chronic devastating neurodegenerative disorders. The pathophysiological processes clearly involve both excitotoxicity and reduced gene transcription due to the decreased level of histone acetylation, accompanied by the loss of γ-aminobutyric acidergic (GA...
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| Veröffentlicht in: | Pharmacology, biochemistry and behavior biochemistry and behavior, 2009-11, Vol.94 (1), p.148-153 |
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| creator | Zádori, Dénes Geisz, Andrea Vámos, Enikő Vécsei, László Klivényi, Péter |
| description | Huntington's disease (HD) is one of the chronic devastating neurodegenerative disorders. The pathophysiological processes clearly involve both excitotoxicity and reduced gene transcription due to the decreased level of histone acetylation, accompanied by the loss of γ-aminobutyric acidergic (GABAergic) medium-sized spiny neurons in the striatum as a pathological hallmark of HD. Thus, the antiepileptic drug valproate, which has proved GABAergic, antiexcitotoxic and histone deacetylase inhibitor effects, might be of value by exerting a beneficial neuroprotective effect. We have now tested this drug in the N171-82Q transgenic mouse model of HD, following its chronic intraperitoneal administration in a daily dose of 100 mg/kg. Valproate significantly prolonged the survival of the transgenic mice and significantly ameliorated their diminished spontaneous locomotor activity, without exerting any noteworthy side-effect on their behaviour or the striatal dopamine content at the dose administered. The beneficial effect of valproate is probably explained by its complex pharmacological activity. As several previous clinical trials carried out with valproate did not indicate any positive effect in HD, it is worth considering the design of new studies based on a well-planned treatment regime with higher dose, using valproate in monotherapy or in combination therapy with a high number of participating patients. |
| doi_str_mv | 10.1016/j.pbb.2009.08.001 |
| format | Article |
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The pathophysiological processes clearly involve both excitotoxicity and reduced gene transcription due to the decreased level of histone acetylation, accompanied by the loss of γ-aminobutyric acidergic (GABAergic) medium-sized spiny neurons in the striatum as a pathological hallmark of HD. Thus, the antiepileptic drug valproate, which has proved GABAergic, antiexcitotoxic and histone deacetylase inhibitor effects, might be of value by exerting a beneficial neuroprotective effect. We have now tested this drug in the N171-82Q transgenic mouse model of HD, following its chronic intraperitoneal administration in a daily dose of 100 mg/kg. Valproate significantly prolonged the survival of the transgenic mice and significantly ameliorated their diminished spontaneous locomotor activity, without exerting any noteworthy side-effect on their behaviour or the striatal dopamine content at the dose administered. The beneficial effect of valproate is probably explained by its complex pharmacological activity. As several previous clinical trials carried out with valproate did not indicate any positive effect in HD, it is worth considering the design of new studies based on a well-planned treatment regime with higher dose, using valproate in monotherapy or in combination therapy with a high number of participating patients.</description><identifier>ISSN: 0091-3057</identifier><identifier>EISSN: 1873-5177</identifier><identifier>DOI: 10.1016/j.pbb.2009.08.001</identifier><identifier>PMID: 19698736</identifier><identifier>CODEN: PBBHAU</identifier><language>eng</language><publisher>Kidlington: Elsevier Inc</publisher><subject>3,4-Dihydroxyphenylacetic Acid - metabolism ; Adult and adolescent clinical studies ; Animals ; Behavior, Animal - drug effects ; Biological and medical sciences ; Corpus Striatum - metabolism ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; Disease Models, Animal ; Disease Progression ; Dopamine - metabolism ; Exploratory Behavior - drug effects ; Female ; Homovanillic Acid - metabolism ; Huntington Disease - drug therapy ; Huntington Disease - mortality ; Huntington's disease ; Injections, Intraperitoneal ; Kaplan-Meier Estimate ; Male ; Medical sciences ; Mice ; Mice, Transgenic ; Motor Activity - drug effects ; N171-82Q ; Nervous system (semeiology, syndromes) ; Nervous system as a whole ; Neurology ; Neuropharmacology ; Neuroprotective Agents - administration & dosage ; Neuroprotective Agents - adverse effects ; Neuroprotective Agents - therapeutic use ; Organic mental disorders. Neuropsychology ; Pharmacology. Drug treatments ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) ; Psychology. Psychoanalysis. 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The pathophysiological processes clearly involve both excitotoxicity and reduced gene transcription due to the decreased level of histone acetylation, accompanied by the loss of γ-aminobutyric acidergic (GABAergic) medium-sized spiny neurons in the striatum as a pathological hallmark of HD. Thus, the antiepileptic drug valproate, which has proved GABAergic, antiexcitotoxic and histone deacetylase inhibitor effects, might be of value by exerting a beneficial neuroprotective effect. We have now tested this drug in the N171-82Q transgenic mouse model of HD, following its chronic intraperitoneal administration in a daily dose of 100 mg/kg. Valproate significantly prolonged the survival of the transgenic mice and significantly ameliorated their diminished spontaneous locomotor activity, without exerting any noteworthy side-effect on their behaviour or the striatal dopamine content at the dose administered. The beneficial effect of valproate is probably explained by its complex pharmacological activity. As several previous clinical trials carried out with valproate did not indicate any positive effect in HD, it is worth considering the design of new studies based on a well-planned treatment regime with higher dose, using valproate in monotherapy or in combination therapy with a high number of participating patients.</description><subject>3,4-Dihydroxyphenylacetic Acid - metabolism</subject><subject>Adult and adolescent clinical studies</subject><subject>Animals</subject><subject>Behavior, Animal - drug effects</subject><subject>Biological and medical sciences</subject><subject>Corpus Striatum - metabolism</subject><subject>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</subject><subject>Disease Models, Animal</subject><subject>Disease Progression</subject><subject>Dopamine - metabolism</subject><subject>Exploratory Behavior - drug effects</subject><subject>Female</subject><subject>Homovanillic Acid - metabolism</subject><subject>Huntington Disease - drug therapy</subject><subject>Huntington Disease - mortality</subject><subject>Huntington's disease</subject><subject>Injections, Intraperitoneal</subject><subject>Kaplan-Meier Estimate</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Motor Activity - drug effects</subject><subject>N171-82Q</subject><subject>Nervous system (semeiology, syndromes)</subject><subject>Nervous system as a whole</subject><subject>Neurology</subject><subject>Neuropharmacology</subject><subject>Neuroprotective Agents - administration & dosage</subject><subject>Neuroprotective Agents - adverse effects</subject><subject>Neuroprotective Agents - therapeutic use</subject><subject>Organic mental disorders. 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Psychiatry</subject><subject>Psychopharmacology</subject><subject>Time Factors</subject><subject>Transgenic mice</subject><subject>Valproate</subject><subject>Valproic Acid - administration & dosage</subject><subject>Valproic Acid - adverse effects</subject><subject>Valproic Acid - therapeutic use</subject><issn>0091-3057</issn><issn>1873-5177</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1vFDEMQCNERZfCD-CCcgFOMzjzlUScqgooUqVeCtcokzglq5nJkGRW6r8ny67gxsmW_WzZj5A3DGoGbPi4r9dxrBsAWYOoAdgzsmOCt1XPOH9OdqXBqhZ6fkleprQHgK4Z-AtyyeQgCzfsyPpDT2sMOiPVM04-xJImmn8iTVs8-IOeqF7sn8Iccoh0xehCnPVikPqFapqjXtIjLt4UYktHzuJEg6O325L98pjD8iFR6xPqhK_IhdNTwtfneEW-f_n8cHNb3d1__XZzfVeZrh9yNdqRiQFGwNEgZxoBJZejdW3XdSBa2UjRdI3orDN86J3F1qFtZM_7XrpxaK_I-9Pe8t2vDVNWs08Gp0kvWK5UDQjGYRAFZCfQxJBSRKfW6GcdnxQDddSs9qpoVkfNCoQqmsvM2_PybZzR_ps4ey3AuzOgk9GTK4qMT3-5poHyRtcX7tOJw6Li4DGqZDwWtdZHNFnZ4P9zxm8akpxV</recordid><startdate>20091101</startdate><enddate>20091101</enddate><creator>Zádori, Dénes</creator><creator>Geisz, Andrea</creator><creator>Vámos, Enikő</creator><creator>Vécsei, László</creator><creator>Klivényi, Péter</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QO</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20091101</creationdate><title>Valproate ameliorates the survival and the motor performance in a transgenic mouse model of Huntington's disease</title><author>Zádori, Dénes ; Geisz, Andrea ; Vámos, Enikő ; Vécsei, László ; Klivényi, Péter</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c456t-bdb1860b0ebce71ae0e979bdf3444083929824284dfc765fde3fed2957559fb63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>3,4-Dihydroxyphenylacetic Acid - metabolism</topic><topic>Adult and adolescent clinical studies</topic><topic>Animals</topic><topic>Behavior, Animal - drug effects</topic><topic>Biological and medical sciences</topic><topic>Corpus Striatum - metabolism</topic><topic>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</topic><topic>Disease Models, Animal</topic><topic>Disease Progression</topic><topic>Dopamine - metabolism</topic><topic>Exploratory Behavior - drug effects</topic><topic>Female</topic><topic>Homovanillic Acid - metabolism</topic><topic>Huntington Disease - drug therapy</topic><topic>Huntington Disease - mortality</topic><topic>Huntington's disease</topic><topic>Injections, Intraperitoneal</topic><topic>Kaplan-Meier Estimate</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Motor Activity - drug effects</topic><topic>N171-82Q</topic><topic>Nervous system (semeiology, syndromes)</topic><topic>Nervous system as a whole</topic><topic>Neurology</topic><topic>Neuropharmacology</topic><topic>Neuroprotective Agents - administration & dosage</topic><topic>Neuroprotective Agents - adverse effects</topic><topic>Neuroprotective Agents - therapeutic use</topic><topic>Organic mental disorders. Neuropsychology</topic><topic>Pharmacology. Drug treatments</topic><topic>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer</topic><topic>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</topic><topic>Psychology. Psychoanalysis. Psychiatry</topic><topic>Psychopathology. Psychiatry</topic><topic>Psychopharmacology</topic><topic>Time Factors</topic><topic>Transgenic mice</topic><topic>Valproate</topic><topic>Valproic Acid - administration & dosage</topic><topic>Valproic Acid - adverse effects</topic><topic>Valproic Acid - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zádori, Dénes</creatorcontrib><creatorcontrib>Geisz, Andrea</creatorcontrib><creatorcontrib>Vámos, Enikő</creatorcontrib><creatorcontrib>Vécsei, László</creatorcontrib><creatorcontrib>Klivényi, Péter</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Biotechnology Research Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Pharmacology, biochemistry and behavior</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zádori, Dénes</au><au>Geisz, Andrea</au><au>Vámos, Enikő</au><au>Vécsei, László</au><au>Klivényi, Péter</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Valproate ameliorates the survival and the motor performance in a transgenic mouse model of Huntington's disease</atitle><jtitle>Pharmacology, biochemistry and behavior</jtitle><addtitle>Pharmacol Biochem Behav</addtitle><date>2009-11-01</date><risdate>2009</risdate><volume>94</volume><issue>1</issue><spage>148</spage><epage>153</epage><pages>148-153</pages><issn>0091-3057</issn><eissn>1873-5177</eissn><coden>PBBHAU</coden><abstract>Huntington's disease (HD) is one of the chronic devastating neurodegenerative disorders. The pathophysiological processes clearly involve both excitotoxicity and reduced gene transcription due to the decreased level of histone acetylation, accompanied by the loss of γ-aminobutyric acidergic (GABAergic) medium-sized spiny neurons in the striatum as a pathological hallmark of HD. Thus, the antiepileptic drug valproate, which has proved GABAergic, antiexcitotoxic and histone deacetylase inhibitor effects, might be of value by exerting a beneficial neuroprotective effect. We have now tested this drug in the N171-82Q transgenic mouse model of HD, following its chronic intraperitoneal administration in a daily dose of 100 mg/kg. Valproate significantly prolonged the survival of the transgenic mice and significantly ameliorated their diminished spontaneous locomotor activity, without exerting any noteworthy side-effect on their behaviour or the striatal dopamine content at the dose administered. The beneficial effect of valproate is probably explained by its complex pharmacological activity. As several previous clinical trials carried out with valproate did not indicate any positive effect in HD, it is worth considering the design of new studies based on a well-planned treatment regime with higher dose, using valproate in monotherapy or in combination therapy with a high number of participating patients.</abstract><cop>Kidlington</cop><pub>Elsevier Inc</pub><pmid>19698736</pmid><doi>10.1016/j.pbb.2009.08.001</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 3,4-Dihydroxyphenylacetic Acid - metabolism Adult and adolescent clinical studies Animals Behavior, Animal - drug effects Biological and medical sciences Corpus Striatum - metabolism Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Disease Models, Animal Disease Progression Dopamine - metabolism Exploratory Behavior - drug effects Female Homovanillic Acid - metabolism Huntington Disease - drug therapy Huntington Disease - mortality Huntington's disease Injections, Intraperitoneal Kaplan-Meier Estimate Male Medical sciences Mice Mice, Transgenic Motor Activity - drug effects N171-82Q Nervous system (semeiology, syndromes) Nervous system as a whole Neurology Neuropharmacology Neuroprotective Agents - administration & dosage Neuroprotective Agents - adverse effects Neuroprotective Agents - therapeutic use Organic mental disorders. Neuropsychology Pharmacology. Drug treatments Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopathology. Psychiatry Psychopharmacology Time Factors Transgenic mice Valproate Valproic Acid - administration & dosage Valproic Acid - adverse effects Valproic Acid - therapeutic use |
| title | Valproate ameliorates the survival and the motor performance in a transgenic mouse model of Huntington's disease |
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