| Valproic acid is neuroprotective in the rotenone rat model of Parkinson's disease: involvement of alpha-synuclein. | |
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MedLine Citation:
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PMID: 19626387 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Valproic acid (VPA), an established antiepileptic and antimanic drug, has recently emerged as a promising neuroprotective agent. Among its many cellular targets, VPA has been recently demonstrated to be an effective inhibitor of histone deacetylases. Accordingly, we have adopted a schedule of dietary administration (2% VPA added to the chow) that results in a significant inhibition of histone deacetylase activity and in an increase of histone H3 acetylation in brain tissues of 4 weeks-treated rats. We have tested this schedule of VPA treatment in an animal model of Parkinson's disease (PD), in which degeneration of nigro-striatal dopaminergic neurons is obtained through sub-chronic administration of the mitochondrial toxin, rotenone, via osmotic mini pumps implanted to rats. The decrease of the dopaminergic marker tyrosine hydroxylase in substantia nigra and striatum caused by 7 days toxin administration was prevented in VPA-fed rats. VPA treatment also significantly counteracted the death of nigral neurons and the 50% drop of striatal dopamine levels caused by rotenone administration. The PD-marker protein alpha-synuclein decreased, in its native form, in substantia nigra and striatum of rotenone-treated rats, while monoubiquitinated alpha-synuclein increased in the same regions. VPA treatment counteracted both these alpha-synuclein alterations. Furthermore, monoubiquitinated alpha-synuclein increased its localization in nuclei isolated from substantia nigra of rotenone-treated rats, an effect also prevented by VPA treatment. Nuclear localization of alpha-synuclein has been recently described in some models of PD and its neurodegenerative effect has been ascribed to histone acetylation inhibition. Thus, the ability of VPA to increase histone acetylation is a novel candidate mechanism for its neuroprotective action. |
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Authors:
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Barbara Monti; Valentina Gatta; Francesca Piretti; Simonetta S Raffaelli; Marco Virgili; Antonio Contestabile |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-07-21 |
Journal Detail:
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Title: Neurotoxicity research Volume: 17 ISSN: 1476-3524 ISO Abbreviation: Neurotox Res Publication Date: 2010 Feb |
Date Detail:
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Created Date: 2009-12-24 Completed Date: 2010-03-02 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100929017 Medline TA: Neurotox Res Country: United States |
Other Details:
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Languages: eng Pagination: 130-41 Citation Subset: IM |
Affiliation:
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Department of Biology, University of Bologna, Bologna, Italy. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Analysis of Variance Animals Brain / drug effects, metabolism, pathology Cell Death / drug effects Chromatography, High Pressure Liquid / methods DNA Fragmentation / drug effects Disease Models, Animal Dopamine / metabolism Drug Administration Schedule Gene Expression Regulation / drug effects Histone Deacetylases / metabolism Immunoprecipitation / methods Insecticides / toxicity* Male Molecular Weight Neuroprotective Agents / administration & dosage, pharmacology* Parkinson Disease, Secondary* / chemically induced, metabolism, prevention & control Rats Rats, Wistar Rotenone / toxicity* Valproic Acid / administration & dosage, pharmacology* alpha-Synuclein / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Insecticides; 0/Neuroprotective Agents; 0/alpha-Synuclein; 83-79-4/Rotenone; 99-66-1/Valproic Acid; EC 3.5.1.98/Histone Deacetylases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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