Document Detail


Pharmacological doses of gamma-hydroxybutyrate (GHB) potentiate histone acetylation in the rat brain by histone deacetylase inhibition.
MedLine Citation:
PMID:  19427877     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Several small chain fatty acids, including butyrate, valproate, phenylbutyrate and its derivatives, inhibit several HDAC activities in the brain at a several hundred micromolar concentration. Gamma-hydroxy-butyrate (GHB), a natural compound found in the brain originating from the metabolism of GABA, is structurally related to these fatty acids. The average physiological tissue concentration of GHB in the brain is below 50 microM, but when GHB is administered or absorbed for therapeutic or recreative purposes, its concentration reaches several hundred micromolars. In the present scenario, we demonstrate that pharmacological concentrations of GHB significantly induce brain histone H3 acetylation with a heterogeneous distribution in the brain and reduce in vitro HDAC activity. The degree of HDAC inhibition was also different according to the region of the brain considered. Taking into account the multiple physiological and functional roles attributed to the modification of histone acetylation and its consequences at the level of gene expression, we propose that part of the therapeutic or toxic effects of high concentrations of GHB in the brain after therapeutic administration of the drug could be partly due to GHB-induced epigenetic factors. In addition, we hypothesize that GHB, being naturally synthesized in the cytosolic compartment of certain neurons, could penetrate into the nuclei and may reach sufficient levels that could significantly modulate histone acetylation and may participate in the epigenetic modification of gene expression.
Authors:
Christian Klein; V??ronique Kemmel; Omar Taleb; Dominique Aunis; Michel Maitre
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Publication Detail:
Type:  In Vitro; Journal Article     Date:  2009-05-08
Journal Detail:
Title:  Neuropharmacology     Volume:  57     ISSN:  1873-7064     ISO Abbreviation:  Neuropharmacology     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-07-20     Completed Date:  2010-01-06     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0236217     Medline TA:  Neuropharmacology     Country:  England    
Other Details:
Languages:  eng     Pagination:  137-47     Citation Subset:  IM    
Affiliation:
Department of Biochemistry and INSERM U-575, Faculty of Medicine, University of Strasbourg, France.
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MeSH Terms
Descriptor/Qualifier:
Acetylation / drug effects
Analysis of Variance
Animals
Blotting, Western
Brain / drug effects,  metabolism*
Brain Stem / drug effects,  metabolism
Central Nervous System Agents / pharmacology*
Cerebellum / drug effects,  metabolism
Cerebral Cortex / drug effects,  metabolism
Chromatography
Hippocampus / drug effects,  metabolism
Histone Deacetylases / antagonists & inhibitors*,  metabolism
Histones / metabolism*
Immunohistochemistry
Male
Neurons / drug effects,  metabolism
Rats
Rats, Wistar
Sodium Oxybate / pharmacology*
Time Factors
Chemical
Reg. No./Substance:
0/Central Nervous System Agents; 0/Histones; 502-85-2/Sodium Oxybate; EC 3.5.1.98/Histone Deacetylases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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