Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats: potential roles of histone deacetylase inhibition and heat shock protein induction.
Growing evidence from in vitro studies supports that valproic acid (VPA), an anti-convulsant and mood-stabilizing drug, has neuroprotective effects. The present study investigated whether VPA reduces brain damage and improves functional outcome in a transient focal cerebral ischemia model of rats. Subcutaneous injection of VPA (300 mg/kg) immediately after ischemia followed by repeated injections every 12 h, was found to markedly decrease infarct size and reduce ischemia-induced neurological deficit scores measured at 24 and 48 h after ischemic onset. VPA treatment also suppressed ischemia-induced neuronal caspase-3 activation in the cerebral cortex. VPA treatments resulted in a time-dependent increase in acetylated histone H3 levels in the cortex and striatum of both ipsilateral and contralateral brain hemispheres of middle cerebral artery occlusion (MCAO) rats, as well as in these brain areas of normal, non-surgical rats, supporting the in vitro finding that VPA is a histone deacetylase (HDAC) inhibitor. Similarly, heat shock protein 70 (HSP70) levels were time-dependently up-regulated by VPA in the cortex and striatum of both ipsilateral and contralateral sides of MCAO rats and in these brain areas of normal rats. Altogether, our results demonstrate that VPA is neuroprotective in the cerebral ischemia model and suggest that the protection mechanisms may involve HDAC inhibition and HSP induction.
Ren
Ming
M
Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, MSC 1363, Bethesda, MD 20892-1363, USA.
Leng
Yan
Y
Jeong
MiRa
M
Leeds
Peter R
PR
Chuang
De-Maw
DM
D000107:Acetylation; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D002544:Cerebral Infarction / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D018682:GABA Agents / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D017072:Neostriatum / Q000378:metabolism; D009460:Neurologic Examination / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects; D014635:Valproic Acid / Q000627:therapeutic use*
D018682:GABA Agents; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D018696:Neuroprotective Agents; D014635:Valproic Acid; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D006655:Histone Deacetylases