title: Neuroprotective effects of valproic acid following transient global ischemia in rats.
abstract: OBJECTIVE
  A growing number of studies demonstrate that valproic acid (VPA), an anti-convulsant and mood-stabilizing drug, is neuroprotective against various insults. This study investigated whether treatment of ischemic stroke with VPA ameliorated hippocampal cell death and cognitive deficits. Possible mechanisms of action were also investigated.
  
  
  METHODS
  Global cerebral ischemia was induced to mimic ischemia/reperfusion (I/R) damage. The pyramidal cells within the CA1 field were stained with cresyl violet. Cognitive ability was measured 7 days after I/R using a Morris water maze. The anti-inflammatory effects of VPA on microglia were also investigated by immunohistochemistry. Pro-inflammatory cytokine production was determined using enzyme-linked immunosorbent assays (ELISA). Western blot analysis was performed to determine the levels of acetylated H3, H4 and heat shock protein 70 (HSP70) in extracts from the ischemic hippocampus.
  
  
  RESULTS
  VPA significantly increased the density of neurons that survived in the CA1 region of the hippocampus on the 7th day after transient global ischemia. VPA ameliorated severe deficiencies in spatial cognitive performance induced by transient global ischemia. Post-insult treatment with VPA also dramatically suppressed the activation of microglia but not astrocytes, reduced the number of microglia, and inhibited other inflammatory markers in the ischemic brain. VPA treatment resulted in a significant increase in levels of acetylated histones H3 and H4 as well as HSP70 in the hippocampus.
  
  
  CONCLUSIONS
  Our results indicated that VPA protected against hippocampal cell loss and cognitive deficits. Treatment with VPA following cerebral ischemia probably involves multiple mechanisms of action, including inhibition of ischemia-induced cerebral inflammation, inhibition of histone deacetylase (HDAC) and induction of HSP.
authors.affiliation: Department of Anatomy, Guangzhou Medical College, 195 Dongfeng Xi Road, Guangzhou 510182, China. xag2005@sohu.com
authors.forename: Aiguo
authors.initials: A
authors.lastname: Xuan
authors.forename: Dahong
authors.initials: D
authors.lastname: Long
authors.forename: Jianhua
authors.initials: J
authors.lastname: Li
authors.forename: Weidong
authors.initials: W
authors.lastname: Ji
authors.forename: Lepeng
authors.initials: L
authors.lastname: Hong
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects*; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000150:complications / Q000188:drug therapy*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D018840:HSP70 Heat-Shock Proteins; D006657:Histones; D018696:Neuroprotective Agents; D014635:Valproic Acid