Valproic acid attenuates ischemia-reperfusion injury in the rat brain through inhibition of oxidative stress and inflammation

Eur J Pharmacol. 2013 May 5;707(1-3):26-31. doi: 10.1016/j.ejphar.2013.03.020. Epub 2013 Mar 26.


Valproic acid (VPA), widely used in clinical contexts for the treatment of seizures and bipolar mood disorder, has neuroprotective properties in cellular and animal models. However, the precise mechanisms underlying its neuroprotection against stroke remain unknown. In the present study, we explored the effect of VPA on experimental ischemic stroke. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion for 90 min, followed by reperfusion. The animals received a single injection of VPA (300 mg/kg) immediately, 90, or 270 min after the induction of ischemia. Vehicle-treated animals underwent the same procedure with physiological saline. Infarct volume and neurological symptoms were evaluated 24 h after reperfusion. Immunohistochemical staining for myeloperoxidase (MPO), microglia (Iba1), 4-hydroxy-2-nonenal (4-HNE), or 8-hydroxy-deoxyguanosine (8-OHdG) was performed. Ischemic boundary zone cell death was determined by TUNEL staining. VPA injected immediately or 90 min after ischemia induction significantly reduced infarct volume and improved neurological deficit compared with vehicle (P<0.05). VPA was ineffective when given 270 min after ischemia induction. VPA significantly reduced TUNEL-positive cells, MPO-positive cells, Iba1-positive cells, 4-HNE-positive cells, and 8-OHdG-positive cells compared with vehicle in the ischemic boundary zone (P<0.05). The therapeutic time window for single injection of VPA is between 0 and 90 min in this model. Our results demonstrate that single injection of VPA may have anti-inflammatory as well as antioxidative effects, leading to reduced cell death in ischemia-reperfusion injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / administration & dosage
  • Anti-Inflammatory Agents / pharmacology
  • Antioxidants / administration & dosage
  • Antioxidants / pharmacology
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / pathology
  • Disease Models, Animal
  • In Situ Nick-End Labeling
  • Inflammation / drug therapy
  • Inflammation / pathology
  • Injections, Intraperitoneal
  • Male
  • Neuroprotective Agents / administration & dosage
  • Neuroprotective Agents / pharmacology
  • Oxidative Stress / drug effects*
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / drug therapy
  • Reperfusion Injury / pathology
  • Stroke / drug therapy*
  • Stroke / pathology
  • Time Factors
  • Valproic Acid / administration & dosage
  • Valproic Acid / pharmacology*


  • Anti-Inflammatory Agents
  • Antioxidants
  • Neuroprotective Agents
  • Valproic Acid