Neuroprotection by Valproic Acid in Mouse Models of Permanent and Transient Focal Cerebral Ischemia
Open Access
- 1 January 2010
- journal article
- Published by The Korean Physiological Society and The Korean Society of Pharmacology in Korean Journal of Physiology & Pharmacology
- Vol. 14 (6), 435-440
- https://doi.org/10.4196/kjpp.2010.14.6.435
Abstract
Valproic acid (VPA) is a well-known anti-epileptic and mood stabilizing drug. A growing number of reports demonstrate that VPA is neuroprotective against various insults. Despite intensive efforts to develop new therapeutics for stroke over the past two decades, all treatments have thus far failed to show clinical effect because of treatment-limiting side effects of the drugs. Therefore, a safety-validated drug like VPA would be an attractive candidate if it has neuroprotective effects against ischemic insults. The present study was undertaken to examine whether pre- and post-insult treatments with VPA protect against brain infarct and neurological deficits in mouse transient (tMCAO) and permanent middle cerebral artery occlusion (pMCAO) models. In the tMCAO (2 hr MCAO and 22 hr reperfusion) model, intraperitoneal injection of VPA (300 mg/kg, i.p.) 30 min prior to MCAO significantly reduced the infarct size and the neurological deficit. VPA treatment immediately after reperfusion significantly reduced the infarct size. The administration of VPA at 4 hr after reperfusion failed to reduce the infarct size and the neurological deficit. In the pMCAO model, treatment with VPA (300 mg/kg, i.p.) 30 min prior to MCAO significantly attenuated the infarct size, but did not affect the neurological deficit. Western blot analysis of acetylated H3 and H4 protein levels in extracts from the ischemic cortical area showed that treatment with VPA increased the expression of acetylated H3 and H4 at 2 hrs after MCAO. These results demonstrated that treatment with VPA prior to ischemia attenuated ischemic brain damage in both mice tMCAO and pMCAO models and treatment with VPA immediately after reperfusion reduced the infarct area in the tMCAO model. VPA could therefore be evaluated for clinical use in stroke patients.Keywords
This publication has 18 references indexed in Scilit:
- Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemiaAmerican Journal of Physiology-Heart and Circulatory Physiology, 2005
- Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neuronsThe Pharmacogenomics Journal, 2004
- The neurobiology of antiepileptic drugsNature Reviews Neuroscience, 2004
- Mechanisms, challenges and opportunities in strokeNature Reviews Neuroscience, 2003
- Valproic acid, a mood stabilizer and anticonvulsant, protects rat cerebral cortical neurons from spontaneous cell death: a role of histone deacetylase inhibitionFEBS Letters, 2003
- Neuroprotective effects of anticonvulsants in rat hippocampal slice cultures exposed to oxygen/glucose deprivationNeuroscience Letters, 2003
- Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylationJournal of Neurochemistry, 2002
- Levetiracetam: The Preclinical Profile of a New Class of Antiepileptic Drugs?Epilepsia, 2001
- Temporary and permanent focal cerebral ischemia in the mouse: assessment of cerebral blood flow, brain damage and blood-brain barrier permeability.2000
- Recommendations for Standards Regarding Preclinical Neuroprotective and Restorative Drug DevelopmentStroke, 1999