Received for publication January 23, 2007.
Revised March 16, 2007.
Accepted for publication March 16, 2007.

HDAC Inhibitors Exhibit Anti-inflammatory and Neuroprotective Effects in a Rat Permanent Ischemic Model of Stroke: Multiple Mechanisms of Action

Abstract

The pathophysiology of cerebral ischemia involves multiple mechanisms including neuroinflammation mediated by activated microglia and infiltrating macrophages/monocytes. The present study employed a rat permanent middle cerebral artery occlusion (pMCAO) model to study effects of histone deacetylase (HDAC) inhibition on ischemia-induced brain infarction, neuroinflammation, gene expression, and neurological deficits. We found that post-pMCAO injections with HDAC inhibitors, valproic acid (VPA), sodium butyrate (SB) or trichostatin A (TSA) decreased brain infarct volume. Post-insult treatment with VPA or SB also suppressed microglial activation, reduced the number of microglia and inhibited other inflammatory markers in the ischemic brain. The reduction in levels of acetylated histone H3 in the ischemic brain was prevented by treatment with VPA, SB or TSA. Moreover, injections with HDAC inhibitors super-induced heat-shock protein 70, and blocked pMCAO-induced downregulation of phospho-Akt, as well as ischemia-elicited upregulation of p53, iNOS and COX-2. The motor, sensory and reflex performance of pMCAO-rats was improved by VPA, SB or TSA treatment. The beneficial effects of SB and VPA in reducing brain infarct volume and neurological deficits occurred when either drug was administrated at least 3 h after ischemic onset and the behavioral improvement was long-lasting. Together, our results demonstrate robust neuroprotective effects of HDAC inhibitors against cerebral ischemia-induced brain injury. The neuroprotection likely involves multiple mechanisms including suppression of ischemia-induced cerebral inflammation. Given that there is no effective treatment for stroke, HDAC inhibitors such as VPA, SB and TSA should be evaluated for their potential use for clinical trials in stroke patients.

Key words: Anti-inflammation, Cerebral ischemia, HDAC inhibitors, Neuroprotection, sodium butyrate, valproic acid

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