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CELLULAR AND MOLECULAR

Histone Deacetylase Inhibitors Exhibit Anti-Inflammatory and Neuroprotective Effects in a Rat Permanent Ischemic Model of Stroke: Multiple Mechanisms of Action

Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (H.J.K., M.Ro., M.Re., D.-M.C.); and Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (J.-S.H., P.-S.C.)

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. Postinsult 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 superinduced heat-shock protein 70 and blocked pMCAO-induced down-regulation of phospho-Akt, as well as ischemia-elicited up-regulation of p53, inducible nitric oxide synthase, and cyclooxygenase-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 probably 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.

Address correspondence to: Dr. De-Maw Chuang, Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Building 10, Room 4C-206, 10 Center Drive, MSC-1363, Bethesda, MD 20892-1363. E-mail: chuang{at}mail.nih.gov

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				Y. Leng, M.-H. Liang, M. Ren, Z. Marinova, P. Leeds, and D.-M. Chuang Synergistic Neuroprotective Effects of Lithium and Valproic Acid or Other Histone Deacetylase Inhibitors in Neurons: Roles of Glycogen Synthase Kinase-3 Inhibition J. Neurosci., March 5, 2008; 28(10): 2576 - 2588. [Abstract] [Full Text] [PDF]