title: Histone deacetylase 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. 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.
authors: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Building 10, Bethesda, MD 20892-1363, USA.
authors: Hyeon Ju
authors: HJ
authors: Kim
authors: Michael
authors: M
authors: Rowe
authors: Ming
authors: M
authors: Ren
authors: Jau-Shyong
authors: JS
authors: Hong
authors: Po-See
authors: PS
authors: Chen
authors: De-Maw
authors: DM
authors: Chuang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications; D002087:Butyrates / Q000494:pharmacology; D039481:CD11b Antigen / Q000032:analysis; D002544:Cerebral Infarction / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D053331:Ectodysplasins / Q000032:analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D017628:Microglia / Q000737:chemistry / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D002087:Butyrates; D039481:CD11b Antigen; D053331:Ectodysplasins; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; C012589:trichostatin A; D014635:Valproic Acid; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051057:Proto-Oncogene Proteins c-akt