Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: Multiple mechanisms of action
Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: Multiple mechanisms of action
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DOI：
10.1124/jpet.107.120188
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发表时间：
2007-06-01
影响因子：
3.5
通讯作者：
Chuang, De-Maw
中科院分区：
文献类型：
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作者：
Kim, Hyeon Ju;Rowe, Michael;Chuang, De-Maw
脑缺血的病理生理学涉及多种机制，包括由活化的小胶质细胞以及浸润的巨噬细胞/单核细胞介导的神经炎症。本研究采用大鼠大脑中动脉永久性闭塞（pMCAO）模型来研究组蛋白去乙酰化酶（HDAC）抑制剂对缺血诱导的脑梗死、神经炎症、基因表达以及神经功能缺损的影响。我们发现，在pMCAO术后注射HDAC抑制剂丙戊酸（VPA）、丁酸钠（SB）或曲古抑菌素A（TSA）可减少脑梗死体积。VPA或SB在损伤后的治疗还可抑制小胶质细胞的活化，减少小胶质细胞的数量，并抑制缺血大脑中的其他炎症标志物。VPA、SB或TSA治疗可阻止缺血大脑中乙酰化组蛋白H3水平的降低。此外，注射HDAC抑制剂可过度诱导热休克蛋白70，并阻断pMCAO诱导的磷酸化Akt的下调，以及缺血引发的p53、诱导型一氧化氮合酶和环氧合酶 - 2的上调。VPA、SB或TSA治疗可改善pMCAO大鼠的运动、感觉和反射能力。当在缺血发生后至少3小时给予SB或VPA时，它们在减少脑梗死体积和神经功能缺损方面具有有益效果，且行为改善是持久的。总之，我们的结果表明HDAC抑制剂对脑缺血诱导的脑损伤具有强大的神经保护作用。这种神经保护作用可能涉及多种机制，包括抑制缺血诱导的脑部炎症。鉴于目前对中风没有有效的治疗方法，应评估HDAC抑制剂（如VPA、SB和TSA）在中风患者临床试验中的潜在应用。
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.