The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) Confers Acute Neuroprotection After Intracerebral Hemorrhage in Mice
The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) Confers Acute Neuroprotection After Intracerebral Hemorrhage in Mice
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DOI：
10.1007/s12975-015-0421-y
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发表时间：
2016-04-01
影响因子：
6.9
通讯作者：
Dhandapani, Krishnan M.
中科院分区：
文献类型：
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作者：
Sukumari-Ramesh, Sangeetha;Alleyne, Cargill H., Jr.;Dhandapani, Krishnan M.
自发性脑内出血（ICH）是一种目前尚无有效治疗的卒中亚型。虽然脑出血可引起严重的神经系统损伤，但脑出血后神经系统损伤的分子机制仍不清楚。鉴于表观遗传机制在神经退行性变中的新作用，本研究评估了辛二酰苯胺异羟肟酸（SAHA：伏立诺他），一种临床耐受性良好的泛组蛋白脱乙酰酶抑制剂（HDACi），是否会在ICH的临床前模型中减轻神经损伤并改善功能结局。在诱导ICH后，对小鼠给予SAHA或溶剂，并评估急性神经元死亡、神经胶质活化和神经学结局。SAHA处理的小鼠表现出较少的神经退行性变，同时神经系统结果比溶剂处理的小鼠有所改善。此外，SAHA下调神经胶质细胞活化和血红素加氧酶-1的表达，血红素加氧酶-1是一种应激诱导酶，在脑出血后的神经损伤中起关键作用。总之，这些数据有力地表明了表观遗传机制在诱导ICH后神经损伤中的作用，并提高了SAHA用于ICH后治疗干预的可能临床效用。
Spontaneous intracerebral hemorrhage (ICH) is a stroke subtype with no effective treatment. Though ICH is known to induce severe neurological damage, the molecular mechanisms of neurological injury after ICH remain largely unclear. Given the emerging role of epigenetic mechanisms in neurodegeneration, the present study evaluated whether suberoylanilide hydroxamic acid (SAHA: vorinostat), a clinically well-tolerated pan-histone deacetylase inhibitor (HDACi), would attenuate neurological injury and improve functional outcomes in a preclinical model of ICH. Mice were administered with SAHA or vehicle after an induction of ICH and acute neuronal death, glial activation, and neurological outcomes were assessed. SAHA-treated mice exhibited less neurodegeneration with concomitant improvement in neurological outcomes than vehicle-treated mice. Furthermore, SAHA downregulated glial activation and the expression of heme oxygenase-1, a stress-inducible enzyme that plays critical roles in neurological damage after ICH. Altogether, the data strongly suggest the role of epigenetic mechanisms in inducing neurological injury after ICH and raise the possible clinical utility of SAHA for therapeutic intervention after ICH.