Enhancement of Autophagy by Histone Deacetylase Inhibitor Trichostatin A Ameliorates Neuronal Apoptosis After Subarachnoid Hemorrhage in Rats
Enhancement of Autophagy by Histone Deacetylase Inhibitor Trichostatin A Ameliorates Neuronal Apoptosis After Subarachnoid Hemorrhage in Rats
复制标题
组蛋白脱乙酰酶抑制剂曲古抑菌素 A 增强自噬可改善大鼠蛛网膜下腔出血后的神经元凋亡
DOI：
10.1007/s12035-014-8986-0
复制
发表时间：
2016-01-01
影响因子：
5.1
通讯作者：
Hong, Yuan
中科院分区：
文献类型：
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作者：
Shao, Anwen;Wang, Zhen;Hong, Yuan
曲古抑菌素A（TSA）是一种泛组蛋白去乙酰化酶抑制剂，具有多种神经保护作用。本研究旨在探讨TSA是否可以增强自噬，从而减少神经细胞凋亡，并最终减轻蛛网膜下腔出血（SAH）后的早期脑损伤（EBI）。采用血管内穿孔法行SAH，术后24 h评价死亡率、神经功能评分和脑含水量。蛋白质印迹法用于定量乙酰化组蛋白H3、LC 3-II、LC 3-I、Beclin-1、细胞色素、Bax和切割的caspase-3表达。进行免疫荧光用于Beclin-1和神经元核（NeuN）的共定位。采用末端脱氧核苷酸转移酶介导的5′-三磷酸尿苷-生物素缺口末端标记法（TUNEL）和NeuN双染法检测神经元凋亡。自噬抑制剂3-甲基腺嘌呤（3-MA）被用来操纵拟议的途径。我们的研究结果表明TSA在SAH后24小时减少脑水肿并减轻神经功能缺损。TSA显著增加皮质中乙酰化组蛋白H3、LC 3-II/LC 3-I比率和Beclin-1，同时降低Bax和切割的caspase-3。Beclin-1和NeuN、TUNEL和NeuN分别共定位于皮质细胞中。TSA处理后，同侧基底皮质神经元凋亡明显抑制。相反，3-MA逆转了TSA的有益作用。这些结果表明，TSA的管理增强自噬，这有助于减轻神经细胞凋亡，改善神经功能，并减轻EBI后SAH。
Trichostatin A (TSA), a pan-histone deacetylase inhibitor, exerts multiple neuroprotective properties. This study aims to examine whether TSA could enhance autophagy, thereby reduce neuronal apoptosis and ultimately attenuate early brain injury (EBI) following subarachnoid hemorrhage (SAH). SAH was performed through endovascular perforation method, and mortality, neurological score, and brain water content were evaluated at 24 h after surgery. Western blot were used for quantification of acetylated histone H3, LC3-II, LC3-I, Beclin-1, cytochromec, Bax, and cleaved caspase-3 expression. Immunofluorescence was performed for colocalization of Beclin-1 and neuronal nuclei (NeuN). Apoptotic cell death of neurons was quantified with double staining of terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick end-labeling (TUNEL) and NeuN. The autophagy inhibitor 3-methyladenine (3-MA) was used to manipulate the proposed pathway. Our results demonstrated that TSA reduced brain edema and alleviated neurological deficits at 24 h after SAH. TSA significantly increased acetylated histone H3, the LC3-II/LC3-I ratio, and Beclin-1 while decreased Bax and cleaved caspase-3 in the cortex. Beclin-1 and NeuN, TUNEL, and NeuN, respectively, were colocalized in cortical cells. Neuronal apoptosis in the ipsilateral basal cortex was significantly inhibited after TSA treatment. Conversely, 3-MA reversed the beneficial effects of TSA. These results proposed that TSA administration enhanced autophagy, which contributes to alleviation of neuronal apoptosis, improvement of neurological function, and attenuation of EBI following SAH.