AUTOPHAGY ACTIVATION IS ASSOCIATED WITH NEUROPROTECTION AGAINST APOPTOSIS VIA A MITOCHONDRIAL PATHWAY IN A RAT MODEL OF SUBARACHNOID HEMORRHAGE
AUTOPHAGY ACTIVATION IS ASSOCIATED WITH NEUROPROTECTION AGAINST APOPTOSIS VIA A MITOCHONDRIAL PATHWAY IN A RAT MODEL OF SUBARACHNOID HEMORRHAGE
复制标题
在蛛网膜下腔出血大鼠模型中，自噬激活与通过线粒体途径对抗细胞凋亡的神经保护有关
DOI：
10.1016/j.neuroscience.2012.03.055
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发表时间：
2012-06-28
期刊：
影响因子：
3.3
通讯作者：
Chen, G.
中科院分区：
文献类型：
--
作者：
Jing, C. -H.;Wang, L.;Chen, G.
自噬，细胞质成分的大量细胞内降解，可以是一个促生存或促死亡的机制，这取决于上下文。最近的研究表明，自噬在蛛网膜下腔出血（SAH）后的早期脑损伤阶段被激活。然而，SAH后的自噬激活是保护性的还是有害的仍然是难以捉摸的。本研究旨在确定自噬通路激活在SAH后早期脑损伤中的潜在作用。在SAH发作前，大鼠脑室内灌注自噬诱导剂雷帕霉素（RAP）或抑制剂3-甲基腺嘌呤（3-MA）。电镜观察结果表明，RAP处理引起自噬体空泡形成，3-MA诱导神经元凋亡。RAP治疗显著增加SAH后自噬蛋白Atg 5和Beclin 1的表达，微管相关蛋白1轻链3（LC 3）-II与LC 3-I的比值，降低caspase-3活性，末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记（TUNEL）阳性细胞数，脑水肿和神经功能缺损。相反，3-MA治疗加重了早期脑损伤。RAP治疗显著增加SAH后自噬蛋白Atg 5和Beclin 1的表达，LC 3-II与LC 3-I的比值，降低caspase-3活性，TUNEL阳性细胞数，脑水肿和神经功能缺损。相反，3-MA治疗逆转了这些变化并加重了早期脑损伤。为了进一步阐明自噬保护机制，我们研究了关键的自噬相关分子的表达水平。结果表明，RAP给药减少了Bax向线粒体的易位和下游细胞色素c从线粒体向胞质溶胶的释放。总之，我们的研究表明，自噬途径的激活减少了SAH后早期脑损伤。这种神经保护作用可能是由抗凋亡机制发挥的。(C)2012年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Autophagy, the bulk intracellular degradation of cytoplasmic constituents, can be a pro-survival or a pro-death mechanism depending on the context. A recent study showed that autophagy was activated in the phase of early brain injury following subarachnoid hemorrhage (SAH). However, whether autophagy activation after SAH is protective or harmful is still elusive. This study was undertaken to determine the potential role of autophagy pathway activation in early brain injury following SAH. The rats were pre-treated with intracerebral ventricular infusion of either the autophagy inducer rapamycin (RAP) or inhibitor 3-methyladenine (3-MA) before SAH onset. The results from electron microscopic examinations showed that RAP administration caused the formation of autophagosomal vacuoles, and 3-MA induced neuronal apoptosis. RAP treatment significantly increased the expression of autophagic proteins Atg5 and Beclin 1, the ratio of microtubule-associated protein 1 light chain 3 (LC3)-II to LC3-I and reduced caspase-3 activity, the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL)-positive cells, brain edema and neurological deficits after SAH. Conversely, 3-MA treatment exacerbated early brain injury. RAP treatment significantly increased the expression of the autophagic proteins Atg5 and Beclin 1, the ratio of LC3-II to LC3-I and reduced caspase-3 activity, the number of TUNEL-positive cells, brain edema and neurological deficits after SAH. Conversely, 3-MA treatment reversed these changes and exacerbated early brain injury. To further clarify the mechanism of autophagy protection, we investigated the expression levels of key apoptosis-related molecules. The results showed that RAP administration decreased Bax translocation to the mitochondria and downstream cytochrome c release from the mitochondria to the cytosol. Taken together, our study indicates that activation of autophagic pathways reduces early brain injury after SAH. This neuroprotective effect is likely exerted by anti-apoptotic mechanisms. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.