INHIBITION OF RAPAMYCIN-INDUCED AUTOPHAGY CAUSES NECROTIC CELL DEATH ASSOCIATED WITH BAX/BAD MITOCHONDRIAL TRANSLOCATION
INHIBITION OF RAPAMYCIN-INDUCED AUTOPHAGY CAUSES NECROTIC CELL DEATH ASSOCIATED WITH BAX/BAD MITOCHONDRIAL TRANSLOCATION
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DOI：
10.1016/j.neuroscience.2011.12.021
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发表时间：
2012-02-17
期刊：
影响因子：
3.3
通讯作者：
Balduini, W.
中科院分区：
文献类型：
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作者：
Carloni, S.;Buonocore, G.;Balduini, W.
雷帕霉素是一种亲脂性大环内酯类抗生素，已被发现在不同的神经退行性疾病模型中可以减少损伤。我们先前已经证明，在缺氧缺血(HI)的新生大鼠中，雷帕霉素的神经保护作用与自噬增加和caspase-3活性降低有关。我们发现，雷帕霉素对caspase-3活性的强烈抑制至少部分是由于其对线粒体固有的凋亡途径的影响，因为在雷帕霉素处理后，Bax和Bad向线粒体的易位显著减少，细胞色素c的释放和caspase-3的激活。多聚(ADP-核糖)聚合酶1(PARP-1)的裂解和dUDP缺口末端标记(TUNEL)阳性细胞的数量也减少。为了评估雷帕霉素的抗凋亡作用如何与药物诱导的强烈自噬信号有关，我们用3-甲基腺嘌呤(3MA)阻断了自噬小体的形成。3MA在雷帕霉素作用10min后，再次引起Bax和Bad易位到线粒体，但不引起细胞色素c的释放和caspase-3的激活。3MA处理后，细胞发生坏死细胞死亡。这些数据表明，在HI之前给予雷帕霉素可以阻止通过线粒体途径发生的细胞凋亡信号。我们假设雷帕霉素提供了一种预适应样的保护，并建议在使用针对自噬的药物进行神经保护之前必须谨慎，因为它们可能干扰内源性保护机制。(C)2011年IBRO。爱思唯尔有限公司出版。保留所有权利。
Rapamycin, a lipophilic macrolide antibiotic, has been found to reduce injury in different models of neurodegenerative disorders. We have previously shown that in neonatal rats subjected to hypoxia-ischemia (HI) the neuroprotective effect of rapamycin was associated with increased autophagy and decreased caspase-3 activation. We show here that the strong reduction of caspase-3 activation after rapamycin was due, at least in part, to its effect on the intrinsic apoptotic mitochondrial pathway because after rapamycin treatment there was a marked reduction of Bax and Bad translocation to mitochondria, cytochrome c release, and caspase-3 activation. Poly (ADP-ribose) polymerase 1 (PARP-1) cleavage and the number of terminal dUDP nick-end labeling (TUNEL)-positive cells were also reduced. To assess how the antiapoptotic effect of rapamycin was linked to the strong autophagy signal induced by the drug, we blocked the formation of autophagosomes with 3-methyladenine (3MA). 3MA administered 10 min after rapamycin, elicited again Bax and Bad translocation to the mitochondria but did not cause cytochrome c release and caspase-3 activation. After 3MA treatment, cells underwent necrotic cell death. These data indicate that rapamycin administered before HI prevents the apoptotic signaling taking place through the mitochondrial pathway. We hypothesize that rapamycin confers a preconditioning-like protection and suggest that caution is necessary before using pharmacological agents targeting autophagy in neuroprotection because they could interfere with endogenous protective mechanisms. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.