Inhibition of mitochondrial permeability transition pore opening contributes to the neuroprotective effects of ischemic postconditioning in rats
Inhibition of mitochondrial permeability transition pore opening contributes to the neuroprotective effects of ischemic postconditioning in rats
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DOI：
10.1016/j.brainres.2011.11.055
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发表时间：
2012-02-03
期刊：
影响因子：
2.9
通讯作者：
Xiong, Lize
中科院分区：
文献类型：
--
作者：
Sun, Jing;Luan, Qi;Xiong, Lize
缺血后处理（Ischemic postconditioning，IPost）可减轻脑缺血再灌注损伤。然而，这一机制仍然难以捉摸。由于线粒体渗透性转换孔（MPTP）的开放是缺血再灌注后细胞死亡的关键决定因素，因此我们假设IPost的神经保护作用可能与MPTP开放的抑制有关。在本研究的第1部分中，戊巴比妥麻醉大鼠大脑中动脉闭塞90分钟，然后再灌注72小时，分配接受以下治疗之一：IPost的三个周期（各15 s）、侧脑室注射生理盐水（对照）、给予MPTP抑制剂环孢菌素A（CsA）（2 μ mol/L，15 μ L）或其赋形剂乙醇，给予MPTP开放剂CsA/Atr（2 mmol/L，15 μ L）或IPost + CsA/Atr处理。评估神经功能缺损评分（NDS）和梗死体积。再灌注后观察线粒体超微结构和肿胀情况。第二部分：对照组和Post组分别行缺血90 min和再灌注15 min。CsA和Atr组按照第1部分所述进行治疗。再灌注后分离脑线粒体并测定MPTP活性。IPost或CsA治疗显著改善NDS和减少梗死体积，而Atr逆转IPost的神经保护作用，并减弱IPost或CsA诱导的线粒体肿胀的减少。因此，抑制MPTP开放可能在IPost的神经保护作用中起重要作用，其可能具有潜在的临床应用价值。(C)2011 Elsevier B. V.保留所有权利。
Ischemic postconditioning (IPost) has been shown to attenuate cerebral ischemia-reperfusion injury. However, the mechanism remains elusive. Because opening of the mitochondrial permeability transition pore (MPTP) is a crucial determinant of cell death after ischemia-reperfusion, we hypothesized that the neuroprotective effect of IPost may be associated with inhibition of MPTP opening. In part 1 of this study, pentobarbital-anesthetized rats subjected to middle cerebral artery occlusion for 90 min, followed by reperfusion for 72 h, were assigned to receive one of the following treatments: three cycles of IPost (15 s each), intracerebroventricular injection of saline (control), administration of the MPTP inhibitor cyclosporin A (CsA) (2 mu mol/L, 15 mu L) or its vehicle alcohol, administration of the MPTP opener atractyloside (Atr) (2 mmol/L, 15 (mu L), or IPost plus CsA/Atr treatment. Neurological deficit scores (NDS) and infarct volumes were assessed. Mitochondrial ultrastructure and swelling were also examined after reperfusion. In part 2, control and Post groups underwent ischemia (90 min) and reperfusion (15 min). CsA and Atr groups were treated as described in part 1. Brain mitochondria were isolated after reperfusion and MPTP activity was evaluated. IPost or CsA treatment significantly improved NDS and reduced infarction volume, while Atr reversed the neuroprotective effects of IPost, and attenuated the decrease in mitochondrial swelling induced by IPost or CsA. Thus, inhibiting MPTP opening may play a crucial role in the neuroprotective effects of IPost, which may have potential clinical value against cerebral ischemia-reperfusion injury. (C) 2011 Elsevier B.V. All rights reserved.