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Mitochondrial Permeability Transition Dynamics: An Indicator of Mitochondrial Potassium Channel Opener

机译：线粒体通透性转变动力学：线粒体钾通道开放剂的指标。

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Mitochondrial permeability transition (MPT) is an intracellular event that is closely related to apoptosis and necrosis. However, whether this process underlies the recently reported neuroprotective potency of mitochondrial potassium channel openers applied in vivo remains uncertain. This study aims to clarify this issue by determining the effects of potassium channel openers on MPT dynamics in vitro along with their in vivo effects. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 90 min, followed by reperfusion. 30mul of diazoxide, an opener of the mitochondrial adenosine triphosphate-sensitive K+ channel (mitoKATP ), or NS1619, an opener of the mitochondrial Ca2+-activated potassium channel (mitoKCa) (2 mM and 0.1 mM respectively), was infused into the right lateral cerebral ventricle 15 min before the induction of ischemia. Neurological scores were assessed 24 h after MCAO and then infarct area was determined by standard 2,3,5-triphenyltetrazolium chloride staining techniques. To further clarify the capacity of diazoxide and NS1619 to protect mitochondria from Ca2+-induced MPT, we isolated brain-derived non-synaptosomal mitochondria and evaluated the effects of diazoxide and NS1619 on Ca2+-induced MPT dynamics through measurement of spectrophotometric alterations in light scattering at 520 nm. Neurological scores and infarct size were improved in animals pretreated with diazoxide and NS1619. In isolated mitochondria, MPT was readily induced by 200 muM Ca2+ and was effectively inhibited by diazoxide and NS1619. The specific MPT pore opener atractyloside abolished the inhibitory effects. According to time-constant analysis, MPT dynamics was in accordance with the neuroprotective effects of channel openers in vivo. Therefore, measuring MPT dynamics provides a new means of predicting the neuroprotective effects of mitochondrial potassium channel openers
机译：线粒体通透性转变（MPT）是一种细胞内事件，与细胞凋亡和坏死密切相关。但是，该过程是否为最近报道的体内应用的线粒体钾通道开放剂的神经保护效力奠定了基础，目前尚不确定。这项研究旨在通过确定钾通道开放剂在体外对MPT动力学及其体内效应的影响来阐明这一问题。对雄性Sprague-Dawley大鼠进行大脑中动脉闭塞（MCAO）90分钟，然后再灌注。线粒体三磷酸腺苷三磷酸敏感性K + 通道的开放剂（mitoK ATP ）的二氮嗪30mul或线粒体Ca 2+ <的开放剂的NS1619 / sup>激活的钾通道（mitoK Ca ）（分别为2 mM和0.1 mM）在诱导缺血前15分钟注入右脑侧脑室。在MCAO后24小时评估神经学评分，然后通过标准的2,3,5-三苯基四唑氯化锌染色技术确定梗塞面积。为了进一步阐明二氮嗪和NS1619保护线粒体免受Ca 2 + 诱导的MPT的能力，我们分离了脑源性非突触线粒体，并评估了二氮嗪和NS1619对Ca 2的作用+ 诱导的MPT动力学，通过测量520 nm处的光散射中的分光光度法变化。用二氮嗪和NS1619预处理的动物的神经学评分和梗死面积得到改善。在分离的线粒体中，MPT易于被200μMCa 2 + 诱导，并被二氮嗪和NS1619有效抑制。 MPT特定的开孔剂白术苷消除了抑制作用。根据时间常数分析，MPT动态与体内通道开放剂的神经保护作用一致。因此，测量MPT动态提供了一种预测线粒体钾通道开放剂神经保护作用的新方法。

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