Rekuviene Evelina, Ivanoviene Laima, Borutaite Vilmante, Morkuniene Ramune
Department of Biochemistry, Lithuanian University of Health Sciences, Eiveniu 4, LT-50161 Kaunas, Lithuania.
Neuroscience Institute, Lithuanian University of Health Sciences, Eiveniu 4, LT-50161, Kaunas, Lithuania.
Neurosci Lett. 2017 Jul 13;653:45-50. doi: 10.1016/j.neulet.2017.05.028. Epub 2017 May 17.
The mitochondrial permeability transition pore (mPTP) is thought to be implicated in brain ischemia-induced cell death. Here we sought to determine whether complex I (CI) of the mitochondrial electron transfer system may be involved in regulation of mPTP opening during ischemia and whether a specific inhibitor of this complex - rotenone can protect against ischemia-induced cell death in an experimental model of total ischemia in adult rat brains. Anesthetized Wistar rats were administered a single injection of rotenone (0.01mg/kg) to the tail vein and brains were removed and subjected to 120min ischemia. We found that intravenous injection of rotenone 20min before ischemia increased resistance to Ca-induced mPTP opening and decreased production of reactive oxygen species (ROS) in mitochondria isolated from ischemia-damaged cortex and cerebellum. Rotenone administration before ischemia decreased infarct size in both brain regions (cortex and cerebellum). Rotenone added directly to normal, non-ischemic cortical or cerebellar mitochondria increased their resistance to Ca-induced mPTP opening at concentration which fully inhibited NAD-dependent mitochondrial respiration. Our data demonstrate that rotenone used intravenously may be protective against acute brain ischemia-induced injuries by inhibition of mPTP opening and ROS production. These findings suggest that CI of mitochondrial electron transfer system plays a role in mPTP regulation during cerebral ischemia in mature brains and that agents acting on CI activity may be clinically useful for stroke therapy.
线粒体通透性转换孔（mPTP）被认为与脑缺血诱导的细胞死亡有关。在此，我们试图确定线粒体电子传递系统的复合体I（CI）是否参与缺血期间mPTP开放的调节，以及该复合体的一种特异性抑制剂——鱼藤酮是否能在成年大鼠全脑缺血实验模型中预防缺血诱导的细胞死亡。将麻醉的Wistar大鼠经尾静脉单次注射鱼藤酮（0.01mg/kg），然后取出大脑并进行120分钟的缺血处理。我们发现，在缺血前20分钟静脉注射鱼藤酮可增加对钙诱导的mPTP开放的抗性，并减少从缺血损伤的皮质和小脑中分离出的线粒体中活性氧（ROS）的产生。缺血前给予鱼藤酮可减小两个脑区（皮质和小脑）的梗死面积。将鱼藤酮直接添加到正常的、非缺血的皮质或小脑线粒体中，在完全抑制NAD依赖性线粒体呼吸的浓度下，可增加其对钙诱导的mPTP开放的抗性。我们的数据表明，静脉注射鱼藤酮可能通过抑制mPTP开放和ROS产生来预防急性脑缺血诱导的损伤。这些发现表明，线粒体电子传递系统的CI在成熟大脑的脑缺血期间的mPTP调节中起作用，并且作用于CI活性的药物可能在临床上对中风治疗有用。
