Wu Jing, Zhang Mingqiang, Li Huihui, Sun Xiaoru, Hao Shuangying, Ji Muhuo, Yang Jianjun, Li Kuanyu
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, 210093 Nanjing, PR China; Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, 210002 Nanjing, PR China.
Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, 210002 Nanjing, PR China.
Behav Brain Res. 2016 May 15;305:115-21. doi: 10.1016/j.bbr.2016.02.036. Epub 2016 Mar 2.
Mitochondrial dysfunction has been linked to the earliest pathogenesis of isoflurane-induced cognitive impairments in developing or aging mammalian brain. However, its molecular mechanism is poorly understood and a pharmacologic treatment to rapidly reverse mitochondrial dysfunction is lacking. Fifteen-month-old male C57BL/6 mice were exposed to isoflurane for two hours following intraperitoneal administration of mitochondrion-targeted peptide SS-31 or vehicle with 30min interval. The hippocampus was immediately removed for biochemical assays and mitochondria isolation after inhalation. Behavioral tests were evaluated by the open field test and fear conditioning test 24h after the experiment. We showed that cognitive deficits induced by exposure of the aging mice to isoflurane were accompanied by mitochondrial dysfunction in hippocampus due to loss of the enzymatic activity of complex I. This loss resulted in the increase of reactive oxygen species production, decrease of ATP production and mitochondrial membrane potential, and opening of mitochondrial permeability transition pore. Further, we provided evidence that the BDNF signaling pathway was involved in this process to regulate synaptic plasticity-related proteins, for instance, downregulation of synapsin 1, PSD-95 and p-CREB, and upregulation of NR2A, NR2B, CaMKIIα and CaMKIIβ. Of note, the isoflurane-induced cognitive deficits were rescued by SS-31 through reversal of mitochondrial dysfunction, which facilitated the regulation of BDNF signaling including the expression reversal of aforementioned important synaptic-signaling proteins in aging mice. Our data demonstrate that reversing mitochondrial dysfunction by SS-31 enhances BDNF signaling pathway and synaptic plasticity, and provides protective effects on cognitive function, thereby support the notion that SS-31 may have therapeutic benefits for elderly humans undertaking anesthesia.
线粒体功能障碍与发育中或衰老的哺乳动物大脑中异氟烷诱导的认知障碍的最早发病机制有关。然而，其分子机制尚不清楚，并且缺乏快速逆转线粒体功能障碍的药物治疗方法。15个月大的雄性C57BL/6小鼠在腹腔注射线粒体靶向肽SS-31或载体后间隔30分钟暴露于异氟烷中两小时。吸入后立即取出海马进行生化分析和线粒体分离。实验24小时后通过旷场试验和恐惧条件试验评估行为测试。我们发现，衰老小鼠暴露于异氟烷诱导的认知缺陷伴随着海马体中的线粒体功能障碍，这是由于复合体I酶活性丧失所致。这种丧失导致活性氧产生增加、ATP产生减少和线粒体膜电位降低，以及线粒体通透性转换孔开放。此外，我们提供证据表明，BDNF信号通路参与了这一过程，以调节突触可塑性相关蛋白，例如，突触素1、PSD-95和p-CREB的下调，以及NR2A、NR2B、CaMKIIα和CaMKIIβ的上调。值得注意的是，SS-31通过逆转线粒体功能障碍挽救了异氟烷诱导的认知缺陷，这促进了BDNF信号通路的调节，包括衰老小鼠中上述重要突触信号蛋白的表达逆转。我们的数据表明，SS-31逆转线粒体功能障碍可增强BDNF信号通路和突触可塑性，并对认知功能提供保护作用，从而支持SS-31可能对接受麻醉的老年人具有治疗益处的观点。
