ROS-independent preconditioning in neurons via activation of mitoKATP channels by BMS-191095
ROS-independent preconditioning in neurons via activation of mitoKATP channels by BMS-191095
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DOI：
10.1038/sj.jcbfm.9600611
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发表时间：
2008-06-01
影响因子：
6.3
通讯作者：
Busija, David W.
中科院分区：
文献类型：
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作者：
Gaspar, Tamas;Snipes, James A.;Busija, David W.
以前，我们已经证明选择性线粒体三磷酸腺苷敏感钾通道开放剂BMS-191095(BMS)诱导神经元预适应(PC)；然而，BMS诱导神经保护的确切机制尚不清楚。在这项研究中，我们利用分离的大鼠脑线粒体和原代培养的大鼠皮质神经元，鉴定了导致BMS延迟神经元PC的级联反应的关键成分。BMS使分离的线粒体去极化，而不增加活性氧物种(ROS)的产生，并诱导Akt和糖原合成酶-3β的快速磷酸化。长期(3天)用BMS处理神经元，导致线粒体持续去极化，基础ROS生成减少，ATP水平升高。这种治疗还对谷氨酸兴奋毒性产生了几乎完全的保护作用，这种保护可以用磷脂酰肌醇3-激酶(PI3K)抑制剂Wortmannin取消，但不能用超氧化物歧化酶(SOD)模拟物M40401取消。长期BMS处理诱导依赖PI3K的过氧化氢酶表达和活性增加，而对锰和铜/锌依赖的超氧化物歧化酶没有影响。最后，过氧化氢酶抑制剂3-氨基三氮唑呈剂量依赖性拮抗BMS诱导的PC的神经保护作用。综上所述，BMS使线粒体去极化而不产生ROS，激活PI3K-Akt途径，提高ATP含量，并增加过氧化氢酶的表达。这些机制似乎在BMS的神经保护作用中起着重要作用。
Previously, we have shown that the selective mitochondrial ATP-sensitive potassium ( mitoKATP) channel opener BMS-191095 (BMS) induces neuronal preconditioning (PC); however, the exact mechanism of BMS-induced neuroprotection remains unclear. In this study, we have identified key components of the cascade resulting in delayed neuronal PC with BMS using isolated rat brain mitochondria and primary cultures of rat cortical neurons. BMS depolarized isolated mitochondria without an increase in reactive oxygen species (ROS) generation and induced rapid phosphorylation of Akt and glycogen synthase kinase-3 beta. Long-term (3 days) treatment of neurons with BMS resulted in sustained mitochondrial depolarization, decreased basal ROS generation, and elevated ATP levels. This treatment also elicited almost complete protection against glutamate excitotoxicity, which could be abolished using the phosphoinositide 3-kinase (PI3K) inhibitor wortmannin, but not with the superoxide dismutase (SOD) mimetic M40401. Long-term BMS treatment induced a PI3K-dependent increase in the expression and activity of catalase without affecting manganese SOD and copper/zinc-dependent SOD. Finally, the catalase inhibitor 3-aminotriazole dose-dependently antagonized the neuroprotective effect of BMS-induced PC. In summary, BMS depolarizes mitochondria without ROS generation, activates the PI3K - Akt pathway, improves ATP content, and increases catalase expression. These mechanisms appear to play important roles in the neuroprotective effect of BMS.