Mitochondrial targets for stroke: focusing basic science research toward development of clinically translatable therapeutics.
Mitochondrial targets for stroke: focusing basic science research toward development of clinically translatable therapeutics.
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DOI：
10.1161/strokeaha.108.543769
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发表时间：
2009-09
期刊：
影响因子：
8.3
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Vosler PS;Graham SH;Wechsler LR;Chen J
中风是死亡和残疾的主要原因，因此必须开发治疗方法来减轻中风相关损伤。尽管前景广阔，但在中风动物模型中成功转化神经保护剂的尝试却取得了非常有限的临床成功。这篇综述根据测试的治疗靶点和中风的病理生理学讨论了缺乏转化成功的原因。讨论了有关线粒体介导的细胞死亡的新的再通疗法和替代治疗策略。线粒体死亡调节途径分为三类：上游信号传导途径、直接靶向线粒体的药物和下游死亡执行效应器。以凋亡信号相关激酶/c-Jun 末端激酶通路为例，说明为什么抑制线粒体功能障碍上游的信号通路是一种有前途的治疗方法。最后，讨论了与中风相关的自噬和线粒体生物发生机制。越来越多的证据表明，再灌注对于改善中风后的神经系统结果是必要的。开发具有增加治疗窗的改进的再通方法将有助于改善临床结果。还必须开发辅助神经保护干预措施，以确保最大限度地挽救脑组织。针对线粒体损伤上游的prodeath信号通路有望成为潜在的临床有效治疗方法。进一步了解自噬和线粒体生物发生平衡在中风发病机制中的作用也可能带来新的治疗方法。
Stroke is a major cause of death and disability, and it is imperative to develop therapeutics to mitigate stroke-related injury. Despite many promising prospects, attempts at translating neuroprotective agents that show success in animal models of stroke have resulted in very limited clinical success. This review discusses reasons for the lack of translational success based on the therapeutic targets tested and the pathophysiology of stroke. New recanalization therapies and alternative therapeutic strategies are discussed concerning mitochondria-mediated cell death. Mitochondrial death-regulation pathways are divided into 3 categories: Upstream signaling pathways, agents that target mitochondria directly, and downstream death-execution effectors. The apoptosis signal-related kinase/c-Jun–terminal kinase pathway is used as an example to provide rationale as to why inhibiting signaling pathway upstream of mitochondrial dysfunction is a promising therapeutic approach. Finally, the mechanisms of autophagy and mitochondrial biogenesis are discussed in relation to stroke. Increasing evidence suggests that reperfusion is necessary for improved neurological outcomes after stroke. Development of improved recanalization methods with increased therapeutic windows will aid in improving clinical outcome. Adjunct neuroprotective interventions must also be developed to ensure maximal brain tissue salvage. Targeting prodeath signaling pathways upstream of mitochondrial damage is promising for potential clinically effective treatment. Further understanding of the roles of equilibrium of autophagy and mitochondrial biogenesis in the pathogenesis of stroke could also lead to novel therapeutics.