Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University,188 Shizi Street, Suzhou 215006, China.
Center of Excellence for Aging and Brain Repair, Department of Neurosurgery & Brain Repair, University of South Florida Morsani College of Medicine,12901 Bruce B Downs Blvd Tampa, FL 33612 USA.
Prog Neurobiol. 2018 Apr-May;163-164:79-97. doi: 10.1016/j.pneurobio.2017.04.002. Epub 2017 Apr 13.
Accumulating evidence advances the critical role of autophagy in brain pathology after stroke. Investigations employing autophagy induction or inhibition using pharmacological tools or autophagy-related gene knockout mice have recently revealed the biological significance of intact and functional autophagy in stroke. Most of the reported cases attest to a pro-survival role for autophagy in stroke, by facilitating removal of damaged proteins and organelles, which can be recycled for energy generation and cellular defenses. However, these observations are difficult to reconcile with equally compelling evidence demonstrating stroke-induced upregulation of brain cell death index that parallels enhanced autophagy. This begs the question of whether drug-induced autophagy during stroke culminates in improved or worsened pathological outcomes. A corollary fascinating hypothesis, but presents as a tricky conundrum, involves the effects of autophagy on cell death and inflammation, which are two main culprits in the disease progression of stroke-induced brain injury. Evidence has extended the roles of autophagy in inflammation via cytokine regulation in an unconventional secretion manner or by targeting inflammasomes for degradation. Moreover, in the recently concluded Vancouver Autophagy Symposium (VAS) held in 2014, the potential of selective autophagy for clinical treatment has been recognized. The role of autophagy in ischemic stroke has been reviewed previously in detail. Here, we evaluate the strength of laboratory and clinical evidence by providing a comprehensive summary of the literature on autophagy, and thereafter we offer our perspectives on exploiting autophagy as a drug target for cerebral ischemia, especially in hemorrhagic stroke.
越来越多的证据表明自噬在中风后的脑病理中起着关键作用。最近，使用药理学工具或自噬相关基因敲除小鼠诱导或抑制自噬的研究揭示了完整和功能性自噬在中风中的生物学意义。大多数报道的病例证明自噬在中风中具有促生存作用，通过促进清除受损的蛋白质和细胞器，这些蛋白质和细胞器可以被回收用于能量产生和细胞防御。然而，这些观察结果很难与同样令人信服的证据相协调，这些证据表明中风诱导的脑细胞死亡指数上调与增强的自噬平行。这就提出了一个问题，即在中风期间诱导的自噬是否会导致病理结果的改善或恶化。一个相关的有趣假设，但提出了一个棘手的难题，涉及自噬对细胞死亡和炎症的影响，这是中风引起的脑损伤疾病进展的两个主要罪魁祸首。证据通过非传统分泌方式调节细胞因子或靶向炎症小体进行降解，扩展了自噬在炎症中的作用。此外，在 2014 年举行的最近一次温哥华自噬研讨会（VAS）上，已经认识到选择性自噬在临床治疗中的潜力。自噬在缺血性中风中的作用以前已经在详细审查。在这里，我们通过提供自噬文献的综合总结来评估实验室和临床证据的强度，然后我们提供了我们对利用自噬作为脑缺血的药物靶点的看法，特别是在出血性中风中。
