Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, China.
Mol Neurobiol. 2015 Feb;51(1):220-9. doi: 10.1007/s12035-014-8725-6. Epub 2014 May 10.
Accumulating evidence suggests that ischemic preconditioning (IPC) increases cerebral tolerance to the subsequent ischemic exposure. However, the underlying mechanisms are still not fully understood. In the present study, we tested the hypothesis that AMP-activated protein kinase (AMPK)-dependent autophagy contributed to the neuroprotection of IPC in rats with permanent cerebral ischemia. Male Sprague-Dawley rats were pretreated with vehicle, compound C (an AMPK inhibitor), or 3-methyladenine (3-MA, an autophagy inhibitor) and then were subjected to IPC induced by a 10-min middle cerebral artery occlusion. Afterward, the brain AMPK activity and autophagy biomarkers were measured. At 24 h after IPC, permanent cerebral ischemia was induced in these rats, and infarct volume, neurological deficits as well as cell apoptosis were evaluated 24 h later. We demonstrated that IPC activated AMPK and induced autophagy in the brain, which was accompanied by a reduction of infract volume, neurological deficits, and cell apoptosis after cerebral ischemia. Meanwhile, the IPC-induced autophagy was inhibited by compound C while the neuroprotection of IPC was abolished by compound C or 3-MA. These findings suggest that AMPK-mediated autophagy contributes to the neuroprotection of IPC, highlighting AMPK as a therapeutic target for stroke prevention and treatment.
越来越多的证据表明，缺血预处理 (IPC) 可提高大脑对随后缺血暴露的耐受能力。然而，其潜在机制仍不完全清楚。在本研究中，我们验证了一个假设，即 AMP 激活的蛋白激酶 (AMPK) 依赖性自噬有助于 IPC 对永久性脑缺血大鼠的神经保护作用。雄性 Sprague-Dawley 大鼠用载体、化合物 C（AMPK 抑制剂）或 3-甲基腺嘌呤（3-MA，自噬抑制剂）预处理，然后进行 10 分钟大脑中动脉闭塞诱导的 IPC。之后，测量大脑 AMPK 活性和自噬生物标志物。在 IPC 后 24 小时，这些大鼠诱导永久性脑缺血，并在 24 小时后评估梗死体积、神经功能缺损和细胞凋亡。结果表明，IPC 激活了大脑中的 AMPK 并诱导了自噬，这伴随着脑缺血后梗死体积、神经功能缺损和细胞凋亡的减少。同时，化合物 C 抑制了 IPC 诱导的自噬，而化合物 C 或 3-MA 则消除了 IPC 的神经保护作用。这些发现表明，AMPK 介导的自噬有助于 IPC 的神经保护作用，凸显了 AMPK 作为预防和治疗中风的治疗靶点。
