Pre-ischemia melatonin treatment alleviated acute neuronal injury after ischemic stroke by inhibiting endoplasmic reticulum stress-dependent autophagy via PERK and IRE1 signalings
Pre-ischemia melatonin treatment alleviated acute neuronal injury after ischemic stroke by inhibiting endoplasmic reticulum stress-dependent autophagy via PERK and IRE1 signalings
复制标题
缺血前褪黑素治疗通过 PERK 和 IRE1 信号传导抑制内质网应激依赖性自噬，减轻缺血性中风后的急性神经元损伤
DOI：
10.1111/jpi.12395
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发表时间：
2017-04-01
影响因子：
10.3
通讯作者：
Qu, Yan
中科院分区：
文献类型：
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作者：
Feng, Dayun;Wang, Bao;Qu, Yan
褪黑激素具有中枢神经系统保护作用。因此，它是有趣的，以确定是否预缺血褪黑激素管理可以保护脑缺血/再灌注（IR）相关的损伤和潜在的分子机制。在这项研究中，我们发现，IR损伤显着激活内质网（ER）应激和自噬在大脑中动脉闭塞小鼠模型。缺血前褪黑激素治疗能够减弱IR诱导的ER应激和自噬。此外，与串联RFP-GFP-LC 3腺相关病毒，我们证明缺血前褪黑激素显着减轻IR诱导的自噬通量。此外，我们发现IR通过ER应激相关信号诱导神经元凋亡。此外，IR诱导的自噬被ER应激抑制剂（4-PBA）以及ER相关信号传导抑制剂（PERK抑制剂，GSK; IRE 1抑制剂，3，5-二溴水杨醛）显著阻断。最后，我们发现，褪黑激素显着减轻脑梗死，脑水肿，神经元凋亡，神经功能缺损，这是显着取消衣霉素（ER应激激活剂）和雷帕霉素（自噬激活剂），分别。总之，我们的研究提供了强有力的证据表明，缺血前褪黑激素管理显着保护脑IR损伤，通过抑制ER应激依赖性自噬。我们的研究结果揭示了新的预防和治疗策略，每天管理褪黑激素，特别是在人群中的高风险的缺血性脑卒中。
Melatonin has demonstrated a potential protective effect in central nervous system. Thus, it is interesting to determine whether pre-ischemia melatonin administration could protect against cerebral ischemia/reperfusion (IR)-related injury and the underlying molecular mechanisms. In this study, we revealed that IR injury significantly activated endoplasmic reticulum (ER) stress and autophagy in a middle cerebral artery occlusion mouse model. Pre-ischemia melatonin treatment was able to attenuate IR-induced ER stress and autophagy. In addition, with tandem RFP-GFP-LC3 adeno-associated virus, we demonstrated pre-ischemic melatonin significantly alleviated IR-induced autophagic flux. Furthermore, we showed that IR induced neuronal apoptosis through ER stress related signalings. Moreover, IR-induced autophagy was significantly blocked by ER stress inhibitor (4-PBA), as well as ER-related signaling inhibitors (PERK inhibitor, GSK; IRE1 inhibitor, 3,5-dibromosalicylaldehyde). Finally, we revealed that melatonin significantly alleviated cerebral infarction, brain edema, neuronal apoptosis, and neurological deficiency, which were remarkably abolished by tunicamycin (ER stress activator) and rapamycin (autophagy activator), respectively. In summary, our study provides strong evidence that pre-ischemia melatonin administration significantly protects against cerebral IR injury through inhibiting ER stress-dependent autophagy. Our findings shed light on the novel preventive and therapeutic strategy of daily administration of melatonin, especially among the population with high risk of cerebral ischemic stroke.