Melatonin Offers Dual-Phase Protection to Brain Vessel Endothelial Cells in Prolonged Cerebral Ischemia-Recanalization Through Ameliorating ER Stress and Resolving Refractory Stress Granule
Melatonin Offers Dual-Phase Protection to Brain Vessel Endothelial Cells in Prolonged Cerebral Ischemia-Recanalization Through Ameliorating ER Stress and Resolving Refractory Stress Granule
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DOI：
10.1007/s12975-022-01084-7
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发表时间：
2022-10
影响因子：
6.9
通讯作者：
Danli Lu;Yuxin Liu;Huipeng Huang;M. Hu;Tiemei Li;Shisi Wang;Shishi Shen;Ruizhen Wu;
中科院分区：
文献类型：
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作者：
Danli Lu;Yuxin Liu;Huipeng Huang;M. Hu;Tiemei Li;Shisi Wang;Shishi Shen;Ruizhen Wu;
缺血再灌注损伤限制了急性缺血性脑卒中（AIS）再通治疗的时间窗。脑血管内皮细胞（brainvesselendothelialcells，BVECs）是血脑屏障（blood-brain barrier，BBB）的第一层，是缺血再灌注损伤的第一受害者。目前的研究表明，褪黑激素可以减少梗死体积，减轻脑水肿，改善神经功能缺损，并保护BBB的完整性在延长中风小鼠。在这里，我们证明，内质网（ER）相关的损伤有助于BVEC死亡的硬脑膜阶段的再灌注后，长时间缺血。当遇到缺血时，ER应激出现，特别是激活PERK-EIF 2 α信号传导和随后的程序性细胞死亡。长期缺血导致应激颗粒（SG）是难治性的，在再通过程中，这些颗粒仍未得到解决并在ER中积聚。在再灌注期间，难治性SG激活PKR-EIF 2 α并进一步加重BVEC损伤。我们报告说，褪黑激素治疗下调ER应力在缺血期和增强解离的难治性SGs在再灌注过程中，从而提供双相保护BVECs在长期脑卒中。从机制上讲，褪黑激素增强了BVEC中的自噬，这保留了ER功能并解决了难治性SG。因此，我们认为褪黑激素是一种潜在的治疗方法，可以延长AIS延迟再通治疗的时间窗。
Ischemic-reperfusion injury limits the time window of recanalization therapy in cerebral acute ischemic stroke (AIS). Brain vessel endothelial cells (BVECs) form the first layer of the blood–brain barrier (BBB) and are thus the first sufferer of ischemic-reperfusion disorder. The current study demonstrates that melatonin can reduce infarct volume, alleviate brain edema, ameliorate neurological deficits, and protect BBB integrity in prolonged-stroke mice. Here, we demonstrate that endoplasmic reticulum (ER)–associated injury contributes to BVEC death in the dural phase of reperfusion after prolonged ischemia. When encountering ischemia, ER stress arises, specifically activating PERK-EIF2α signaling and the subsequent programmed cell death. Prolonged ischemia leads stress granules (SGs) to be refractory, which remain unresolved and accumulate in ER during recanalization. During reperfusion, refractory SGs activate PKR-EIF2α and further exacerbate BVEC injury. We report that melatonin treatment downregulates ER stress in the ischemic period and enhances dissociation of the refractory SGs during reperfusion, thus offering dual-phase protection to BVECs in prolonged cerebral stroke. Mechanistically, melatonin enhances autophagy in BVECs, which preserves ER function and resolves refractory SGs. We, therefore, propose that melatonin is a potential treatment to extend the time window of delayed recanalization therapy in AIS.