1. Academic Validation
  2. 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

  • Transl Stroke Res. 2022 Oct 1. doi: 10.1007/s12975-022-01084-7.
Danli Lu # 1 Yuxin Liu # 1 Huipeng Huang # 1 Mengyan Hu 1 Tiemei Li 1 Shisi Wang 1 Shishi Shen 1 Ruizhen Wu 1 Wei Cai 2 3 Tingting Lu 4 Zhengqi Lu 5
Affiliations

Affiliations

  • 1 Department of Neurology, Mental and Neurological Disease Research Center, the Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou, 510630, China.
  • 2 Department of Neurology, Mental and Neurological Disease Research Center, the Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou, 510630, China. caiw29@mail.sysu.edu.cn.
  • 3 Center of Clinical Immunology, Mental and Neurological Disease Research Center, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China. caiw29@mail.sysu.edu.cn.
  • 4 Department of Neurology, Mental and Neurological Disease Research Center, the Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou, 510630, China. lutingting_sysu@163.com.
  • 5 Department of Neurology, Mental and Neurological Disease Research Center, the Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou, 510630, China. luzhq@mail.sysu.edu.cn.
  • # Contributed equally.
Abstract

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.

Keywords

Autophagy; Caspase-7; ER stress; Endothelial cells; Melatonin; Stress granules; Stroke.

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