Cannabinoid CB1 receptor agonist ACEA alleviates brain ischemia/reperfusion injury via CB1-Drp1 pathway.
Cannabinoid CB1 receptor agonist ACEA alleviates brain ischemia/reperfusion injury via CB1-Drp1 pathway.
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大麻素 CB1 受体激动剂 ACEA 通过 CB1-Drp1 通路减轻脑缺血/再灌注损伤
DOI：
10.1038/s41420-020-00338-3
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发表时间：
2020
影响因子：
7
通讯作者：
Zhao J
中科院分区：
文献类型：
--
作者：
Yang S;Hu B;Wang Z;Zhang C;Jiao H;Mao Z;Wei L;Jia J;Zhao J
激活大麻素CB1受体可诱导抗脑缺血再灌注损伤(IRI)的神经保护作用，但其机制尚不清楚。本研究采用缺氧-葡萄糖剥夺/复氧(OGD/R)诱导的神经细胞损伤和大脑中动脉闭塞(MCAO)诱导的大鼠脑缺血再灌注(IRI)模型，模拟缺血性脑损伤，并假设CB1受体激动剂花生四烯基-2-氯乙胺(ACEA)通过抑制线粒体动力蛋白相关蛋白1(Drp1)的分裂而保护缺血神经元。我们发现OGD/R损伤降低了细胞存活率和线粒体功能，增加了乳酸脱氢酶(LDH)的释放，增加了细胞的凋亡和线粒体的分裂。值得注意的是，ACEA显著消除了上述OGD/R诱导的神经元损伤。同样，ACEA显著逆转了MCAO引起的脑梗塞体积增加、神经元凋亡和线粒体分裂，导致神经功能的恢复。联合应用CB1受体拮抗剂AM251或上调DRp1表达可明显阻断ACEA的神经保护作用，提示ACEA通过CB1-Drp1途径减轻脑缺血再灌注损伤。我们的发现表明，CB1受体将线粒体的异常分裂与脑IRI联系起来，为脑IRI的治疗提供了一个新的治疗靶点。
Activation of the cannabinoid CB1 receptor induces neuroprotection against brain ischemia/reperfusion injury (IRI); however, the mechanism is still unknown. In this study, we used oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury in neuronal cells and middle cerebral artery occlusion (MCAO)-induced brain IRI in rats to mimic ischemic brain injury, and hypothesized that the CB1 receptor agonist arachidonyl-2-chloroethylamide (ACEA) would protect ischemic neurons by inhibiting mitochondrial fission via dynamin-related protein 1 (Drp1). We found that OGD/R injury reduced cell viability and mitochondrial function, increased lactate dehydrogenase (LDH) release, and increased cell apoptosis, and mitochondrial fission. Notably, ACEA significantly abolished the OGD/R-induced neuronal injuries described above. Similarly, ACEA significantly reversed MCAO-induced increases in brain infarct volume, neuronal apoptosis and mitochondrial fission, leading to the recovery of neurological functions. The neuroprotective effects of ACEA were obviously blocked by coadministration of the CB1 receptor antagonist AM251 or by the upregulation of Drp1 expression, indicating that ACEA alleviates brain IRI via the CB1–Drp1 pathway. Our findings suggest that the CB1 receptor links aberrant mitochondrial fission to brain IRI, providing a new therapeutic target for brain IRI treatment.