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Cannabinoid CB1 receptor agonist ACEA alleviates brain ischemia/reperfusion injury via CB1–Drp1 pathway
Cell Death Discovery ( IF 7 ) Pub Date : 2020-10-12 , DOI: 10.1038/s41420-020-00338-3
Shuai Yang 1 , Bin Hu 1 , Zongming Wang 1 , Changming Zhang 1 , Haosen Jiao 1 , Zhigang Mao 1 , Liguang Wei 2 , Ji Jia 3 , Jingling Zhao 4
Affiliation  

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.



中文翻译:

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

大麻素 CB1 受体的激活可诱导针对脑缺血/再灌注损伤 (IRI) 的神经保护作用;然而,其机制仍不清楚。在这项研究中,我们使用氧糖剥夺/复氧 (OGD/R) 诱导的神经元细胞损伤和大脑中动脉闭塞 (MCAO) 诱导的大鼠脑 IRI 来模拟缺血性脑损伤,并假设 CB1 受体激动剂花生四烯基-2-氯乙酰胺 (ACEA) 可通过动力相关蛋白 1 (Drp1) 抑制线粒体裂变,从而保护缺血性神经元。我们发现 OGD/R 损伤降低了细胞活力和线粒体功能,增加了乳酸脱氢酶 (LDH) 的释放,并增加了细胞凋亡和线粒体裂变。值得注意的是,ACEA 显着消除了上述 OGD/R 诱导的神经元损伤。同样,ACEA 显着逆转 MCAO 引起的脑梗塞体积、神经元凋亡和线粒体裂变的增加,从而导致神经功能的恢复。ACEA 的神经保护作用明显被 CB1 受体拮抗剂 AM251 的共同给药或 Drp1 表达上调所阻断,表明 ACEA 通过 CB1-Drp1 途径减轻脑 IRI。我们的研究结果表明,CB1 受体将异常线粒体裂变与脑 IRI 联系起来,为脑 IRI 治疗提供了新的治疗靶点。

更新日期:2020-10-12
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