Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China.
Department of Pathology and Pathophysiology, The Fourth Military Medical University, Xi'an, 710032, China.
Neuropharmacology. 2018 Jun;135:211-222. doi: 10.1016/j.neuropharm.2018.03.024. Epub 2018 Mar 21.
Cannabinoid type 1 (CB1) receptor agonist arachidonyl-2-chloroethylamide (ACEA) induces neuroprotection against brain ischemia, and the mechanism, however, is still elusive. In this study, we used bilateral common carotid artery occlusion (BCCAO) in mice and oxygen-glucose deprivation (OGD) in primary cultured neurons to mimic brain ischemic injury, and hypothesized that cannabinoid CB1 receptor agonist ACEA protects ischemic neurons via inhibiting the opening of mitochondrial permeability transition pore (MPTP). In vivo, we found that BCCAO treatment reduced the neurological functions, increased the number of apoptotic neuronal cells and deteriorated the mitochondrial morphology in the ischemic brain tissue. And in vitro, we observed that OGD injury reduced cell viability, mitochondrial function and anti-oxidant SOD2 expression, increased lactate dehydrogenase (LDH), mitochondrial cytochrome C (Cyto C) and apoptosis-inducing factor (AIF) releases, elevated the cell apoptosis and mitochondrial superoxide level. And the CB1 receptor agonist ACEA significantly abolished the BCCAO and OGD-induced neuronal injury above. However, the MPTP opener atractyloside (Atr) markedly reversed the ACEA-induced neuroprotective effects, inhibited the mitochondrial Cyto C and AIF releases and relieved the mitochondrial swelling, but the MPTP inhibitor cyclosporin A (CsA) did not cause significant effects on the ACEA-induced neuroprotection above. These findings indicated that inhibition of MPTP opening may be involved in the cannabinoid CB1 receptor agonist ACEA-induced neuroprotection.
大麻素 1 型（CB1）受体激动剂花生四烯酸 2-氯乙基酰胺（ACEA）可诱导对脑缺血的神经保护作用，但作用机制仍不清楚。在本研究中，我们使用双侧颈总动脉闭塞（BCCAO）和原代培养神经元氧葡萄糖剥夺（OGD）来模拟脑缺血损伤，并假设大麻素 CB1 受体激动剂 ACEA 通过抑制线粒体通透性转换孔（MPTP）的开放来保护缺血神经元。在体内，我们发现 BCCAO 处理降低了神经功能，增加了凋亡神经元细胞的数量，并恶化了缺血脑组织中的线粒体形态。在体外，我们观察到 OGD 损伤降低了细胞活力、线粒体功能和抗氧化 SOD2 表达，增加了乳酸脱氢酶（LDH）、线粒体细胞色素 C（Cyto C）和凋亡诱导因子（AIF）的释放，升高了细胞凋亡和线粒体超氧化物水平。而 CB1 受体激动剂 ACEA 显著消除了上述 BCCAO 和 OGD 诱导的神经元损伤。然而，MPTP 开放剂苍术苷（Atr）显著逆转了 ACEA 诱导的神经保护作用，抑制了线粒体 Cyto C 和 AIF 的释放，并缓解了线粒体肿胀，但 MPTP 抑制剂环孢素 A（CsA）对 ACEA 诱导的神经保护作用没有明显影响。这些发现表明，抑制 MPTP 开放可能参与了大麻素 CB1 受体激动剂 ACEA 诱导的神经保护作用。
