Department of Anesthesiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China.
Department of Anesthesiology, The First People's Hospital of Chenzhou/Affiliated Chenzhou Hospital, Southern Medical University, Chenzhou, 423000, China.
Fundam Clin Pharmacol. 2020 Dec;34(6):640-649. doi: 10.1111/fcp.12557. Epub 2020 Apr 13.
Recently, several studies have reported that the pharmacological effects exerted by cannabidiol (CBD) are partially related to the regulation of autophagy. Increasing evidence indicates that autophagy provides protection against ischemia-induced brain injury. However, the protective effect of CBD against mitochondrial-dependent apoptosis in hemorrhagic shock (HS)-induced brain injury has not been studied. In the present study, we observed the protective effects of CBD against neural mitochondrial-dependent apoptosis in a rat model of HS. In addition, CBD increased Beclin-1 and LC3II expression and reduced P62 expression, which were indicative of autophagy. CBD treatment attenuated the neural apoptosis induced by HS, as reflected by restoring mitochondrial dysfunction, downregulation of BAX, neuro-apoptosis ratio and NF-κB signaling activation, and upregulation of BCL2 in the cerebral cortex. Such protective effects were reversed by 3-Methyladenine, a specific autophagy inhibitor, indicating that the protective effects of CBD treatment involved autophagy. LY294002, a PI3K inhibitor, significantly inhibited CBD-induced autophagy, demonstrating that PI3K/AKT signaling is involved in the CBD's regulation of autophagy. Furthermore, we found that CBD treatment upregulated PI3K/AKT signaling via cannabinoid receptor 1. Therefore, these findings suggested that CBD treatment protects against cerebral injury induced by HS-mediated mitochondrial-dependent apoptosis by activating the PI3K/AKT signaling pathway to reinforce autophagy.
最近，有几项研究报告称，大麻二酚（CBD）的药理作用部分与自噬的调节有关。越来越多的证据表明，自噬为缺血性脑损伤提供了保护。然而，CBD 对出血性休克（HS）诱导的脑损伤中线粒体依赖性细胞凋亡的保护作用尚未得到研究。在本研究中，我们观察了 CBD 对 HS 诱导的大鼠模型中神经线粒体依赖性细胞凋亡的保护作用。此外，CBD 增加了 Beclin-1 和 LC3II 的表达，降低了 P62 的表达，表明自噬被激活。CBD 治疗减轻了 HS 诱导的神经细胞凋亡，表现为线粒体功能障碍的恢复、BAX 的下调、神经凋亡比例和 NF-κB 信号的激活以及大脑皮层中 BCL2 的上调。这种保护作用被 3-甲基腺嘌呤（一种特异性自噬抑制剂）逆转，表明 CBD 治疗的保护作用涉及自噬。PI3K 抑制剂 LY294002 显著抑制了 CBD 诱导的自噬，表明 PI3K/AKT 信号通路参与了 CBD 对自噬的调节。此外，我们发现 CBD 通过大麻素受体 1 上调了 PI3K/AKT 信号通路。因此，这些发现表明，CBD 通过激活 PI3K/AKT 信号通路增强自噬来保护 HS 介导的线粒体依赖性细胞凋亡引起的脑损伤。
