Department of Anaesthesiology and Perioperative Medicine.
Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
Br J Anaesth. 2017 Dec 1;119(6):1213-1223. doi: 10.1093/bja/aex267.
Isoflurane preconditioning (IPC) induces cerebral ischaemic tolerance, but the mechanism remains poorly understood. The aim of this study was to determine changes in mitochondrial function in the brain after IPC, and whether the cannabinoid receptor 1 (CB1R) could be involved in the mechanism of mitochondrial protection mediated by IPC.
Adult male Sprague-Dawley rats were pretreated with isoflurane 2% for 1 h day -1 , for 5 days consecutively, and then subjected to 120 min right middle cerebral artery occlusion. Cannabinoid receptor 1 expression in the cellular and mitochondrial membrane was measured. The CB1R agonist HU-210 was administered alone, or the antagonists AM251 and SR141716A were given to the animals before each preconditioning. Neurological scores, infarct volume, apoptosis, and mitochondrial function were examined after middle cerebral artery occlusion.
Expression of CB1R on cellular and mitochondrial membranes was increased 6 h after preconditioning. Both IPC and HU-210 administration before middle cerebral artery occlusion improved neurological outcomes and reduced infarct volume. Isoflurane preconditioning increased the expression of the anti-apoptotic proteins Bcl-2 and Bcl-X L and reduced apoptosis in neurones. Isoflurane preconditioning and HU-210 also markedly preserved the activity of respiratory chain complexes, reduced mitochondrial radical generation, preserved mitochondrial membrane potential, and inhibited mitochondrial permeability transition pore opening. Cannabinoid receptor 1 antagonists abolished the improvement in mitochondrial function and the neuroprotective effects induced by IPC.
Our results indicate that IPC elicits brain ischaemic tolerance and mitochondrial protection by activating the CB1R, which provides a new mechanism for IPC-induced neuroprotection against cerebral ischaemia.
异氟烷预处理（IPC）可诱导脑缺血耐受，但机制仍不清楚。本研究旨在确定 IPC 后大脑中线粒体功能的变化，以及大麻素受体 1（CB1R）是否参与 IPC 介导的线粒体保护机制。
成年雄性 Sprague-Dawley 大鼠连续 5 天每天接受 2%异氟烷预处理 1 小时，然后进行 120 分钟右侧大脑中动脉闭塞。测量细胞和线粒体膜中的大麻素受体 1 表达。单独给予大麻素受体 1 激动剂 HU-210，或在每次预处理前给予拮抗剂 AM251 和 SR141716A。在大脑中动脉闭塞后检查神经功能评分、梗死体积、凋亡和线粒体功能。
预处理后 6 小时，细胞膜和线粒体膜上的 CB1R 表达增加。IPC 和 HU-210 预处理均可改善神经功能并减少梗死体积。异氟烷预处理增加了抗凋亡蛋白 Bcl-2 和 Bcl-XL 的表达，并减少了神经元的凋亡。异氟烷预处理和 HU-210 还明显保留了呼吸链复合物的活性，减少了线粒体自由基的生成，维持了线粒体膜电位，并抑制了线粒体通透性转换孔的开放。大麻素受体 1 拮抗剂消除了 IPC 诱导的线粒体功能改善和神经保护作用。
我们的结果表明，IPC 通过激活 CB1R 引发脑缺血耐受和线粒体保护，为 IPC 诱导的脑缺血神经保护提供了新的机制。
