Activation of cannabinoid receptor 1 is involved in protection against mitochondrial dysfunction and cerebral ischaemic tolerance induced by isoflurane preconditioning

Background. 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. Methods. 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. Results. 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. Conclusions. 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.