摘要：Mitochondrial dysfunction contributes to cell death after cerebral ischemia/reperfusion (I/R) injury. Cannabinoid CB1 receptor is expressed in neuronal mitochondrial membranes (mtCB1R) and involved in regulating mitochondrial functions under physiological conditions. However, whether mtCB1R affords neuroprotection against I/R injury remains unknown. We used mouse models of cerebral I/R, primary cultured hippocampal neurons exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) and Ca2+-induced injury in purified neuronal mitochondria to investigate the role of mtCB1R in neuroprotection. Our results showed selective cell-permeant CB1 receptor agonist, arachidonyl-2-chloroethylamide (ACEA), significantly up-regulated the expression of mtCB1R protein in hippocampal neurons and tissue. In vitro , ACEA restored cell viability, inhibited generation of reactive oxygen species (ROS), decreased lactate dehydrogenase (LDH) release and reduced apoptosis, improved mitochondrial function. In vivo , ACEA ameliorated neurological scores, diminished the number of TUNEL-positive neurons and decreased the expression of cleaved caspase-3. However, ACEA-induced benefits were blocked by the selective cell-permeant CB1 receptor antagonist AM251, but just partially by the selective cell-impermeant CB1 receptor antagonist hemopressin. In purified neuronal mitochondria, mtCB1R activation attenuated Ca2+-induced mitochondrial injury. In conclusion, mtCB1R is involved in ACEA-induced protective effects on neurons and mitochondrial functions, suggesting mtCB1R may be a potential novel target for the treatment of brain ischemic injury.
