Abstract
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.
Highlights
I/R injury therapeutics[7,8,9]
We observed that mtCB1R expression was significantly increased at 2 h after reperfusion compared with Sham group (P = 0.046) and ACEA increased the mtCB1R expression more obviously (P < 0.001)
We found that mtCB1R expression was significantly up-regulated after the administration of ACEA, leading to neuroprotection against OGD/R and cerebral I/R injury
Summary
Approaches that regulate mitochondria effectively after cerebral I/R injury are still poorly understood. Cannabinoid CB1 receptor is a G protein-coupled receptor expressed mainly in neuronal plasma membrane, modulating neuronal metabolism, activity and functions strictly[10,11,12]. Studies indicated that the marijuana-derivative cannabis Δ 9-tetrahydrocannabinol (THC) could induce neuroprotection by up-regulating CB1 receptor and maintain mitochondrial function[10,13,14]. Whether up-regulation of mtCB1R modulates mitochondrial functions and exerts neuroprotection against I/R injury is still unknown. We used mouse models of global cerebral I/R, primary cultured hippocampal neurons OGD/R and Ca2+-induced injury in purified intact mitochondria from hippocampal neurons to investigate the role of mtCB1R in neuroprotection and improvement of mitochondrial function
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
