Propofol Attenuates Brain Ischemic Injury Through the Cannabinoid Type 1 (CB1) Receptor

Background and objective Although the anesthetic propofol has been shown to reduce ischemic brain injury, its precise neuroprotective mechanisms remain unclear. Many studies have reported that propofol injection can increase endocannabinoid levels in vivo and in vitro. This study investigates the cerebroprotective pathways mediated by propofol during ischemic insults. Methods In vivo studies used a rat middle cerebral artery occlusion (MCAO) model to simulate stroke-related cerebral ischemia/reperfusion injury. In vitro, oxygen-glucose deprivation/reoxygenation (OGD/R) models were used to mimic ischemic neuronal conditions in primary cultured neurons. Propofol was used to treat rats with MCAO and neurons receiving OGD/R injury. After the treatments, injury levels in rats and neurons were evaluated. Results In animal models, treatment with propofol significantly reduced cerebral infarction volume, improved neurological outcomes, decreased neuronal apoptosis, and lowered oxidative stress markers, including NOX2 gp91 subunit expression and malondialdehyde concentrations, compared to the untreated MCAO controls (P < 0.05). Concurrently, propofol administration elevated antioxidant defenses by enhancing superoxide dismutase 2 activity and glutathione production. Cellular experiments demonstrated propofol's ability to preserve membrane integrity (reduced lactate dehydrogenase leakage), decrease apoptotic signaling, and restore redox balance by modulating reactive oxygen species (ROS) generation and antioxidant reserves (P < 0.05). Pharmacological intervention revealed that cannabinoid type 1 (CB1) receptor blockade, but not cannabinoid type 2 receptor antagonism (P > 0.05), effectively negated propofol's protective effects in both experimental models. Biochemical analyses identified that endogenous cannabinoids (anandamide (AEA) and 2-arachidonoylglycerol (2-AG)) were increased in the serum following propofol administration in ischemic subjects. Conclusions The findings of this investigation demonstrate that propofol induces neuroprotection and produces endocannabinoids (AEA and 2-AG) in vivo and in vitro. In vivo, propofol protects ischemic brain tissue in rats and reduces oxidative stress. In vitro, propofol reduces MCAO-induced neuronal injury by decreasing ROS generation and restoring antioxidant levels. However, the CB1 receptor antagonist abolishes propofol's protective effects in vivo and in vitro, indicating that the CB1 receptor mediates propofol's neuroprotective activity against ischemic cerebral damage.