Modulation of the balance between cannabinoid CB1 and CB2 receptor activation during cerebral ischemic/reperfusion injury

Cannabinoid receptor activation has been shown to modulate both neurotransmission (CB1) and neuroinflammatory (CB2) responses. There are conflicting reports in the literature describing the influence of cannabinoid receptor activation on ischemic/reperfusion injury. The goal of this study was to evaluate how changing the balance between CB1 and CB2 activation following cerebral ischemia influences outcome. CB1 and CB2 expression were tested at different times after transient middle cerebral artery occlusion (MCAO) in mice by real-time RT-PCR. Animals subjected to 1 h MCAO were randomly assigned to receive different treatments: a CB1 antagonist, a CB2 antagonist, a CB2 agonist, a CB1 antagonist plus CB2 agonist, a CB2 antagonist plus CB2 agonist or an equal volume of vehicle as control. Cerebral blood flow was continuously monitored during ischemia; cerebral infarction and neurological deficit were tested 24 h after MCAO. Cerebral CB1 and CB2 mRNA expression undertook dynamic changes during cerebral ischemia. The selective CB1 antagonist significantly decreased cerebral infarction by 47%; the selective CB2 antagonist increased infarction by 26% after 1 h MCAO followed by 23 h reperfusion in mice. The most striking changes were obtained by combining a CB1 antagonist with a CB2 agonist. This combination elevated the cerebral blood flow during ischemia and reduced infarction by 75%. In conclusion, during cerebral ischemia/reperfusion injury, inhibition of CB1 receptor activation is protective while inhibition of CB2 receptor activation is detrimental. The greatest degree of neuroprotection was obtained by combining an inhibitor of CB1 activation with an exogenous CB2 agonist.