Contribution of hypothermia and CB1 receptor activation to protective effects of TAK-937, a cannabinoid receptor agonist, in rat transient MCAO model

Abstract

Background: Cannabinoid (CB) receptor agonists are expected to alleviate ischemic brain damage by modulating neurotransmission and neuroinflammatory responses via CB1 and CB2 receptors, respectively. In a previous study, TAK-937, a novel potent and selective CB1 and CB2 receptor agonist, was shown to exert significant cerebroprotective effects accompanied by hypothermia after transient middle cerebral artery occlusion (MCAO) in rats. Sustained hypothermia itself induces significant neuroprotective effects. In the present studies, we examined the relative contribution of hypothermia and CB1 receptor activation to the cerebroprotective effects of TAK-937. Methodology/Principal Findings: Using a multichannel brain temperature controlling system we developed, the brain temperature of freely moving rats was telemetrically monitored and maintained between 37 and 38°C during intravenous infusion of TAK-937 (100 μg/kg/h) or vehicle for 24 h after 2 h MCAO. AM251, a selective CB1 receptor antagonist, was administered intraperitoneally at 30 mg/kg 30 min before starting intravenous infusion of TAK-937 (100 μg/kg/h) for 24 h. Rats were sacrificed and their brains were isolated 26 h after MCAO in both experiments. When the hypothermic effect of TAK-937 was completely reversed by a brain temperature controlling system, the infarct-reducing effect of TAK-937 was attenuated in part, but remained significant. On the other hand, concomitant AM251 treatment with TAK-937 completely abolished the hypothermic and infarct-reducing effects of TAK-937. Conclusions/Significance: We conclude that the cerebroprotective effects of TAK-937 were at least in part mediated by induction of hypothermia, and mainly mediated by CB1 receptor activation. © 2012 Suzuki et al.