contribution of hypothermia and cb1 receptor activation to protective effects of tak-937, a cannabinoid receptor agonist, in rat transient mcao model贡献的体温过低和cb1受体激活tak - 937的保护作用,大麻素受体激动剂,老鼠瞬态mcao模型.pdf

Contribution of Hypothermia and CB1 Receptor Activation to Protective Effects of TAK-937, a Cannabinoid Receptor Agonist, in Rat Transient MCAO Model 1 1 1 1,2 1 Noriko Suzuki , Motohisa Suzuki , Kazuhiro Hamajo , Koji Murakami , Tetsuya Tsukamoto , Masato Shimojo1* 1 Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan, 2 Division of Pharmaceutical Sciences, Kanazawa University Graduate School of Natural Science and Technology, Kanazawa, Japan 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 38uC during intravenous infusion of TAK-937 (100 mg/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 mg/kg/h) for 24 h