Drug-Induced Hypothermia Reduces Ischemic Damage

Abstract

Cannabinoids confer neuroprotection in several experimental paradigms, but the responsible mechanisms remain unknown. Therefore, we sought to examine whether the synthetic CB1 agonist HU-210 is capable of reducing ischemic damage and to determine the mechanisms responsible for such protection. Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (PMCAO). After dose-response and therapeutic time window-finding experiments, the rats were injected with HU-210 (45 microg/kg IV) or vehicle 1 hour after PMCAO. Physiological parameters and cerebral blood flow in the peri-infarct zone were monitored. The animals were examined with a motor disability scale, and the infarct volumes were measured 72 hours later. We also examined the effects of the selective CB1 antagonist SR-141716 and of controlled warming on the neuroprotection conferred by HU-210. HU-210 reduced blood pressure and heart rate but did not alter the cerebral blood flow in the infarct border zone. Motor disability and infarct volumes were significantly reduced (by up to 77%; P<0.05) in animals treated with HU-210. A single injection of HU-210 significantly lowered the body temperature compared with vehicle as measured both at 1 hour (32.3+/-1.3 degrees C versus 35+/-1.6 degrees C; P=0.0024) and at 24 hours (31.5+/-2.5 degrees C versus 37.25+/-0.3 degrees C; P=0.0031) after PMCAO. The protective effects of HU-210 were partially reversed by pretreatment with SR-141716 but were completely abolished by warming of the animals to the levels observed in controls. HU-210 confers robust protection against ischemic damage. This protection is mediated at least in part by binding to CB1 receptors and is also associated with the indirect protective effects of hypothermia.