Hu-211, a novel noncompetitive n-methyl-d-aspartate antagonist, improves neurological deficit and reduces infarct volume after reversible focal cerebral ischemia in the rat

Background and Purpose: HU-211 is a nonpsychotropic cannabinoid analogue that has been shown to act as a functional N-methyl-D-aspartate receptor blocker. We investigated the neuroprotective efficacy of HU-211 in a model of reversible middle cerebral artery occlusion (MCAo) in rats. Methods: Male Wistar rats were anesthetized with halothane and subjected to 90 minutes of temporary MCAo by retrograde insertion of an intraluminal nylon suture, coated with poly-L-lysine, through the external carotid artery into the internal carotid artery and MCA. The drug (HU-211 in cosolvent, 4 mg/kg IV) or vehicle was administered in a blinded fashion 70 minutes after onset of MCAo. Behavioral tests were evaluated during occlusion (60 minutes) and for a 3-day period after MCAo. Three days after MCAo, brains were perfusion-fixed, and infarct volumes were determined. Results: HU-211 significantly improved the neurological score compared with vehicle during the 3 days after MCAo. Treatment with HU-211 also significantly reduced both infarct volume (mean±SEM, 66.6±12.5 versus 149.8±36.3 mm³) and brain swelling (2.61±1.33% versus 6.66±1.24%) compared with vehicle-treated rats (n=17 in each group). Conclusions: These results demonstrate the neuroprotective ability of HU-211 in focal cerebral ischemia as judged by neurological score, infarct size, and brain swelling. Reversible MCAo with the use of a poly-L- lysine-coated intraluminal suture proved to be a reliable and effective modification of this technique, yielding consistent results.