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

Abstract

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 mm 3 ) 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.