Calpain inhibitor AK295 protects neurons from focal brain ischemia: Effects of postocdusion intra-arterial administration

Abstract

Background and Purpose This research was performed to determine whether a selective inhibitor of the calcium-dependent protease, calpain, could reduce ischemia-associated brain damage when peripherally administered after a vascular occlusion. Methods A variation of the rat middle cerebral artery occlusion model was used. A range of doses of AK295 (a novel calpain inhibitor synthesized for this purpose) was continuously infused through the internal carotid artery, beginning 1.25 hours from the initiation of the occlusion. Rats were killed at 21 hours, and the infarct volume was quantified. Results Postocdusion (1.25-hour) infusion of the calpain inhibitor AK295 elicited a dose-dependent neuroprotective effect after focal ischemia. The highest dose tested (3 mg/kg per hour) afforded the maximum effect, illustrated by a 32% reduction in infarct volume 21 hours after the ischemia (vehicle, 81.7±4.7 mm3; AK295, 54.9±6.9 mm3; P