CALPAIN INHIBITOR AK295 PROTECTS NEURONS FROM FOCAL BRAIN ISCHEMIA - EFFECTS OF POSTOCCLUSION INTRAARTERIAL ADMINISTRATION

Background and Purpose This research was performed to determine whethe r a selective inhibitor of the calcium-depen dent protease, calpain, c ould reduce ischemia-associated brain damage when peripherally adminis tered after a vascular occlusion. Methods A variation of the rat middl e cerebral artery occlusion model was used. A range of doses of AK295 (a novel calpain inhibitor synthesized for this purpose) was continuou sly infused through the internal carotid artery, beginning 1.25 hours from the initiation of the occlusion. Rats were killed at 21 hours, an d the infarct volume was quantified. Results Postocclusion (1.25-hour) infusion of the calpain inhibitor AK295 elicited a dose-dependent neu roprotective effect after focal ischemia. The highest dose tested (3 m g/kg per hour) afforded the maximum effect, illustrated by a 32% reduc tion in infarct volume 21 hours after the ischemia (vehicle, 81.7+/-4. 7 mm(3); AK295, 54.9+/-6.9 mm(3); P<.007). Conclusions These data prov ide the first evidence that a peripherally administered calpain inhibi tor can protect against ischemic brain damage. They offer further supp ort for an important role of calpain proteolysis in the brain degenera tion associated with cerebral ischemic events and suggest that selecti ve calpain inhibitors provide a rational, novel, and viable means of t reating such neurodegenerative problems.