Stroke, Vol 25, 2265-2270, Copyright © 1994 by American Heart Association
RT Bartus, NJ Hayward, PJ Elliott, SD Sawyer, KL Baker, RL Dean, A Akiyama, JA Straub, SL Harbeson and Z Li
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: Postocclusion (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
< .007). CONCLUSIONS: These data provide the first evidence that a
peripherally administered calpain inhibitor can protect against ischemic
brain damage. They offer further support for an important role of calpain
proteolysis in the brain degeneration associated with cerebral ischemic
events and suggest that selective calpain inhibitors provide a rational,
novel, and viable means of treating such neurodegenerative problems.
ARTICLES
Calpain inhibitor AK295 protects neurons from focal brain ischemia. Effects of postocclusion intra-arterial administration
Alkermes Inc, Cambridge, MA 02139.
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