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.
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 ratmiddle 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.
Authors: K K Wang; R Nath; A Posner; K J Raser; M Buroker-Kilgore; I Hajimohammadreza; W Probert A; F W Marcoux; Q Ye; E Takano; M Hatanaka; M Maki; H Caner; J L Collins; A Fergus; K S Lee; E A Lunney; S J Hays; P Yuen Journal: Proc Natl Acad Sci U S A Date: 1996-06-25 Impact factor: 11.205
Authors: Susan B Glantz; Carol D Cianci; Rathna Iyer; Deepti Pradhan; Kevin K W Wang; Jon S Morrow Journal: Biochemistry Date: 2007-01-16 Impact factor: 3.162
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Authors: Raja B Singh; Sucheta P Dandekar; Vijayan Elimban; Suresh K Gupta; Naranjan S Dhalla Journal: Mol Cell Biochem Date: 2004-08 Impact factor: 3.396
Authors: Matthew B Bevers; Eric Lawrence; Margaret Maronski; Neasa Starr; Michael Amesquita; Robert W Neumar Journal: J Neurochem Date: 2009-01-22 Impact factor: 5.372