BACKGROUND AND PURPOSE: Excessive elevation of intracellular calcium and uncontrolled activation of calcium-sensitive events are believed to play a central role in ischemic neuronal damage. Calcium-activated proteolysis by calpain is a candidate to participate in this form of pathology because it is activated under ischemic conditions and its activation results in the degradation of crucial cytoskeletal and regulatory proteins. The present studies examined the effects of a cell-penetrating inhibitor of calpain on the pathological outcome after transient focal ischemia in the brain. METHODS: Twenty-five male Sprague-Dawley rats were divided into four groups: a saline-treated group, a vehicle-treated group, and two calpain inhibitor-treated groups (Cbz-Val-Phe-H; 30-mg/kg and 60-mg/kg cumulative doses). Ischemia was induced by occluding the left middle cerebral artery and both common carotid arteries for 3 hours followed by reperfusion. Animals were killed 72 hours after surgery, and quantitative measurements of infarction volumes were performed using histological techniques. Eight additional rats were killed 30 minutes after ischemia and examined for the extent of proteolysis using immunoblot techniques. A final group of 12 animals was decapitated after injection of vehicle or calpain inhibitor, and the proteolytic response was measured after 60 minutes of total ischemia. RESULTS: Rats treated with Cbz-Val-Phe-H exhibited significantly smaller volumes of cerebral infarction than saline-treated or vehicle-treated control animals. Intravenous injections of cumulative doses of 30 mg/kg or 60 mg/kg of Cbz-Val-Phe-H were effective in reducing infarction, edema, and calcium-activated proteolysis. The proteolytic response to postdecapitation ischemia was also reduced by the calpain inhibitor. CONCLUSIONS: These results demonstrate the neuroprotective effect of a cell-penetrating calpain inhibitor when administered systemically. The findings suggest that targeting intracellular, calcium-activated mechanisms, such as proteolysis, represents a viable therapeutic strategy for limiting neurological damage after ischemia.
BACKGROUND AND PURPOSE: Excessive elevation of intracellular calcium and uncontrolled activation of calcium-sensitive events are believed to play a central role in ischemic neuronal damage. Calcium-activated proteolysis by calpain is a candidate to participate in this form of pathology because it is activated under ischemic conditions and its activation results in the degradation of crucial cytoskeletal and regulatory proteins. The present studies examined the effects of a cell-penetrating inhibitor of calpain on the pathological outcome after transient focal ischemia in the brain. METHODS: Twenty-five male Sprague-Dawley rats were divided into four groups: a saline-treated group, a vehicle-treated group, and two calpain inhibitor-treated groups (Cbz-Val-Phe-H; 30-mg/kg and 60-mg/kg cumulative doses). Ischemia was induced by occluding the left middle cerebral artery and both common carotid arteries for 3 hours followed by reperfusion. Animals were killed 72 hours after surgery, and quantitative measurements of infarction volumes were performed using histological techniques. Eight additional rats were killed 30 minutes after ischemia and examined for the extent of proteolysis using immunoblot techniques. A final group of 12 animals was decapitated after injection of vehicle or calpain inhibitor, and the proteolytic response was measured after 60 minutes of total ischemia. RESULTS:Rats treated with Cbz-Val-Phe-H exhibited significantly smaller volumes of cerebral infarction than saline-treated or vehicle-treated control animals. Intravenous injections of cumulative doses of 30 mg/kg or 60 mg/kg of Cbz-Val-Phe-H were effective in reducing infarction, edema, and calcium-activated proteolysis. The proteolytic response to postdecapitation ischemia was also reduced by the calpain inhibitor. CONCLUSIONS: These results demonstrate the neuroprotective effect of a cell-penetrating calpain inhibitor when administered systemically. The findings suggest that targeting intracellular, calcium-activated mechanisms, such as proteolysis, represents a viable therapeutic strategy for limiting neurological damage after ischemia.
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: Isaac T Schiefer; Subhasish Tapadar; Vladislav Litosh; Marton Siklos; Rob Scism; Gihani T Wijewickrama; Esala P Chandrasena; Vaishali Sinha; Ehsan Tavassoli; Michael Brunsteiner; Mauro Fa'; Ottavio Arancio; Pavel Petukhov; Gregory R J Thatcher Journal: J Med Chem Date: 2013-07-22 Impact factor: 7.446
Authors: James R Frederick; Zhaoming Chen; Matthew B Bevers; Lori P Ingleton; Marek Ma; Robert W Neumar Journal: Crit Care Med Date: 2008-11 Impact factor: 7.598
Authors: Michael Fricker; Aviva M Tolkovsky; Vilmante Borutaite; Michael Coleman; Guy C Brown Journal: Physiol Rev Date: 2018-04-01 Impact factor: 37.312
Authors: Mandana Amini; Chun-lei Ma; Rasoul Farazifard; Guoqi Zhu; Yi Zhang; Jacqueline Vanderluit; Joanna Susie Zoltewicz; Fadi Hage; Joseph M Savitt; Diane C Lagace; Ruth S Slack; Jean-Claude Beique; Michel Baudry; Peter A Greer; Richard Bergeron; David S Park Journal: J Neurosci Date: 2013-03-27 Impact factor: 6.167
Authors: K E Saatman; H Murai; R T Bartus; D H Smith; N J Hayward; B R Perri; T K McIntosh Journal: Proc Natl Acad Sci U S A Date: 1996-04-16 Impact factor: 11.205