期刊
BRAIN RESEARCH
卷 901, 期 1-2, 页码 94-101出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/S0006-8993(01)02289-2
关键词
cathepsin B; cysteine protease; middle cerebral artery occlusion; focal cerebral ischemia; cathepsin L; protease inhibitor; rat
资金
- NINDS NIH HHS [NS39075-01] Funding Source: Medline
Ischemic neuronal injury mediated by cysteine proteases such as calpains and caspases has been demonstrated in various experimental models. Cathepsins B and L are also cysteine proteases which may contribute to neuronal death after ischemia. The authors measured in vitro and in vivo toxicity and post-ischemic cytoprotective effects of a cysteine protease inhibitor which does not block calpain or caspase but, rather, is relatively selective for cathepsins B and L. The compound belongs to the peptidyl-diazomethane family (cysteine protease inhibitor 1, termed CP-1). In vitro toxicity was measured using an assay of cell viability, and in vivo toxicity was measured by histological tissue analysis after infusion of CP-1 in rats. Two hours of middle cerebral artery (MCA) occlusion in rats was performed by the intravascular suture method. Immediately following reperfusion, intravenous infusion of CP-1 or vehicle was performed for 4 h at 0.9 ml/h. After a 7-day survival, the infarct volumes were measured. CP-1 was non-toxic to cultured glial cells to a local concentration of 200 muM, and relatively non-toxic to cultured endothelial cells at concentrations of 100-200 muM. No animal exhibited toxic effects at any of the doses used. Histologic comparisons revealed no signs of tissue toxicity. CP-1 significantly reduced hemispheric infarct volume compared to control (37+/-8.2%) at concentrations of 10, 50, and 250 muM [22+/-15%, P = 0.008; 20+/-13%. P = 0.002; 23+/-15%, P = 0.022, respectively (mean+/-standard deviation: N = 7-10 per group)]. CP-1. at the concentration of 50 muM, improved the functional score of the animals, but did not significantly alter cerebral blood flow. This study supports the hypothesis that the lysosomal cathepsins B and/or L contribute to cerebral injury after focal ischemia with reperfusion. Cysteine protease inhibitors which are relatively selective for cathepsins B and L, but not the calpains or caspases, are effective at reducing infarct volume after intravenous post-ischemic administration. (C) 2001 Elsevier Science B.V. All rights reserved.
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