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Role of matrix metalloproteinases in apoptosis after transient focal cerebral ischemia in rats and mice
Author(s) -
Copin JeanChristophe,
Goodyear MarieChristelle,
Gidday Jeffrey M.,
Shah Aarti R.,
Gascon Eduardo,
Dayer Alexandre,
Morel Denis M.,
Gasche Yvan
Publication year - 2005
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2005.04367.x
Subject(s) - matrix metalloproteinase , apoptosis , transient (computer programming) , ischemia , neuroscience , matrix (chemical analysis) , medicine , microbiology and biotechnology , chemistry , biology , computer science , genetics , chromatography , operating system
The involvement of matrix metalloproteinases (MMPs) in cerebral ischemia‐induced apoptosis was investigated in a model of transient focal cerebral ischemia in rats treated intracerebroventricularly (i.c.v.) with 4‐((3‐(4‐phenoxylphenoxy)propylsulfonyl)methyl)‐tetrahydropyran‐4‐carboxylic acid N‐hydroxy amide, a broad spectrum non‐peptidic hydroxamic acid MMP inhibitor, and in MMP‐9‐deficient mice. Our results showed that MMP inhibition reduced DNA fragmentation by 51% ( P < 0.001) and cerebral infarct by 60% ( P < 0.05) after ischemia. This protection was concomitant with a 29% reduction of cytochrome c release into the cytosol ( P < 0.005) and a 54% reduction of calpain‐related α‐spectrin degradation ( P < 0.05), as well as with an 84% increase in the immunoreactive signal of the native form of poly(ADP) ribose polymerase ( P < 0.01). By contrast, specific targeting of the mmp9 gene in mice did reduce cerebral damage by 34% ( P < 0.05) but did not modify the apoptotic response after cerebral ischemia. However, i.c.v. injection of MMP‐9‐deficient mice with the same broad‐spectrum inhibitor used in rats significantly reduced DNA degradation by 32% ( P < 0.05) and contributed even further to the protection of the ischemic brain. Together, our pharmacological and genetic results indicate that MMPs other than MMP‐9 are actively involved in cerebral ischemia‐induced apoptosis.