Role of matrix metalloproteinases in apoptosis after transient focal cerebral ischemia in rats and mice.
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 alpha-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.
Copin
Jean-Christophe
JC
Department of Neuroscience, University Medical Center, 1211 Geneva, Switzerland. Jean-Christophe.Copin@medecine.unige.ch
Goodyear
Marie-Christelle
MC
Gidday
Jeffrey M
JM
Shah
Aarti R
AR
Gascon
Eduardo
E
Dayer
Alexandre
A
Morel
Denis M
DM
Gasche
Yvan
Y
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western / Q000379:methods; D002545:Brain Ischemia / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D002154:Calpain / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D007839:Functional Laterality / Q000502:physiology; D006877:Hydroxamic Acids; D020287:In Situ Nick-End Labeling / Q000379:methods; D007276:Injections, Intraventricular / Q000379:methods; D007375:Interleukin-1 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D013194:Staining and Labeling / Q000379:methods; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides
C455462:CH6631; D006877:Hydroxamic Acids; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D013449:Sulfonamides; D045304:Cytochromes c; D002154:Calpain; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9