title: Gelatinase B and TIMP-1 are regulated in a cell- and time-dependent manner in association with neuronal death and glial reactivity after global forebrain ischemia.
abstract: Matrix metalloproteinases (MMPs) belong to a large family of endopeptidases that regulate the pericellular environment through the cleavage of protein components of the extracellular matrix, membrane receptors and cytokines. MMP activity is controlled by the multifunctional tissue inhibitors of metalloproteinases (TIMPs). Proteases and their inhibitors are critically involved in developmental and pathological processes in numerous organs, including the brain. Global transient cerebral ischemia induces selective delayed neuronal death and neuroinflammation. We compared, in discrete vulnerable and resistant areas of the ischemic rat hippocampus, the kinetics and cellular distribution of gelatinase B and its principal inhibitor TIMP-1 and we assessed by in situ zymography, the net gelatinolytic activity at the cellular level. We show that gelatinases are expressed and active in neurons, suggesting that MMPs play a role in maintaining neural homeostasis. In the ischemic rat brain, expression and activity of gelatinase B, and expression of TIMP-1 are altered in a time-, region- and cell-dependent manner. Gelatinase B is induced first in reactive microglia and subsequently in reactive astrocytes. In situ, increases in gelatinase activity accompanied the progression of neuronal death and glial reactivity. Our results suggest that MMPs and TIMPs are involved in cell viability and tissue remodelling in the ischemic brain, and reinforces the idea that the MMP/TIMP system contributes both to neuronal demise and tissue repair in the context of glial reactivity.
authors.affiliation: IFR Jean Roche, Faculté de Médecine Nord, Boulevard Pierre Dramard, 13916 Marseille Cedex 20, France. santiago.rivera@medecine.univ-mrs.fr
authors.forename: Santiago
authors.initials: S
authors.lastname: Rivera
authors.forename: Crystel
authors.initials: C
authors.lastname: Ogier
authors.forename: Jérôme
authors.initials: J
authors.lastname: Jourquin
authors.forename: Serge
authors.initials: S
authors.lastname: Timsit
authors.forename: Arkadius W
authors.initials: AW
authors.lastname: Szklarczyk
authors.forename: Karen
authors.initials: K
authors.lastname: Miller
authors.forename: Andrew J H
authors.initials: AJ
authors.lastname: Gearing
authors.forename: Leszek
authors.initials: L
authors.lastname: Kaczmarek
authors.forename: Michel
authors.initials: M
authors.lastname: Khrestchatisky
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016548:Prosencephalon / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9