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An important step in the cascade leading to neuronal cell death is degradation of laminin and other components of the brain extracellular matrix by microglia-derived proteases. Excitotoxic cell death of murine hippocampal neurones in vivo can be prevented by inhibitors of tissue plasminogen activator (tPA) or by inhibitors of plasmin. Plasmin is a potent activator of the matrix metalloproteinases (MMPs), which are made by resident and recruited leukocytes following CNS injury. In this study, we show, using Taqman RT-PCR, that MMP mRNAs, but not other calcium-dependent proteases such as calpain mRNAs, are acutely up-regulated after an excitotoxic challenge in vivo. alpha(2)-antiplasmin or BB-3103, a broad-spectrum inhibitor of the MMPs, co-injected with kainic acid into the striatum, inhibits excitotoxic cell death in the rat striatum, and reduces both the number of recruited macrophages and the size of the lesion. We also show that leukocyte populations differentially express MMPs, which may account, in part, for the expression profile we observe in the challenged brain. Our results show that inhibition of the MMPs in the rat will prevent kainic acid-induced cell death in the brain. These studies suggest that MMP inhibitors have therapeutic potential for use in stroke, and support the increasing evidence that microglial activation may contribute to neuronal cell death.

Original publication

DOI

10.1111/j.1471-4159.2004.02441.x

Type

Journal article

Journal

J Neurochem

Publication Date

06/2004

Volume

89

Pages

1378 - 1386

Keywords

Animals, Animals, Newborn, Brain, Calpain, Cell Death, Cells, Cultured, Enzyme Inhibitors, Fibrinolysin, Kainic Acid, Leukocytes, Matrix Metalloproteinase Inhibitors, Matrix Metalloproteinases, Microglia, Neurotoxins, Neutrophil Infiltration, RNA, Messenger, Rats, Rats, Wistar, Reverse Transcriptase Polymerase Chain Reaction, Up-Regulation, alpha-2-Antiplasmin