Reduction of excitotoxicity and associated leukocyte recruitment by a broad-spectrum matrix metalloproteinase inhibitor.
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.
Campbell
Sandra J
SJ
Molecular Neuropathology Laboratory, School of Biological Sciences, University of Southampton, Biomedical Sciences Building, Southampton SO16 7PX, UK.
Finlay
Malcolm
M
Clements
John M
JM
Wells
Graham
G
Miller
Karen M
KM
Perry
V Hugh
VH
Anthony
Daniel C
DC
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002154:Calpain / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005341:Fibrinolysin / Q000037:antagonists & inhibitors / Q000378:metabolism; D007608:Kainic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity; D007962:Leukocytes / Q000187:drug effects* / Q000201:enzymology*; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics; D017628:Microglia / Q000166:cytology / Q000201:enzymology; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D020556:Neutrophil Infiltration / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects; D000979:alpha-2-Antiplasmin / Q000494:pharmacology
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D009498:Neurotoxins; D012333:RNA, Messenger; D000979:alpha-2-Antiplasmin; D005341:Fibrinolysin; D002154:Calpain; D020782:Matrix Metalloproteinases; D007608:Kainic Acid