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Previous Article | Next Article
The Journal of Neuroscience, October 1, 2001, 21(19):7724-7732
Effects of Matrix Metalloproteinase-9 Gene Knock-Out on the Proteolysis of Blood-Brain Barrier and White Matter Components after Cerebral Ischemia
Minoru Asahi1, Xiaoying Wang1, Tatsuro Mori1, Toshihisa Sumii1, Jae-Chang Jung2, Michael A. Moskowitz3, M. Elizabeth Fini2, and Eng H. Lo1 1 Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Charlestown, Massachusetts 02129, 2 Vision Research Laboratories, New England Eye Center, Tufts University, Boston, Massachusetts 02111, and 3 Stroke and Neurovascular Regulation Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129
Deleterious processes of extracellular proteolysis may contribute to the progression of tissue damage after acute brain injury. We recently showed that matrix metalloproteinase-9 (MMP-9) knock-out mice were protected against ischemic and traumatic brain injury. In this study, we examined the mechanisms involved by focusing on relevant MMP-9 substrates in blood-brain barrier, matrix, and white matter. MMP-9 knock-out and wild-type mice were subjected to transient focal ischemia. MMP-9 levels increased after ischemia in wild-type brain, with expression primarily present in vascular endothelium. Western blots showed that the blood-brain barrier-associated protein and MMP-9 substrate zonae occludens-1 was degraded after ischemia, but this was reduced in knock-out mice. There were no detectable changes in another blood-brain barrier-associated protein, occludin. Correspondingly, blood-brain barrier disruption assessed via Evans Blue leakage was significantly attenuated in MMP-9 knock-out mice compared with wild types. In white matter, ischemic degradation of the MMP-9 substrate myelin basic protein was significantly reduced in knock-out mice compared with wild types, whereas there was no degradation of other myelin proteins that are not MMP substrates (proteolipid protein and DM20). There were no detectable changes in the ubiquitous structural protein actin or the extracellular matrix protein laminin. Finally, 24 hr lesion volumes were significantly reduced in knock-out mice compared with wild types. These data demonstrate that the protective effects of MMP-9 gene knock-out after transient focal ischemia may be mediated by reduced proteolytic degradation of critical blood-brain barrier and white matter components.
Key words: stroke; extracellular proteolysis; blood-brain barrier; myelin; neuroprotection; mouse
Copyright © 2001 Society for Neuroscience 0270-6474/01/21197724-09$05.00/0
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