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The Journal of Neuroscience, September 15, 2000, 20(18):7037-7042
Effects of Matrix Metalloproteinase-9 Gene Knock-Out on Morphological and Motor Outcomes after Traumatic Brain Injury
Xiaoying Wang1, JaeChang Jung2, Minoru Asahi1, Wilson Chwang1, Laoti Russo2, Michael A. Moskowitz3, C. Edward Dixon4, 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 School of Medicine, Boston, Massachusetts, 3 Stroke and Neurovascular Regulation Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, and 4 Brain Trauma Research Center, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
Matrix metalloproteinases (MMPs) belong to a class of extracellular proteinases responsible for maintaining and remodeling the extracellular matrix. In addition to multiple functions in normal physiology, abnormal MMP expression and activity may also participate in the pathophysiology of cerebral disease. Here, we show that MMP-9 (gelatinase B; EC.3.4.24.35) contributes to the pathophysiology of traumatic brain injury. After controlled cortical impact in mice, MMP-9 was increased in traumatized brain. Total MMP-9 levels at 24 hr were significantly increased as measured by a substrate cleavage assay. Zymograms showed that MMP-9 was elevated as early as 3 hr after traumatic brain injury, reaching a maximum at ~24 hr. Increased MMP-9 levels persisted for up to 1 week. Western blot analysis indicated increased profiles of MMP-9 expression that corresponded with the zymographic data. Knock-out mice deficient in MMP-9 gene expression were compared with wild-type littermates in terms of morphological and motor outcomes after trauma. Motor outcomes were measured at 1, 2, and 7 d after traumatic brain injury by the use of a rotarod device. MMP-9 knock-out mice had less motor deficits than wild-type mice. At 7 d, traumatic brain lesion volumes on Nissl-stained histological sections were significantly smaller in MMP-9 knock-out mice. These data demonstrate that MMP-9 contributes to the pathophysiology of traumatic brain injury and suggest that interruption of the MMP proteolytic cascade may be a possible therapeutic approach for preventing the secondary progression of damage after brain trauma.
Key words: brain trauma; controlled cortical impact; extracellular matrix; proteolysis; neurodegeneration; mouse
Copyright © 2000 Society for Neuroscience 0270-6474/00/20187037-06$05.00/0
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