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The Journal of Neuroscience, January 21, 2004, 24(3):671-678; doi:10.1523/JNEUROSCI.4243-03.2004
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Neurobiology of Disease
Role of Matrix Metalloproteinases in Delayed Neuronal Damage after Transient Global Cerebral Ischemia
Seong-Ryong Lee, Kiyoshi Tsuji, Sun-Ryung Lee, andEng H. Lo Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02114
Mechanisms of selective neuronal death in the hippocampus after global cerebral ischemia remain to be clarified. Here, we explored a possible role for matrix metalloproteinases (MMPs) in this phenomenon. Although many studies have demonstrated detrimental roles for the gelatinase MMP-9 in focal cerebral ischemia, how dysregulated MMP proteolysis influences global cerebral ischemia is less well understood. In this study, CD-1 mice were subjected to transient global ischemia. Transient occlusions of common carotid arteries for periods between 20 and 40 min led to increasing hippocampal neuronal death after 3 d. Gel zymography showed elevations in gelatinase (MMP-2 and MMP-9) activity. In situ zymography showed that gelatinase activity was mostly colocalized with neuron-specific nuclear protein-stained pyramidal neurons. Mice treated with the broad-spectrum metalloproteinase inhibitor BB-94 (50 mg/kg, i.p.) showed reduced hippocampal gelatinase activity after transient global cerebral ischemia and suffered significantly reduced hippocampal neuronal damage compared with vehicle-treated controls (p < 0.01). Additionally, hippocampal gelatinase activity and neuronal damage after transient global ischemia were also significantly reduced in MMP-9 knock-out mice compared with wild-type mice (p < 0.05). These data indicate a potential deleterious role for MMP-9 in the pathogenesis of delayed neuronal damage in the hippocampus after global cerebral ischemia.
Key words: stroke; neuroprotection; hippocampus; mouse; neuroinflammation; MMPs
Received Sep 17, 2003; revised November 4, 2003; accepted November 4, 2003.
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