期刊
NEUROCHEMISTRY INTERNATIONAL
卷 161, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2022.105432
关键词
Ischemia-reperfusion; Tight junction proteins; Inflammation; Neuroprotection; Matrix metalloproteinases
资金
- Department of Neurological Surgery, University of Wisconsin
- US NIH [RO1 NS102573]
- US Department of Veterans Affairs [RO1 NS102573]
- [IK6BX005690]
The increased expression of MMP-12 has been found to mediate blood-brain barrier disruption after stroke, while MMP-12 knockdown protects the brain and promotes functional recovery in mice.
We previously reported that increased expression of matrix metalloproteinase-12 (MMP-12) mediates bloodbrain barrier disruption via tight junction protein degradation after focal cerebral ischemia in rats. Currently, we evaluated whether MMP-12 knockdown protects the post-stroke mouse brain and promotes better functional recovery. Adult male mice were injected with negative siRNA or MMP-12 siRNA (intravenous) at 5 min of reperfusion following 1 h transient middle cerebral artery occlusion. MMP-12 knockdown significantly reduced the post-ischemic infarct volume and improved motor and cognitive functional recovery. Mechanistically, MMP12 knockdown ameliorated degradation of tight junction proteins zonula occludens-1, claudin-5, and occludin after focal ischemia. MMP-12 knockdown also decreased the expression of inflammatory mediators, including monocyte chemoattractant protein-1, tumor necrosis factor-alpha, and interleukin-6, and the expression of apoptosis marker cleaved caspase-3 after ischemia. Overall, the present study indicates that MMP-12 promotes secondary brain damage after stroke and hence is a promising stroke therapeutic target.
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