Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury

Matrix metalloproteinases (MMPs) belong to a class of extracellular protein ases responsible for maintaining and remodeling the extracellular matrix. I n addition to multiple functions in normal physiology, abnormal MMP express ion and activity may also participate in the pathophysiology of cerebral di sease. Here, we show that MMP-9 (gelatinase B; EC. 3.4.24.35) contributes t o the pathophysiology of traumatic brain injury. After controlled cortical impact in mice, MMP-9 was increased in traumatized brain. Total MMP-9 level s 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 tra umatic brain injury, reaching a maximum at aproximate 24 hr. Increased MMP- 9 levels persisted for up to 1 week. Western blot analysis indicated increa sed profiles of MMP-9 expression that corresponded with the zymographic dat a. Knock-out mice deficient in MMP-9 gene expression were compared with wil d-type littermates in terms of morphological and motor outcomes after traum a. Motor outcomes were measured at 1, 2, and 7 d after traumatic brain inju ry by the use of a rotarod device. MMP-9 knock-out mice had less motor defi cits than wild-type mice. At 7 d, traumatic brain lesion volumes on Nissl-s tained 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 proteoly tic cascade may be a possible therapeutic approach for preventing the secon dary progression of damage after brain trauma.