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 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 approximately 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.

Gender difference in dopamine concentration and postischemic neuronal damage in neostriatum after unilateral dopamine depletion.

Most neurons in the dorsal neostriatum die 1 day after 30 min of cerebral ischemia. Dopamine may play a role in the pathogenesis of neuronal injury in neostriatum following ischemia. It has been shown that the number of surviving neurons in the right neostriatum dramatically increased following ischemia after lesions were made in the right substantia nigra (SN), whereas no such protective effect was observed in the left neostriatum after left SN lesion. Using a voltammetric technique, the present study measured the dopamine concentration in neostriatum during ischemia after unilateral dopamine depletion and correlated it with the postischemic neuronal damage in neostriatum of male and female rats. In both genders, dopamine concentrations in the neostriatum of the intact side increased to 50-60 microM during ischemia while those of the lesion side were 15-30 microM. No difference in dopamine concentration was detected between animals with lesions in the left SN and those with lesions in right SN. In male rats, the number of surviving neurons in the right neostriatum (approximately 80% as control) was significantly greater than that in the left neostriatum (approximately 20%) after ipsilateral dopamine depletion, whereas in female animals, the number of surviving neurons in the right neostriatum (approximately 40%) was about the same as that in the left neostriatum (approximately 35%) after dopamine depletion. These results indicate that the asymmetry in ischemic outcome after unilateral dopamine depletion in male rats is not due to the difference in residual dopamine in neostriatum. The lateralization of D2 receptors in male rats may be responsible for the asymmetry of survivability of striatal neurons after transient forebrain ischemia.