The matrix metalloproteinases inhibitor Ro 28-2653 [correction of Ro 26-2853] extends survival in transgenic ALS mice.

In amyotrophic lateral sclerosis (ALS), there is increased expression of matrix metalloproteinases (MMPs) and degradation of the extracellular matrix in postmortem spinal cord tissue. We used zymography and in situ zymography to analyze the expression of MMP-2 and MMP-9 in spinal cord tissue from the G93A transgenic mouse model of ALS. Expression of MMP-9 was increased in the spinal cord of G93A mice. For functional analysis of the role of MMPs, we investigated the effects of oral administration of the MMP inhibitor Ro 28-2653 (100 mg/kg), starting at the age of 30 days (n = 19) and on disease onset (starting at the age of 90 days (n = 10)). Treatment with the MMP inhibitor Ro 28-2653 starting at 30 days of age improved motor performance and significantly (P < 0.05) prolonged the survival time of the animals (136 +/- 12 versus 123 +/- 12 days, mean +/- SD), however, administration at disease onset did not significantly improve survival time. Our experiments show that MMPs are expressed in an animal model of ALS and may play a role in the complex pathophysiologic changes. Early pharmacologic inhibition with a synthetic MMP inhibitor extends survival of the animals which suggest a role of MMPs in the early phase of the disease.

Expression of MMP-2, MMP-9, and MMP-1 and their endogenous counterregulators TIMP-1 and TIMP-2 in postmortem brain tissue of Parkinson's disease.

We investigated the levels and tissue localization of matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) in postmortem brain tissue from Parkinson's disease (PD) and age-matched control cases. Using zymography, we found reduced MMP-2 levels in PD cases in the substantia nigra as compared to controls; levels of MMP-2 were not significantly changed in the cortex and the hippocampus. MMP-9 levels were unchanged in the investigated brain regions. Immunohistochemically, MMP-2 was localized primarily in astrocytes and microglia cells, whereas MMP-9 was predominantly neuronal. Levels of TIMP-1, an endogenous tissue inhibitor of MMPs, were significantly elevated in the substantia nigra, but not in the cortex and hippocampus. TIMP-2 levels were unchanged in PD. To investigate whether increased TIMP-1 levels in the substantia nigra might be due to increased MMP-1 expression, we measured MMP-1 levels using Western blots. MMP-1 levels were unchanged in PD cases compared to controls. Together, these data show alterations of MMP-2 and TIMP-1 in the substantia nigra of PD, consistent with the possibility that alterations in MMPs/TIMPs may contribute to disease pathogenesis.