Matrix metalloproteinases contribute to brain damage in experimental pneumococcal meningitis

The present study was performed to evaluate the role of matrix metalloprote inases (MMP) in the pathogenesis of the inflammatory reaction and the devel opment of neuronal injury in a rat model of bacterial meningitis. mRNA enco ding specific MMPs (MMP-3, MMP-7, MMP-8, and MMP-9) and the inflammatory cy tokine tumor necrosis factor alpha (TNF-alpha) were significantly (P < 0.04 ) upregulated, compared to the beta-actin housekeeping gene, in cortical ho mogenates at 20 h after infection. In parallel, concentrations of MMP-9 and TNF-alpha in cerebrospinal fluid (CSF) were significantly increased in rat s with bacterial meningitis compared to uninfected animals (P = 0.002) and showed a close correlation (r = 0.76; P < 0.001). Treatment with a hydroxam ic acid-type MMP inhibitor (GM6001; 65 mg/kg intraperitoneally every 12 h) beginning at the time of infection significantly lowered the MMP-9 (P < 0.0 2) and TNF-alpha (P < 0.02) levels in CSF. Histopathology at 25.5 +/- 5.7 h after infection showed neuronal injury (median [range], 3.5% [0 to 17.5%] of the cortex), which was significantly (P < 0.01) reduced to 0% (0 to 10.8 %) by GM6001. This is the first report to demonstrate that MMPs contribute to the development of neuronal injury in bacterial meningitis and that inhi bition of MMPs may be an effective approach to prevent brain damage as a co nsequence of the disease.