Inhibition of matrix metalloproteinases and tumour necrosis factor alpha converting enzyme as adjuvant therapy in pneumococcal meningitis

Matrix metalloproteinases (MMPs) and tumour necrosis factor alpha (TNF-alph a) converting enzyme (TACE) contribute synergistically to the pathophysiolo gy of bacterial meningitis. TACE proteolytically releases several cell-surf ace proteins, including the proinflammatory cytokine TNF-alpha and its rece ptors. TNF-alpha in turn stimulates cells to produce active MMPs, which fac ilitate leucocyte extravasation and brain oedema by degradation of extracel lular matrix components. In the present time-course studies of pneumococcal meningitis in infant rats, MMP-8 and -9 were 100- to 1000-fold transcripti onally upregulated, both in CSF cells and in brain tissue. Concentrations o f TNF-alpha and MMP-9 in CSF peaked 12 h after infection and were closely c orrelated. Treatment with BB-1101 (15 mg/kg subcutaneously, twice daily), a hydroxamic acid-based inhibitor of MMP and TACE, downregulated the CSF con centration of TNF-alpha and decreased the incidences of seizures and mortal ity. Therapy with BB-1101, together with antibiotics, attenuated neuronal n ecrosis in the cortex and apoptosis in the hippocampus when given as a pret reatment at the time of infection and also when administration was started 18 h after infection. Functionally, the neuroprotective effect of BB-1101 p reserved learning performance of rats assessed 3 weeks after the disease ha d been cured. Thus, combined inhibition of MMP and TACE offers a novel ther apeutic strategy to prevent brain injury and neurological sequelae in bacte rial meningitis.