Brain, Vol. 124, No. 9, 1734-1742,
September 2001
© 2001 Oxford University Press
Inhibition of matrix metalloproteinases and tumour necrosis factor 
converting enzyme as adjuvant therapy in pneumococcal meningitis
1 Institute for Infectious Diseases, University of Bern, 2 Departments of Neurology and Research, University Hospitals, Basel, Switzerland and 3 British Biotech Pharmaceuticals, Oxford, UK
Correspondence to:
Dr Stephen L. Leib, Institute for Infectious Diseases, University of Berne, Friedbühlstrasse 51, 3010 Berne, Switzerland E-mail: stephen.leib{at}ifik.unibe.ch
Matrix metalloproteinases (MMPs) and tumour necrosis factor 
(TNF-) converting enzyme (TACE) contribute synergistically to the pathophysiology of bacterial meningitis. TACE proteolytically releases several cell-surface proteins, including the proinflammatory cytokine TNF- and its receptors. TNF- in turn stimulates cells to produce active MMPs, which facilitate leucocyte extravasation and brain oedema by degradation of extracellular matrix components. In the present time-course studies of pneumococcal meningitis in infant rats, MMP-8 and -9 were 100- to 1000-fold transcriptionally upregulated, both in CSF cells and in brain tissue. Concentrations of TNF- and MMP-9 in CSF peaked 12 h after infection and were closely correlated. Treatment with BB-1101 (15 mg/kg subcutaneously, twice daily), a hydroxamic acid-based inhibitor of MMP and TACE, downregulated the CSF concentration of TNF- and decreased the incidences of seizures and mortality. Therapy with BB-1101, together with antibiotics, attenuated neuronal necrosis in the cortex and apoptosis in the hippocampus when given as a pretreatment at the time of infection and also when administration was started 18 h after infection. Functionally, the neuroprotective effect of BB-1101 preserved learning performance of rats assessed 3 weeks after the disease had been cured. Thus, combined inhibition of MMP and TACE offers a novel therapeutic strategy to prevent brain injury and neurological sequelae in bacterial meningitis.
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