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

Leib, Stephen L. ; Clements, John M. ; Lindberg, Raija L. P. ; Heimgartner, Chris ; Loeffler, Jutta M. ; Pfister, Luz-Andrea ; Täuber, Martin G. ; Leppert, David

In: Brain, 2001, vol. 124, no. 9, p. 1734-1742

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    Titel
    • Inhibition of matrix metalloproteinases and tumour necrosis factor α converting enzyme as adjuvant therapy in pneumococcal meningitis
    Autor
    • Leib, Stephen L.. Institute for Infectious Diseases, University of Bern
    • Clements, John M.. British Biotech Pharmaceuticals, Oxford, UK
    • Lindberg, Raija L. P.. Departments of Neurology and Research, University Hospitals, Basel, Switzerland and
    • Heimgartner, Chris. Institute for Infectious Diseases, University of Bern
    • Loeffler, Jutta M.. Institute for Infectious Diseases, University of Bern
    • Pfister, Luz-Andrea. Institute for Infectious Diseases, University of Bern
    • Täuber, Martin G.. Institute for Infectious Diseases, University of Bern
    • Leppert, David. Departments of Neurology and Research, University Hospitals, Basel, Switzerland and
    Dokumententyp
    • Postprint
    Sprache
    • Englisch
    Veröffentlicht in
    • Brain, 2001, vol. 124, no. 9, p. 1734-1742. Oxford University Press
    Andere elektronische Ausgabe
    OAI-PMH-ID
    • oai:doc.rero.ch:292219
    Summary
    Matrix metalloproteinases (MMPs) and tumour necrosis factor α (TNF-α) converting enzyme (TACE) contribute synergistically to the pathophysiology of bacterial meningitis. TACE proteolytically releases several cell-surface proteins, including the proinflammatory cytokine TNF-α and its receptors. TNF-α 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-α 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-α 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