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

Abstract

Matrix metalloproteinases (MMPs) and tumour necrosis factor alpha (TNF-alpha) converting enzyme (TACE) contribute synergistically to the pathophysiology of bacterial meningitis. TACE proteolytically releases several cell-surface proteins, including the proinflammatory cytokine TNF-alpha and its receptors. TNF-alpha 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-alpha 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-alpha 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.

• Authors: S L Leib, J M Clements, R L Lindberg, C Heimgartner, J M Loeffler, L A Pfister, M G Täuber, D Leppert
• Journal: Brain : a journal of neurology (Brain) Vol. 124 Issue Pt 9 Pg. 1734-42 (Sep 2001) ISSN: 0006-8950 [Print] England
• PMID: 11522576 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• BB 1101
• Benzyl Compounds
• DNA Primers
• Drug Combinations
• Matrix Metalloproteinase Inhibitors
• Protease Inhibitors
• RNA, Messenger
• Succinates
• Tumor Necrosis Factor-alpha
• Dexamethasone
• ADAM Proteins
• Matrix Metalloproteinases
• Metalloendopeptidases
• Matrix Metalloproteinase 9
• ADAM17 Protein
• Adam17 protein, rat
• Pentoxifylline

Topics

• ADAM Proteins
• ADAM17 Protein
• Animals
• Benzyl Compounds
• DNA Primers
• Dexamethasone (pharmacology)
• Drug Combinations
• Gene Expression Regulation, Enzymologic
• Matrix Metalloproteinase 9 (cerebrospinal fluid, genetics)
• Matrix Metalloproteinase Inhibitors
• Matrix Metalloproteinases (genetics)
• Maze Learning (drug effects, physiology)
• Meningitis, Pneumococcal (drug therapy, metabolism, pathology)
• Metalloendopeptidases (antagonists & inhibitors)
• Pentoxifylline (pharmacology)
• Protease Inhibitors (pharmacology)
• RNA, Messenger (analysis)
• Rats
• Rats, Sprague-Dawley
• Succinates
• Tumor Necrosis Factor-alpha (cerebrospinal fluid)