title: 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.affiliation: Institute for Infectious Diseases, University of Bern, Berne, Switzerland. stephen.leib@ifik.unibe.ch
authors.forename: S L
authors.initials: SL
authors.lastname: Leib
authors.forename: J M
authors.initials: JM
authors.lastname: Clements
authors.forename: R L
authors.initials: RL
authors.lastname: Lindberg
authors.forename: C
authors.initials: C
authors.lastname: Heimgartner
authors.forename: J M
authors.initials: JM
authors.lastname: Loeffler
authors.forename: L A
authors.initials: LA
authors.lastname: Pfister
authors.forename: M G
authors.initials: MG
authors.lastname: Täuber
authors.forename: D
authors.initials: D
authors.lastname: Leppert
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D001593:Benzyl Compounds; D017931:DNA Primers; D003907:Dexamethasone / Q000494:pharmacology*; D004338:Drug Combinations; D015971:Gene Expression Regulation, Enzymologic; D020780:Matrix Metalloproteinase 9 / Q000134:cerebrospinal fluid / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008586:Meningitis, Pneumococcal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D010431:Pentoxifylline / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013386:Succinates; D014409:Tumor Necrosis Factor-alpha / Q000134:cerebrospinal fluid
chemical_list: C101468:BB 1101; D001593:Benzyl Compounds; D017931:DNA Primers; D004338:Drug Combinations; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D012333:RNA, Messenger; D013386:Succinates; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat; D010431:Pentoxifylline