Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085437 (bacterial meningitis)
 4,038 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Inhibition of matrix metalloproteinases and tumour necrosis factor alpha converting enzyme as adjuvant therapy in pneumococcal meningitis. 1152 76

Gram-negative sepsis, bacterial meningitis and endotoxin shock are life-threatening disorders, associated with the rapid release of neutrophil enzymes. Neutrophil collagenase/matrix metalloproteinase-8 (MMP-8) and gelatinase B/matrix metalloproteinase-9 (MMP-9) are contained in granules, are quickly exocytosed upon granulocyte activation and efficiently cleave intact and denatured collagens, respectively. Genetic ablation of gelatinase B protects against endotoxin-induced mortality. Therefore, we designed and synthesized a peptidomimetic gelatinase B inhibitor Regasepin1, and compared the selectivity for the collagenases MMP-1, MMP-8 and MMP-13. Regasepin1 was found to inhibit, almost to the same degree, the neutrophil enzymes MMP-8 and MMP-9 and the monocytic tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE/ADAM-17) in vitro. With the use of mass spectrometry analysis, the plasma half-life of inhibitor levels was determined after an intraperitoneal bolus injection in mice. Plasma peak levels of the inhibitor were reached at 50 min after intraperitoneal injection and the subsequent half-life in the circulation exceeded 40 min. Regasepin1 protected mice against lethal endotoxinemia by intraperitoneal and intravenous injection routes. This proves the principle that early neutrophil MMP inhibition followed by TACE blockade may become a treatment strategy of gram-negative sepsis, endotoxinemia and other life-threatening inflammatory reactions.
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PMID:Targeting neutrophil collagenase/matrix metalloproteinase-8 and gelatinase B/matrix metalloproteinase-9 with a peptidomimetic inhibitor protects against endotoxin shock. 1599 79