Abstract
Matrix metalloproteinases (MMPs) and TNF-alpha converting enzyme (TACE) contribute to the pathophysiology of bacterial meningitis. To date, MMP-inhibitors studied in models of meningitis were compromised by their hydrophobic nature. We investigated the pharmacokinetics and the effect of TNF484, a water-soluble hydroxamate-based inhibitor of MMP and TACE, on disease parameters and brain damage in a neonatal rat model of pneumococcal meningitis. At 1 mg/kg q6h TNF484 reduced soluble TNF-alpha and the collagen degradation product hydroxyproline in the cerebrospinal fluid. Clinically, TNF484 attenuated the incidence of seizures and was neuroprotective in the cortex. Water-soluble MMP-inhibitors may hold promise in the therapy of bacterial meningitis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins
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ADAM17 Protein
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Animals
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Animals, Newborn
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Apoptosis / drug effects
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Cerebral Cortex / drug effects*
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Cerebral Cortex / injuries
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Cerebral Cortex / pathology
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Disease Models, Animal
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology*
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Enzyme-Linked Immunosorbent Assay
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Matrix Metalloproteinase Inhibitors*
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Matrix Metalloproteinases / drug effects
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Meningitis, Pneumococcal / complications
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Meningitis, Pneumococcal / drug therapy*
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Metalloendopeptidases / antagonists & inhibitors*
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Metalloendopeptidases / drug effects
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Rats
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Rats, Sprague-Dawley
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Seizures / drug therapy*
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Seizures / etiology
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Tumor Necrosis Factor-alpha / drug effects
Substances
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Enzyme Inhibitors
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Matrix Metalloproteinase Inhibitors
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Tumor Necrosis Factor-alpha
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ADAM Proteins
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Matrix Metalloproteinases
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Metalloendopeptidases
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ADAM17 Protein
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Adam17 protein, rat