In pneumococcal meningitis a novel water-soluble inhibitor of matrix metalloproteinases and TNF-alpha converting enzyme attenuates seizures and injury of the cerebral cortex.
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.
Meli
D N
DN
Institute for Infectious Diseases, University of Bern, Friedbühlstrasse 51, P.O. Box 61, 3010 Bern, Switzerland.
Loeffler
J M
JM
Baumann
P
P
Neumann
U
U
Buhl
T
T
Leppert
D
D
Leib
S L
SL
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000293:injuries / Q000473:pathology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000187:drug effects; D008586:Meningitis, Pneumococcal / Q000150:complications / Q000188:drug therapy*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat