Matrix metalloproteinase inhibition lowers mortality and brain injury in experimental pneumococcal meningitis.
Pneumococcal meningitis (PM) results in high mortality rates and long-lasting neurological deficits. Hippocampal apoptosis and cortical necrosis are histopathological correlates of neurofunctional sequelae in rodent models and are frequently observed in autopsy studies of patients who die of PM. In experimental PM, inhibition of matrix metalloproteinases (MMPs) and/or tumor necrosis factor (TNF)-converting enzyme (TACE) has been shown to reduce brain injury and the associated impairment of neurocognitive function. However, none of the compounds evaluated in these studies entered clinical development. Here, we evaluated two second-generation MMP and TACE inhibitors with higher selectivity and improved oral availability. Ro 32-3555 (Trocade, cipemastat) preferentially inhibits collagenases (MMP-1, -8, and -13) and gelatinase B (MMP-9), while Ro 32-7315 is an efficient inhibitor of TACE. PM was induced in infant rats by the intracisternal injection of live Streptococcus pneumoniae. Ro 32-3555 and Ro 32-7315 were injected intraperitoneally, starting at 3 h postinfection. Antibiotic (ceftriaxone) therapy was initiated at 18 h postinfection, and clinical parameters (weight, clinical score, mortality rate) were recorded. Myeloperoxidase activities, concentrations of cytokines and chemokines, concentrations of MMP-2 and MMP-9, and collagen concentrations were measured in the cerebrospinal fluid. Animals were sacrificed at 42 h postinfection, and their brains were assessed by histomorphometry for hippocampal apoptosis and cortical necrosis. Both compounds, while exhibiting disparate MMP and TACE inhibitory profiles, decreased hippocampal apoptosis and cortical injury. Ro 32-3555 reduced mortality rates and cerebrospinal fluid TNF, interleukin-1β (IL-1β) and collagen levels, while Ro 32-7315 reduced weight loss and cerebrospinal fluid TNF and IL-6 levels.
Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
Fabian D
FD
Liechti
Denis
D
Grandgirard
David
D
Leppert
Stephen L
SL
Leib
D051722:ADAM Proteins / Q000037:antagonists & inhibitors; D000072198:ADAM17 Protein; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001930:Brain Injuries / Q000473:pathology; D003094:Collagen / Q000134:cerebrospinal fluid; D016207:Cytokines / Q000134:cerebrospinal fluid; D004195:Disease Models, Animal; D006877:Hydroxamic Acids; D007093:Imidazoles; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000134:cerebrospinal fluid*; D008586:Meningitis, Pneumococcal / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009195:Peroxidase / Q000134:cerebrospinal fluid; D051381:Rats; D013449:Sulfonamides; D015431:Weight Loss / Q000187:drug effects
C459386:2-(1-(hydroxycarbamoyl)-4-phenyl-3-butenyl)-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide; D016207:Cytokines; D006877:Hydroxamic Acids; D007093:Imidazoles; D061965:Matrix Metalloproteinase Inhibitors; C106997:Ro 32-3555; D013449:Sulfonamides; D003094:Collagen; D009195:Peroxidase; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat