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.