Matrix metalloproteinase inhibition lowers mortality and brain injury in experimental pneumococcal meningitis

Liechti, Fabian D; Grandgirard, Denis; Leppert, David; Leib, Stephen (2014). Matrix metalloproteinase inhibition lowers mortality and brain injury in experimental pneumococcal meningitis. Infection and immunity, 82(4), pp. 1710-1718. American Society for Microbiology 10.1128/IAI.00073-14

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases > Research
04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases

UniBE Contributor:

Grandgirard, Denis and Leib, Stephen

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0019-9567

Publisher:

American Society for Microbiology

Funders:

[4] Swiss National Science Foundation
[24] Gottfried und Julia Bangerter- Rhyner Stiftung
[UNSPECIFIED] Novartis Foundation for Medical-Biological Research (project 11A18)

Language:

English

Submitter:

Stephen Leib

Date Deposited:

01 Sep 2014 09:36

Last Modified:

08 Feb 2017 13:37

Publisher DOI:

10.1128/IAI.00073-14

PubMed ID:

24491581

BORIS DOI:

10.7892/boris.52650

URI:

https://boris.unibe.ch/id/eprint/52650

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