The matrix metalloproteinase inhibitor RS-130830 attenuates brain injury in experimental pneumococcal meningitis.

Liechti, Fabian D; Bächtold, Fabian; Grandgirard, Denis; Leppert, David; Leib, Stephen (2015). The matrix metalloproteinase inhibitor RS-130830 attenuates brain injury in experimental pneumococcal meningitis. Journal of neuroinflammation, 12(43), p. 43. BioMed Central 10.1186/s12974-015-0257-0

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BACKGROUND Pneumococcal meningitis (PM) is characterized by high mortality and morbidity including long-term neurofunctional deficits. Neuropathological correlates of these sequelae are apoptosis in the hippocampal dentate gyrus and necrosis in the cortex. Matrix metalloproteinases (MMPs) play a critical role in the pathophysiology of PM. RS-130830 (Ro-1130830, CTS-1027) is a potent partially selective inhibitor of MMPs of a second generation and has been evaluated in clinical trials as an anti-arthritis drug. It inhibits MMPs involved in acute inflammation but has low activity against MMP-1 (interstitial collagenase), MMP-7 (matrilysin) and tumour necrosis factor α converting enzyme (TACE). METHODS A well-established infant rat model of PM was used where live Streptococcus pneumoniae were injected intracisternally and antibiotic treatment with ceftriaxone was initiated 18 h post infection (hpi). Treatment with RS-130830 (75 mg/kg bis in die (bid) i.p., n = 40) was started at 3 hpi while control littermates received the vehicle (succinylated gelatine, n = 42). RESULTS Cortical necrosis was significantly attenuated in animals treated with RS-130830, while the extent of hippocampal apoptosis was not influenced. At 18 hpi, concentrations of interleukin (IL)-1β and IL-10 were significantly lower in the cerebrospinal fluid of treated animals compared to controls. RS-130830 significantly reduced weight loss and leukocyte counts in the cerebrospinal fluid of survivors of PM. CONCLUSION This study identifies MMP inhibition, specifically with RS-130830, as an efficient strategy to attenuate disease severity and cortical brain injury in PM.

Item Type:

Journal Article (Original Article)

Division/Institute:

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

UniBE Contributor:

Bächtold, Fabian; Grandgirard, Denis and Leib, Stephen

Subjects:

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

ISSN:

1742-2094

Publisher:

BioMed Central

Funders:

[4] Swiss National Science Foundation
[24] Gottfried und Julia Bangerter- Rhyner Stiftung

Language:

English

Submitter:

Stephen Leib

Date Deposited:

26 May 2015 13:58

Last Modified:

08 Feb 2017 13:24

Publisher DOI:

10.1186/s12974-015-0257-0

PubMed ID:

25890041

BORIS DOI:

10.7892/boris.68885

URI:

https://boris.unibe.ch/id/eprint/68885

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