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) |
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Division/Institute: |
04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases ?? DCD5A442BAF8E17DE0405C82790C4DE2 ?? 04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases > Research |
UniBE Contributor: |
Bächtold, Fabian, Grandgirard, Denis, 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: |
05 Dec 2022 14:47 |
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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