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

Journal of Neuroinflammation

Stephen L Leib¹  David Leppert³  Denis Grandgirard²  Fabian Bächtold²  Fabian D Liechti² 

[1] Biology Division, Spiez Laboratory, Swiss Federal Office for Civil Protection, Austrasse, Spiez CH-3700, Switzerland;Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Friedbühlstr. 51, Bern, CH-3010, Switzerland;F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Grenzacherstrasse 183, Basel, CH-4070, Switzerland

关键词: Neuroinfection;    Streptococcus pneumoniae;    Bacterial meningitis;    MMP inhibitor;    Matrix metalloproteinases;   

Others  :  1137539
DOI  :  10.1186/s12974-015-0257-0

 received in 2014-11-21, accepted in 2015-01-28,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Liechti et al.; licensee BioMed Central.

【 图 表 】

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