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

Abstract

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.

• Authors: Fabian D Liechti, Fabian Bächtold, Denis Grandgirard, David Leppert, Stephen L Leib
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 12 Pg. 43 (Mar 04 2015) ISSN: 1742-2094 [Electronic] England
• PMID: 25890041 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Enzyme Inhibitors
• Hydroxamic Acids
• RS-130830

Topics

• Animals
• Animals, Newborn
• Brain Injuries (drug therapy, etiology, microbiology)
• Cytokines (metabolism)
• Disease Models, Animal
• Enzyme Inhibitors (therapeutic use)
• Hydroxamic Acids (therapeutic use)
• Leukocytes (pathology)
• Meningitis, Pneumococcal (complications)
• Rats
• Rats, Wistar