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

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 aα 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. © 2015 liechti et al.; licensee biomed central.