Abstract
BackgroundPneumococcal 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).MethodsA 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).ResultsCortical 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.ConclusionThis study identifies MMP inhibition, specifically with RS-130830, as an efficient strategy to attenuate disease severity and cortical brain injury in PM.
Highlights
Pneumococcal meningitis (PM) is an acute disease characterized by high mortality and morbidity rates with persisting neurofunctional sequelae [1]
Liechti et al Journal of Neuroinflammation (2015) 12:43 is a potent hydroxamic acid matrix metalloproteinases (MMP) inhibitor of a second generation [9,10]. It was originally designed as a strong inhibitor of MMP-2, -3, -8, -9, -12, -13 and -14 (>1,000× more potent compared to MMP-1 and MMP-7), without inhibiting MMP-1, since inhibition of MMP-1 was believed to be associated with musculoskeletal side effects
In the present study, reach statistical significance (RS) attenuated cortical injury in infant rats with PM, which is in line with previous observations using broad-spectrum MMP inhibitors in PM [8,16,17,18,19]
Summary
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).
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