title: 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.
  
  
  CONCLUSIONS
  This study identifies MMP inhibition, specifically with RS-130830, as an efficient strategy to attenuate disease severity and cortical brain injury in PM.
authors.affiliation: Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Friedbühlstr. 51, CH-3010, Bern, Switzerland. fabian.liechti@ifik.unibe.ch.
authors.forename: Fabian D
authors.initials: FD
authors.lastname: Liechti
authors.affiliation: Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Friedbühlstr. 51, CH-3010, Bern, Switzerland. fabian.baechtold@ifik.unibe.ch.
authors.forename: Fabian
authors.initials: F
authors.lastname: Bächtold
authors.affiliation: Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Friedbühlstr. 51, CH-3010, Bern, Switzerland. denis.grandgirard@ifik.unibe.ch.
authors.forename: Denis
authors.initials: D
authors.lastname: Grandgirard
authors.affiliation: F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Grenzacherstrasse 183, CH-4070, Basel, Switzerland. david.leppert@roche.com.
authors.forename: David
authors.initials: D
authors.lastname: Leppert
authors.affiliation: Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Friedbühlstr. 51, CH-3010, Bern, Switzerland. stephen.leib@ifik.unibe.ch.|Biology Division, Spiez Laboratory, Swiss Federal Office for Civil Protection, Austrasse, Spiez, CH-3700, Switzerland. stephen.leib@ifik.unibe.ch.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Leib
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000188:drug therapy* / Q000209:etiology* / Q000382:microbiology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D007962:Leukocytes / Q000473:pathology; D008586:Meningitis, Pneumococcal / Q000150:complications*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C513962:RS-130830