title: Endothelin inhibition improves cerebral blood flow and is neuroprotective in pneumococcal meningitis.
abstract: By using an infant rat model of pneumococcal meningitis, we determined whether endothelins contribute to neuronal damage in this disease. Cerebrospinal fluid analysis demonstrated a significant increase of endothelin-1 in infected animals compared with uninfected controls. Histopathological examination 24 hours after infection showed brain damage in animals treated with ceftriaxone alone (median, 9.2% of cortex; range, 0-49.1%). In infected animals treated intraperitoneally with the endothelin antagonist bosentan (30 mg/kg, every 12 hours) also, injury was reduced to 0.5% (range, 0-8.6%) of cortex. Cerebral blood flow was reduced in infected animals (6.5 +/- 4.0 ml/min/100 g of brain vs 14.9 +/- 9.1 ml/min/100 g in controls. Treatment with bosentan restored cerebral blood flow to levels similar to controls (12.8 +/- 5.3 ml/min/100 g). Improved blood flow was not mediated by nitric oxide production, because bosentan had no effect on cerebrospinal fluid or plasma nitrite/nitrate concentrations at 6, 12, or 18 hours. These data indicate that endothelins contribute to neuronal injury in this model of pneumococcal meningitis by causing cerebral ischemia.
authors.affiliation: Institute for Medical Microbiology, University of Berne, Switzerland.
authors.forename: L A
authors.initials: LA
authors.lastname: Pfister
authors.forename: J H
authors.initials: JH
authors.lastname: Tureen
authors.forename: S
authors.initials: S
authors.lastname: Shaw
authors.forename: S
authors.initials: S
authors.lastname: Christen
authors.forename: D M
authors.initials: DM
authors.lastname: Ferriero
authors.forename: M G
authors.initials: MG
authors.lastname: Täuber
authors.forename: S L
authors.initials: SL
authors.lastname: Leib
mesh_terms: D000818:Animals; D000077300:Bosentan; D001921:Brain / Q000473:pathology; D002452:Cell Count; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D005260:Female; D008297:Male; D008586:Meningitis, Pneumococcal / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D019332:Endothelin-1; D018696:Neuroprotective Agents; D013449:Sulfonamides; D000077300:Bosentan