Endothelin inhibition improves cerebral blood flow and is neuroprotective in pneumococcal meningitis

Pfister, LA; Tureen, JH; Shaw, S; Christen, S; Ferriero, DM; Täuber, MG; Leib, Stephen L. (2000). Endothelin inhibition improves cerebral blood flow and is neuroprotective in pneumococcal meningitis. Annals of neurology, 47(3), pp. 329-335. Hoboken, N.J.: Wiley-Blackwell 10.1002/1531-8249(200003)47:3<329::AID-ANA8>3.3.CO;2-I

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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.

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