Inhibition of nitric oxide synthase attenuates blood-brain barrier disruption during experimental meningitis.
Increased permeability of the blood-brain (B-B) barrier is observed during meningitis. Preventing B-B barrier alterations is important because adverse neurological outcomes are correlated with breeches in barrier integrity. It was hypothesized that pathological production of nitric oxide (NO) contributes to B-B barrier disruption during meningitis in the rat. Experimental meningitis was induced by intracisternal (i.c.) administration of lipopolysaccharides (LPS) or vehicle. Groups of rats were concomitantly infused intravenously (i.v.) with saline or the NO synthase inhibitor, aminoguanidine (AG). Eight h after i.c. dosing, B-B barrier alterations were quantitated pharmacokinetically using [14C]sucrose. Serum and regional brain tissues were obtained 0-30 min after tracer dosing and sucrose influx transfer coefficients (Kin(app)) were calculated from the brain tissue data. Compared to the control groups (i.c. vehicle/i.v. saline), the Kin(app) of the i.c. LPS/i.v. saline group increased 1.6-2.1-fold in various brain regions, thus confirming previous observations of increased [14C]sucrose barrier penetration during meningeal inflammation. Remarkably, i.v. administration of AG to i.c. LPS-treated rats significantly inhibited meningeal NO synthesis and decreased Kin (app) permeability alterations in the B-B barrier, compared to i.c. LPS/i.v. saline-treated rats. Regional brain Kin (app) estimates in the i.c. LPS/i.v. AG group were similar to control groups (i.c. vehicle/i.v. AG and i.c. vehicle/i.v. saline). In conclusion, these data suggest the general concept that excessive NO production during neuroinflammatory diseases contributes to disruption of the blood-brain barrier.
Boje
K M
KM
Department of Pharmaceutics, School of Pharmacy, University of Buffalo, NY 14260, USA. boje@acsu.buffalo.edu
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001810:Blood Volume / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D002946:Cisterna Magna; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D006146:Guanidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007267:Injections; D007275:Injections, Intravenous; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects; D008070:Lipopolysaccharides; D008297:Male; D008581:Meningitis / Q000134:cerebrospinal fluid / Q000139:chemically induced / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013395:Sucrose / Q000493:pharmacokinetics
D004791:Enzyme Inhibitors; D006146:Guanidines; D008070:Lipopolysaccharides; D013395:Sucrose; D019001:Nitric Oxide Synthase; C004479:pimagedine