ROLES OF NITRIC-OXIDE AND PROSTAGLANDINS IN THE INCREASED PERMEABILITY OF THE BLOOD-BRAIN-BARRIER CAUSED BY LIPOPOLYSACCHARIDE

We investigated the involvement of nitric oxide (NO) and prostaglandin s (PGs) in the damage to the blood-brain barrier (BBB) induced by lipo polysaccharide (LPS), using fluorescein as a tracer in mice. Aminoguan idine, a competitive inhibitor of inducible NO synthase (iNOS), when a dministered s.c. at 5 mg/kg, but not 500 mg/kg, reduced significantly the increase in brain fluorescein level after its i.v. injection in LP S-treated mice. When 1000 mg/kg of L-arginine, a substrate of NOS, wer e co-administered with 5 mg/kg of aminoguanidine to LPS-treated mice, the inhibitory effect of aminoguanidine on the increased fluorescein l evel disappeared. NG-Nitro-L-arginine methyl ester (L-NAME), a non-iso enzyme-selective NOS inhibitor, when administered s.c. at 5 mg/kg, onl y slightly reduced the LPS-induced increase in the brain fluorescein l evel. A pretreatment with dexamethasone, which suppressed the inductio n of both iNOS and cyclooxygenase 2 (COX-2), tended to decrease the br ain fluorescein level in LPS-treated mice. Indomethacin, a COX inhibit or, at 5 mg/kg, but not 10 mg/kg, suppressed significantly the LPS-ind uced increase in the brain fluorescein level. These results involve th at both the NO produced by iNOS and the PGs produced by COX contribute to enhance BBB permeability in LPS-administered mice. (C) 1998 Elsevi er Science B.V.