title: Neuroinflammatory role of prostaglandins during experimental meningitis: evidence suggestive of an in vivo relationship between nitric oxide and prostaglandins.
abstract: Nitric oxide (NO) and prostaglandins are inflammatory mediators produced during meningitis. The purpose of the present study was to pharmacologically inhibit cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS) to 1) explore the prostaglandin contribution to blood-cerebrospinal fluid barrier permeability alterations and 2) elucidate the in vivo concentration relationship between prostaglandin E2 (PGE2) and NO during experimental meningitis. Intracisternal injection of lipopolysaccharides (LPSs, 200 microg) induced neuroinflammation. Rats were dosed with nimesulide (COX-2 inhibitor), aminoguanidine (iNOS inhibitor), or vehicle. Evans blue was used to assess blood-cerebrospinal fluid barrier permeability. Meningeal NO and cerebrospinal fluid PGE2 were assayed using conventional methods. (Results are expressed as mean +/- S.E.M. of 5-9 rats/group.) Nimesulide failed to prevent blood-cerebrospinal fluid barrier disruption [cerebrospinal fluid Evans blue (micrograms per milliliter): control, 0.22 +/- 0.22*; LPS, 11.58 +/- 0.66; LPS + nimesulide, 10.58 +/- 0.86; *p < 0.05; ANOVA]. Although nimesulide decreased PGE2 (picograms per microliter; p < 0.01) in LPS + nimesulide rats (13.9 +/- 1.96) versus LPS + vehicle (73.8 +/- 12.4), meningeal NO production (picomoles/30 min/10(6) cells; p < 0.01) increased unexpectedly in LPS + nimesulide rats (439 +/- 47) versus LPS + vehicle rats (211 +/- 31). In contrast, aminoguanidine inhibited meningeal NO (picomoles/30 min/10(6) cells; p < 0.005) in LPS + aminoguanidine (111 +/- 20) versus LPS (337 +/- 48) but had no effects (p > 0.05) on PGE2. The in vivo relationship between PGE2 and NO was mathematically described by a biphasic, bell-shaped curve (r2 = 0.42; n = 27 rats; p < 0.0001). Based on these results, inhibition of prostaglandin synthesis not only fails to prevent blood-cerebrospinal fluid barrier disruption during neuroinflammation and but also promotes increased meningeal NO production. The in vivo concentration relationship between PGE2 and NO is biphasic, suggesting that inhibition of COX-2 alone may promote NO toxicity through enhanced NO synthesis.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York 14260, USA. boje@buffalo.edu
authors.forename: Kathleen M K
authors.initials: KM
authors.lastname: Boje
authors.forename: David
authors.initials: D
authors.lastname: Jaworowicz
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Raybon
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000134:cerebrospinal fluid; D006146:Guanidines / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D008581:Meningitis / Q000139:chemically induced / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D009569:Nitric Oxide / Q000134:cerebrospinal fluid / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000134:cerebrospinal fluid / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D006146:Guanidines; D007527:Isoenzymes; D008070:Lipopolysaccharides; D011453:Prostaglandins; D013449:Sulfonamides; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; C004479:pimagedine; C012655:nimesulide