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 E-2 (PGE(2)) and NO during experimental meningitis. Intracisternal injection of lipopolysaccharides (LPSs, 200 mug) 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 PGE(2) 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 PGE(2) (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 PGE(2). The in vivo relationship between PGE(2) and NO was mathematically described by a biphasic, bell-shaped curve (r(2)=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 PGE(2) and NO is biphasic, suggesting that inhibition of COX-2 alone may promote NO toxicity through enhanced NO synthesis.
