Vol. 304, Issue 1, 319-325, January 2003

Neuroinflammatory Role of Prostaglandins during Experimental Meningitis: Evidence Suggestive of an in Vivo Relationship between Nitric Oxide and Prostaglandins

Kathleen M. K. Boje, David Jaworowicz, Jr.¹ and Joseph J. Raybon

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York

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 µg) 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/10⁶ 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/10⁶ 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.