Therapeutic administration of 3,4,5-trimethoxy-4'-fluorochalcone,a selective inhibitor of iNOS expression,attenuates the development of adjuvant-induced arthritis in rats

We have previously investigated the effects of a series of dimethoxy- and trimethoxychalcone derivatives, with various patterns of fluorination, on nitric oxide production in LPS-stimulated murine RAW 264.7. The present study was designed to determine if 3,4,5-trimethoxy-4'-fluorochalcone (CH 17) could modulate the production of NO and/or prostaglandins in vivo. On the mouse macrophage cell line RAW 264.7 CH 17 inhibited dose-dependently NO production, with an IC₅₀ value in the nanomolar range, and reduced PGE₂ levels by a 58% at 10 M. This compound had no direct inhibitory effect on iNOS and COX-2 activities. NO reduction was the consequence of inhibition of the expression of iNOS. In vitro experiments indicated that CH 17 is an inhibitor of the nuclear factor-B (NF-B) pathway of cellular activation in macrophages. This compound exhibited in vivo an inhibitory behaviour correlated with its in vitro results on nitrite and PGE₂ accumulation. In the rat adjuvant-induced arthritis, oral administration of CH 17 (25 mg/kg) on days 17–24 after adjuvant injection, significantly inhibited paw oedema, protected from weight loss and reduced the levels of inflammatory mediators (nitrites and PGE₂) in paw homogenates, without affecting PGE₂ levels in stomach homogenates. The profile and potency of this compound, a selective inhibitor of iNOS expression that interferes with NF-B activation, may have relevance for the inhibition of the inflammatory response, representing a new approach to the modulation of different inflammatory pathologies.