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

Abstract

We have previously investigated the effects of a series of dimethoxy- and trimethoxychalcone derivatives, with various patterns of fluorination, on nitric oxide pro duction in LPS-stimulated murine RAW 264.7. The pre sent 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 mac rophage cell line RAW 264.7 CH 17 inhibited dose-de pendently NO production, with an IC50 value in the nano molar range, and reduced PGE2 levels by a 58% at 10 µM. 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 experi ments indicated that CH 17 is an inhibitor of the nuclear factor-κB (NF-κB) pathway of cellular activation in mac rophages. 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 af ter adjuvant injection, significantly inhibited paw oedema, protected from weight loss and reduced the levels of in flammatory mediators (nitrites and PGE2) in paw ho mogenates, without affecting PGE2 levels in stomach ho mogenates. The profile and potency of this compound, a selective inhibitor of iNOS expression that interferes with NF-κB activation, may have relevance for the inhibition of the inflammatory response, representing a new approach to the modulation of different inflammatory pathologies.