Effect of S-diclofenac, a novel hydrogen sulfide releasing derivative, on carrageenan-induced hindpaw oedema fonnation in the rat

S-diclofenac (2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 4-(3H-1,2-dithiole-3-thione-5-yl)-pheny1 ester) is a novel derivative of diclofenac which, in vivo, undergoes enzymatic cleavage of its ester linkage to release hydrogen sulfide (H2S) along with the parent moiety, diclofenac. In this study the anti-inflammatory activity of S-diclofenac and diclofenae was studied in a carrageenan-evoked hindpaw oedema model in the rat. Drugs or vehicle were administered 3 h before carrageenan. Both drugs produced a dose-dependent anti-inflammatory effect in this model. However, S-diclofenac (ED30, 14.2 +/- 0.6 mu mol/kg) was more potent (P<0.05) than diclofenac (ED30, 39.3 +/- 1.4 mu mol/kg) as an inhibitor both of hindpaw swelling and in reducing the caffageenan-evoked rise in hindpaw myeloperoxidase activity reflecting tissue neutrophil infiltration (ED(50)s of 12.0 +/- 2.1 mu mol/kg and 21.9 +/- 2.0 mu mol/kg). Intraplantar carrageenan injection also significantly (P<0.05) increased hindpaw concentrations of prostaglandin E-2 (PGE(2)), nitrite/nitrate and H2S synthesizing activity measured at 6 h. Both S-diclofenac and diclofenac pretreatment reduced the caffageenan-induced rise in hindpaw PGE(2), nitrite/nitrate and H2S synthesizing activity. Whilst treatment with either drug produced similar inhibition of hindpaw PGE(2) and H2S synthesizing activity-S-diclofenac more effectively reduced hindpaw nitrite/nitrate concentration than did diclofenac. It is proposed that the enhanced anti-inflammatory effect of S-diclofenac relates to its ability to release H2S at the inflamed site. These data provide evidence for an anti-inflammatory effect of H2S. (c) 2007 Elsevier B.V. All rights reserved.