Anti-inflammatory and gastrointestinal effects of a novel diclofenac derivative

Abstract

S-diclofenac (2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 4-(3 H-1,2,dithiol-3-thione-5-yl)phenyl ester; ACS 15) is a novel molecule comprising a hydrogen sulfide (H 2S)-releasing dithiol-thione moiety attached by an ester linkage to diclofenac. S-diclofenac administration inhibited lipopolysaccharide-induced inflammation (as evidenced by reduced lung and liver myeloperoxidase activity) and caused significantly less gastric toxicity than diclofenac. S-diclofenac did not affect blood pressure or heart rate of the anesthetized rat. S-diclofenac administration downregulated expression of genes encoding enzymes which synthesize nitric oxide, prostanoids, and H 2S; reduced plasma IL-1β/TNF-α; and elevated plasma IL-10. Reduced liver NF-κB p65 and AP-1/c-fos DNA-binding activity was also observed. These effects were mimicked in large part by a combination of diclofenac plus an H 2S-releasing moiety (ADT-OH). Incubation of S-diclofenac (100 μM) with rat plasma or liver homogenate caused a time-dependent release of H 2S, which was inhibited by sodium fluoride (10 mM). Administration of S-diclofenac (47.2 μmol/kg, ip) to conscious rats significantly increased plasma H 2S concentration (at 45 min and 6 h). We propose that H 2S release from S-diclofenac in vivo contributes to the observed effects.