Enhanced activity of a hydrogen sulphide-releasing derivative of mesalamine (ATB-429) in a mouse model of colitis

Mesalamine is the first-line therapy for colitis, but it lacks potency and is only effective for mild-to-moderate forms of this disease. Hydrogen sulfide has been shown to be a potent, endogenous anti-inflammatory substance, modulating leukocyte-endothelial adhesion and leukocyte migration. The purpose of this study was to det. if an H2S-releasing deriv. of mesalamine (ATB-429) would exhibit increased potency and effectiveness in a mouse model of colitis. Colitis was induced in mice with trinitrobenzene sulfonic acid and the effects of ATB-429 and mesalamine were compared in several treatment regimens. The severity of colitis was detd. using several indexes, including a disease activity score (comprised of scores for diarrhea, wt. loss and fecal blood), colonic myeloperoxidase activity and macroscopic/microscopic scoring of tissue injury. Irresp. of the treatment regiment, ATB-429 was more effective than mesalamine in reducing the severity of colitis. ATB-429 was particularly effective in reducing granulocyte infiltration into the colonic tissue (by .apprx.70%), as well as reducing the expression of mRNA for several key proinflammatory cytokines/chemokines (e.g., TNFa, IFNg). Treatment with ADT-OH, the H2S-releasing moiety of ATB-429, did not affect severity of colitis. ATB-429 exhibits a marked increase in anti-inflammatory activity and potency in a murine model of colitis, as compared to mesalamine. These results are consistent with recently described anti-inflammatory effects of H2S. ATB-429 may represent an attractive alternative to mesalamine for the treatment of inflammatory bowel disease.