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Enhanced activity of a hydrogen sulphide‐releasing derivative of mesalamine (ATB‐429) in a mouse model of colitis
Author(s) -
Fiorucci S,
Orlandi S,
Mencarelli A,
Caliendo G,
Santagada V,
Distrutti E,
Santucci L,
Cirino G,
Wallace J L
Publication year - 2007
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0707193
Subject(s) - colitis , inflammatory bowel disease , proinflammatory cytokine , medicine , potency , myeloperoxidase , pharmacology , immunology , gastroenterology , chemistry , inflammation , disease , biochemistry , in vitro
Background and Purpose: 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 sulphide 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 determine if an H 2 S‐releasing derivative of mesalamine (ATB‐429) would exhibit increased potency and effectiveness in a mouse model of colitis. Experimental Approach: Colitis was induced in mice with trinitrobenzene sulphonic acid and the effects of ATB‐429 and mesalamine were compared in several treatment regimens. The severity of colitis was determined using several indices, including a disease activity score (comprised of scores for diarrhea, weight loss and fecal blood), colonic myeloperoxidase activity and macroscopic/microscopic scoring of tissue injury. Key Results: Irrespective 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 ∼70%), as well as reducing the expression of mRNA for several key proinflammatory cytokines/chemokines (e.g., TNF α , IFN γ ). Treatment with ADT‐OH, the H 2 S‐releasing moiety of ATB‐429, did not affect severity of colitis. Conclusions and Implications: 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 H 2 S. ATB‐429 may represent an attractive alternative to mesalamine for the treatment of inflammatory bowel disease. British Journal of Pharmacology (2007) 150 , 996–1002. doi: 10.1038/sj.bjp.0707193