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

Abstract

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 approximately 70%), as well as reducing the expression of mRNA for several key proinflammatory cytokines/chemokines (e.g., TNFalpha, IFNgamma). 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.

• Authors: S Fiorucci, S Orlandi, A Mencarelli, G Caliendo, V Santagada, E Distrutti, L Santucci, G Cirino, J L Wallace
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 150 Issue 8 Pg. 996-1002 (Apr 2007) ISSN: 0007-1188 [Print] England
• PMID: 17339831 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-amino-2-hydroxybenzoic acid 4-(5-thioxo-5H-(1,2)dithiol-3yl)phenyl ester
• Anti-Inflammatory Agents
• Chemokines
• Cytokines
• Disulfides
• Gastrointestinal Agents
• RNA, Messenger
• Mesalamine
• Trinitrobenzenesulfonic Acid
• Hydrogen Sulfide

Topics

• Animals
• Anti-Inflammatory Agents (metabolism, pharmacology, therapeutic use)
• Chemokines (genetics, metabolism)
• Colitis (chemically induced, drug therapy, metabolism, pathology, prevention & control)
• Colon (drug effects, metabolism, pathology)
• Cytokines (genetics, metabolism)
• Disease Models, Animal
• Disulfides (metabolism, pharmacology, therapeutic use)
• Dose-Response Relationship, Drug
• Female
• Gastrointestinal Agents (metabolism, pharmacology, therapeutic use)
• Gene Expression (drug effects)
• Granulocytes (drug effects, pathology)
• Hydrogen Sulfide (metabolism)
• Mesalamine (metabolism, pharmacology, therapeutic use)
• Mice
• Mice, Inbred BALB C
• RNA, Messenger (metabolism)
• Severity of Illness Index
• Time Factors
• Trinitrobenzenesulfonic Acid