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


METHODS
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.


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
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.
Fiorucci
S
S
Department of Gastroenterology, University of Perugia, Perugia, Italy.
Orlandi
S
S
Mencarelli
A
A
Caliendo
G
G
Santagada
V
V
Distrutti
E
E
Santucci
L
L
Cirino
G
G
Wallace
J L
JL
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004220:Disulfides / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D005765:Gastrointestinal Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects; D006098:Granulocytes / Q000187:drug effects / Q000473:pathology; D006862:Hydrogen Sulfide / Q000378:metabolism*; D019804:Mesalamine / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D013997:Time Factors; D014302:Trinitrobenzenesulfonic Acid
C514446:5-amino-2-hydroxybenzoic acid 4-(5-thioxo-5H-(1,2)dithiol-3yl)phenyl ester; D000893:Anti-Inflammatory Agents; D018925:Chemokines; D016207:Cytokines; D004220:Disulfides; D005765:Gastrointestinal Agents; D012333:RNA, Messenger; D019804:Mesalamine; D014302:Trinitrobenzenesulfonic Acid; D006862:Hydrogen Sulfide