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-tomoderate 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 Sreleasing 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 B70%), as well as reducing the expression of mRNA for several key proinflammatory cytokines/chemokines (e.g., TNFa, IFNg). 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.

Hydrogen sulfide and inflammation: the good, the bad, the ugly and the promising

“…Nonetheless, as a therapeutic tool, pharmaceutical-grade Na 2 S shows great potential and has been successfully used to prevent and treat myocardial infarction, ischemia-reperfusion injury and endotoxic shock [112,113]. It is Table 2 By sharp contrast, no effect was observed with mesalamine or ADT-OH treatment alone, suggesting protective effects in addition to H 2 S release [111] Male Wistar rats: Carageenan-induced hindpaw edema The study concluded that the additional anti-inflammatory effect of S-diclofenac was due to H 2 S release [134] Male Wistar rats: Trinitrobenzene sulfonic acid-induced colitis [125] Male Swiss albino mice: Cecal ligation and puncture-induced sepsis PPT-A gene expression and substance P levels whereas NaSH increased substance P levels and lung injury [71] Balb/C mice: Acute pancreatitis and associated lung inflammation induced by cerulein…”

“…It is highly unlikely that cells or tissues are ever exposed to H 2 S generated in such a rapid manner, generating high local concentrations of H 2 S, since endogenously produced H 2 S through CSE and CBS is relatively slow and sustained [68,92,109,110]. Furthermore, injection of these salts into animals results in a minimal increase in plasma H 2 S concentrations over a very short period of time [21,33,68,111]. Commercially available NaSH rarely exceeds 70% purity and it is possible that the disparate physiological findings with NaSH could reflect the varying amounts of chemical impurities present in the NaSH.…”

Hydrogen sulfide triggers late-phase preconditioning in postischemic small intestine by an NO- and p38 MAPK-dependent mechanism

“…The redox potential of H 2 S in the vascular tissue may also be related to the recent finding that H 2 S mediates vasoactivity in an oxygen-dependent manner (29). Moreover, inhibition of endogenous H 2 S synthesis reduces leukocyte rolling velocity and increases leukocyte adherence to mesenteric postcapillary venules under baseline conditions, whereas NaHS treatment prevents leukocyte-endothelial cell adhesive interactions following exposure to TNF-␣ (13,15). The former results indicate that basal H 2 S production serves as an endogenous modulator of leukocyte-endothelial cell adhesive interactions, whereas the latter observation indicates that H 2 S donors may be effective in preventing adhesive responses induced by proinflammatory mediators.…”

Mechanism of Action of Nonsteroidal Anti-Inflammatory Drugs

“…A diclofenac derivative has been shown to reduce LPS-induced iniltration of neutrophils into the lung and liver [41]; also an H 2 S-releasing derivative of mesalamine profoundly reduced granulocyte iniltration in a mouse model of colitis [42] with efect signiicantly greater than that observed in the parent molecules in each case. H 2 S-releasing diclofenac was also realized to be more potent than diclofenac in reducing paw edema in the carrageenan-induced paw edema model in rat.…”