Mechanistic insights into sitagliptin's action in rat inflammatory bowel disease: involvement of the NO-cGMP-KATP pathway.

BACKGROUND AND PURPOSE: Inflammatory bowel disease (IBD) involves several intestinal disorders that lead to prolonged inflammation of the gastrointestinal tract. Sitagliptin is an antidiabetic drug that works by increasing incretin hormones. This study examined the effect of sitagliptin, as well as the contribution of the NO-cGMP-KATP channel pathway, in acetic acid-induced colitis.

EXPERIMENTAL APPROACH: To induce colitis in rats, 4% acetic acid was administered intrarectally. Subsequently, the animals were intraperitoneally pretreated with L-arginine, L-NAME, sildenafil, methylene blue, diazoxide, and glibenclamide for 3 consecutive days, 15 min before sitagliptin administration (90 mg/kg. p.o.). Finally, microscopic and macroscopic parameters and inflammatory indices, apoptotic gene expression, and histopathological observation were evaluated in colon tissue.

FINDINGS/

RESULTS

The findings showed that sitagliptin diminished both the macroscopic and microscopic injuries caused by acetic acid and also decreased IL-1β and TNF-α levels and TNF-α gene expression. Moreover, it enhanced the gene expression of BCL2. The findings revealed that the effects of sitagliptin were significantly reduced by L-NAME (NOS inhibitor), methylene blue (guanylate cyclase inhibitor), and glibenclamide (ATP-sensitive potassium channel blocker). In addition, pretreatment with L-arginine, diazoxide, and sildenafil preserved the protective effect of sitagliptin.

CONCLUSION AND IMPLICATIONS: Finally, this study revealed that sitagliptin effectively alleviated acetic acid-induced colonic tissue injury by reducing inflammation and regulating genes involved in apoptosis. The NO-cGMP-KATP channel pathway plays a significant role in mediating this protective effect.