Dapagliflozin, an SGLT2 inhibitor, ameliorates acetic acid-induced colitis in rats by targeting NFκB/AMPK/NLRP3 axis

Abstract

The development of effective treatment strategies has been hindered by the complex pathogenesis of ulcerative colitis (UC). UC patients treated with current therapeutic approaches experienced either treatment failure or suffered excessive adverse reactions. Overactivity of NLRP3 inflammasome enhances inflammation, resulting in aggravation of colonic damage. We were interested in exploring, for the first time, the potential coloprotective effect of dapagliflozin (DPZ) on acetic acid-induced UC in rats in comparison with 5-ASA. DPZ improved histologic and macroscopic features of colon tissues and prolonged survival of UC rats. DPZ also prevented colon shortening and declined disease activity. Additionally, DPZ lessened colon tissue neutrophil content and improved antioxidant defense machinery. Further, DPZ specifically declined the colonic inflammatory marker IL-6 and upregulated the anti-inflammatory cytokine IL-10. The pyroptosis process is constrained in consequence of the repressed caspase-1 activity and caspase-1-dependent release of the bioactive cytokines IL-1β and IL-18. These protective effects might be attributed to that DPZ on the one hand, prevented the priming step (signal 1) of NLRP3 inflammasome activation as revealed by modulating NFκB/AMPK interplay and on the other hand, inhibited the activation step (signal 2) as indicated by interrupting NLRP3/caspase-1 signaling. Since DPZ was found to be safe and well tolerated by healthy volunteers with no evidence of hypoglycemia, it might show promise in the future management of UC. However, further investigations are warranted to confirm the reversal of injury and that the coloprotective effect is substantial.

Keywords: AMPK; Acetic acid; Dapagliflozin; NFκB; NLRP3 inflammasome; Ulcerative colitis.