Canagliflozin, an SGLT-2 inhibitor, ameliorates acetic acid-induced colitis in rats through targeting glucose metabolism and inhibiting NOX2.

Background: Inflammatory bowel disease is defined as chronic noninfectious inflammation of the gastrointestinal tract, including ulcerative colitis and Crohn's disease. Its incidence and predominance have increased globally, with no effective agents for preventing its recurrence or treatment until now.
Aim: The current study aimed to investigate the possible role of canagliflozin (CANA), a sodium-glucose co-transporter-2 inhibitor (SGLT-2), to prevent and treat acetic acid (AA)-induced colitis in a rat model.
Methods: Colitis was induced in male Wistar rats by intrarectal instillation of 1 ml of 4% (v/v) AA. Rats were treated orally with either CANA (30 mg/kg/day, p.o.) for 10 days before or after colitis induction or sulfasalazine (360 mg/kg/day, p.o.) for 10 days before colitis induction.
Results: AA resulted in a significant increase in disease activity index, colonic weight over length ratio, colon macroscopic damage score, and histological signs of colitis. All of these effects were significantly decreased by CANA administration. Additionally, CANA markedly inhibited AA-induced oxidative stress and inflammatory responses by significantly reducing the up-regulated levels in malondialdehyde, total nitrite, NF-κB, interleukin-1β, and TNF-α, and significantly increasing the down-regulated levels in reduced glutathione, superoxide dismutase, and interleukin-10. CANA significantly inhibited caspase-3 level while rescued survivin expression in colons. Finally, CANA reduced the elevated levels of pyruvic acid and G6PDH activity, as well as the levels of p22phox and NOX2 in the AA-induced colitis.
Conclusion: Our findings provide novel evidence that CANA has protective and therapeutic effects against AA-induced colitis by the impact of its antioxidant, anti-inflammatory, and anti-apoptotic effects.
(Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)