Gastroprotective potential of canagliflozin in indomethacin-induced peptic ulcer: impact on inflammation, pyroptosis, autophagy, and gut integrity.

A peptic ulcer is recognised as one of the major prevalent illnesses globally. Indomethacin (Indo) is a common analgesic and anti-inflammatory agent used to treat a range of inflammatory diseases. Nevertheless, prolonged use of them is linked to gastrointestinal bleeding, ulcers, and perforations, which are one of the primary triggers of peptic ulcers. Canagliflozin (Cana) is a sodium-glucose co-transporter-2 inhibitor (SGLT-2 inhibitor) that acts as an anti-diabetic compound. It has antioxidant and anti-inflammatory properties. In this research, network pharmacology was applied to predict Cana's targets implicated in curing peptic ulcer with experimental validation in a rat model of Indo-induced peptic ulcer. Sixty rats were separated into 4 groups structured as: control group; ulcerated group; Cana group; Omeprazole group. Net pharmacology predicted 56 shared targets to be targeted by Cana, in addition, Enrichment analyses identified that Cana could modulate tumor necrosis factor-alpha (TNF-α), mitogen-activated protein kinase (MAPK), and Toll-like receptor (TLR) signalling pathways. Rats pretreated with Cana showed a gastroprotective effect by attenuation of ulcerative index (UI) (90.3% as compared to the ulcerated group), oxidation, and inflammation through multiple signalling pathways. It was found that the Cana group displayed a decrease in gastric abundance of the toll-like receptor-4 (TLR-4) pathway and pyroptosis. Furthermore, it enhanced the level of Sirtuin 1 (SIRT-1) and autophagy. Additionally, it restored intestinal permeability, which, in turn, aggravated peptic ulcer via endotoxemia. Hence, Cana is a promising gastroprotective agent against peptic ulcers through multiple cascades, evidenced by network pharmacology and experimental validation.