Dapagliflozin mitigates acute pancreatitis induced by L-arginine in Rats through modulation of TLR-4/NF-κB/NLRP3 pathway: integrated biochemical, histopathological, and in silico study.

BACKGROUND

Acute pancreatitis (AP) is one of the most common gastrointestinal disorders requiring hospitalization worldwide and is characterized by excessive inflammatory and oxidative responses that contribute to pancreatic tissue injury. Dapagliflozin (DAPA), a selective sodium-glucose co-transporter 2 inhibitor, has demonstrated pleiotropic anti-inflammatory and antioxidant properties beyond its glucose-lowering effects.

AIM: To investigate the protective effect of DAPA against L-arginine-induced AP and to elucidate the underlying molecular mechanisms.

METHODS

Twenty-four Wistar rats were randomly divided into three groups (n = 8): control, AP, and DAPA-treated AP. AP was induced by L-arginine administration. DAPA (1 mg/kg, orally) was administered for three consecutive days starting 1 h after AP induction. Markers of pancreatic injury, inflammation, and oxidative stress were assessed. Pancreatic histopathology and immunohistochemical analyses were performed. Furthermore, molecular docking analyses were conducted to evaluate the potential inhibitory interactions of DAPA with toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), and NLR family pyrin domain-containing 3 (NLRP3).

RESULTS

DAPA treatment significantly reduced α-amylase, lipase levels and preserved pancreatic histoarchitecture compared with the untreated AP group. It markedly decreased pancreatic levels of interleukin (IL)-1β, IL-18, tumor necrosis factor-α (TNF-α), TLR4, NLRP3, myeloperoxidase, and malondialdehyde, while significantly increasing superoxide dismutase activity. Immunohistochemical analysis revealed negative expression of NF-κB and caspase-1 in pancreatic tissues from DAPA-treated rats, in contrast to their pronounced expression in the L-arginine-induced AP group. Molecular docking studies demonstrated favorable binding affinities and interactions between DAPA and TLR4, NF-κB, and NLRP3.

CONCLUSION

DAPA attenuates L-arginine-induced acute pancreatitis by suppressing inflammatory, oxidative, and inflammasome-related pathways through modulation of the TLR4/NF-κB/NLRP3 signaling axis.