Frontiers in Pharmacology (Sep 2024)

Activation of AMPK/SIRT1/FOXO3a signaling by BMS-477118 (saxagliptin) mitigates chronic colitis in rats: uncovering new anti-inflammatory and antifibrotic roles

  • Elsayed A. Elmorsy,
  • Mahmoud E. Youssef,
  • Mohamed R. Abdel-Hamed,
  • Mohamed R. Abdel-Hamed,
  • Maha M. Amer,
  • Maha M. Amer,
  • Sahar R. Elghandour,
  • Abdullah S. Alkhamiss,
  • Nahla B. Mohamed,
  • Mostafa M. Khodeir,
  • Mostafa M. Khodeir,
  • Hossam A. Elsisi,
  • Hossam A. Elsisi,
  • Thamir Saad Alsaeed,
  • Manal M. Kamal,
  • Manal M. Kamal,
  • Abousree T. Ellethy,
  • Basem H. Elesawy,
  • Basem H. Elesawy,
  • Sameh Saber

DOI
https://doi.org/10.3389/fphar.2024.1456058
Journal volume & issue
Vol. 15

Abstract

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Ulcerative colitis (UC) is a debilitating chronic disease marked by persistent inflammation and intestinal fibrosis. Despite the availability of various treatments, many patients fail to achieve long-term remission, underscoring a significant unmet therapeutic need. BMS-477118, a reversible inhibitor of dipeptidyl peptidase 4 (DPP4), has demonstrated anti-inflammatory properties in preclinical and clinical studies with minimal adverse effects compared to other antidiabetic agents. However, the potential benefits of BMS-477118 in chronic UC have not yet been explored. In this study, we aimed to investigate the effects of BMS-477118 in rats subjected to chronic dextran sodium sulfate (DSS) administration. Our findings indicate that BMS-477118 activates the interconnected positive feedback loop involving AMPK, SIRT1, and FOXO3a, improving histological appearance in injured rat colons. BMS-477118 also reduced fibrotic changes associated with the chronic nature of the animal model, alleviated macroscopic damage and disease severity, and improved the colon weight-to-length ratio. Additionally, BMS-477118 prevented DSS-induced weight loss and enhanced tight junction proteins. These effects, in conjunction with reduced oxidative stress and its potential anti-inflammatory, antiapoptotic, and autophagy-inducing properties, fostered prolonged survival in rats with chronic UC. To conclude, BMS-477118 has the potential to activate the AMPK/SIRT1/FOXO3a signaling pathway in inflamed colons. These results suggest that the AMPK/SIRT1/FOXO3a pathway could be a new therapeutic target for UC. Further research is mandatory to explore the therapeutic possibilities of this pathway. Additionally, continued studies on the therapeutic potential of BMS-477118 and other DPP4 inhibitors are promising for creating new treatments for various conditions, including UC in diabetic patients.

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