Interference With the AMPKα/mTOR/NLRP3 Signaling and the IL-23/IL-17 Axis Effectively Protects Against the Dextran Sulfate Sodium Intoxication in Rats: A New Paradigm in Empagliflozin and Metformin Reprofiling for the Management of Ulcerative Colitis

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Youssef M.E.; Abd El-Fattah E.E.; Abdelhamid A.M.; Eissa H.; El-Ahwany E.; Amin N.A.; Hetta H.F.; Mahmoud M.H.; Batiha G.E.-S.; Gobba N.; Ahmed Gaafar A.G.; Saber S.

Journal: Frontiers in Pharmacology

Publisher: Frontiers Media S.A.

Publication Date: 16 August 2021

Volume / Issue: Volume 12

Article No.: 719984

ISSN: 16639812

DOI: 10.3389/fphar.2021.719984

Scopus: View on Scopus

Document Type: Article

Access: All Open Access; Gold Open Access; Green Open Access

Authors and Affiliations

Youssef M.E., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Abd El-Fattah E.E., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Abdelhamid A.M., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Eissa H., Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; El-Ahwany E., Department of Immunology, Theodor Bilharz Research Institute, Giza, Egypt; Amin N.A., Department of Hematology, Theodor Bilharz Research Institute, Giza, Egypt; Hetta H.F., Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, United States; Mahmoud M.H., Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia; Batiha G.E.-S., Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt; Gobba N., Department of Pharmacology and Toxicology, College of Pharmacy, Misr University for Science and Technology, 6th of October City, Egypt; Ahmed Gaafar A.G., Department of Pharmacology and Toxicology, Faculty of Pharmacy, Port-Said University, Port-Said, Egypt; Saber S., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt

Abstract

Empagliflozin and metformin are widely used for the treatment of type 2 diabetes. These drugs showed marked anti-inflammatory effects in different animal models via enhancing AMPK activity. Yet, the protective anti-inflammatory effects of their combination against ulcerative colitis have not been previously investigated. The current study aimed to explore the potential of empagliflozin/metformin combination to mitigate the DSS-induced rat colitis model. The modulating effects of empagliflozin and metformin on the AMPK/mTOR/NLRP3 axis and T cell polarization were delineated. In this study, distal colons were examined for macroscopic and microscopic pathological alterations. ELISA, qRT-PCR, and immunohistochemistry techniques were applied to detect proteins and cytokines involved in AMPK/mTOR/NLRP3 axis and T Cell polarization. Oral administration of empagliflozin (10 mg/kg/day) and metformin (200 mg/kg/day) combination alleviated colitis as revealed by the reduced disease activity index, macroscopic damage index, colon weight/length ratio, and histopathologic scoring values. Interestingly, empagliflozin/metformin combination significantly enhanced AMPK phosphorylation and depressed mTOR and NLRP3 expression leading to a subsequent reduction in caspase-1 cleavage and inhibition of several inflammatory cytokines, including IL-1β, and IL-18. Reduced mTOR expression and reduced IL-6 levels led to a reduction in Th17 cell polarization and maintenance. Together, the current study reveals that the protective effects of empagliflozin and metformin against DSS-induced colitis are fundamentally mediated via enhancing AMPK phosphorylation. Since adult humans with diabetes mellitus are at greater risk for developing inflammatory bowel diseases, clinical application of empagliflozin/metformin combination represents a novel therapeutic approach for treating diabetic patients with ulcerative colitis. © Copyright © 2021 Youssef, Abd El-Fattah, Abdelhamid, Eissa, El-Ahwany, Amin, Hetta, Mahmoud, Batiha, Gobba, Ahmed Gaafar and Saber.

Keywords

AMPK; dextran sulfate sodium; empagliflozin; IL-23/1L-17 axis 4; metformin; mTOR; NLRP3; ulcerative colitis; cryopyrin; dextran sulfate; hydroxymethylglutaryl coenzyme A reductase kinase; interleukin 17; interleukin 18; interleukin 1beta; interleukin 1beta converting enzyme; interleukin 23; interleukin 6; mammalian target of rapamycin; adult; animal experiment; animal model; animal tissue; antiinflammatory activity; Article; controlled study; descending colon; disease activity; drug repositioning; enzyme linked immunosorbent assay; enzyme phosphorylation; histopathology; immunohistochemistry; inflammation; male; nonhuman; polarization; protein expression; rat; real time polymerase chain reaction; T lymphocyte; Th17 cell

Citation Information

Scopus Citations: 53

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