Canagliflozin-loaded chitosan-hyaluronic acid microspheres modulate AMPK/NF-κB/NLRP3 axis: A new paradigm in the rectal therapy of ulcerative colitis

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Nasr M.; Cavalu S.; Saber S.; Youssef M.E.; Abdelhamid A.M.; Elagamy H.I.; Kamal I.; Gaafar A.G.A.; El-Ahwany E.; Amin N.A.; Girgis S.; El-Sandarosy R.; Mahmoud F.; Rizk H.; Mansour M.; Hasaballah A.; El-Rafi A.A.; El-Azez R.A.; Essam M.; Mohamed D.; Essam N.; Mohammed O.A.

Journal: Biomedicine and Pharmacotherapy

Publisher: Elsevier Masson s.r.l.

Publication Date: September 2022

Volume / Issue: Volume 153

Article No.: 113409

ISSN: 7533322

DOI: 10.1016/j.biopha.2022.113409

Scopus: View on Scopus

PubMed: 36076534

Document Type: Article

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

Authors and Affiliations

Nasr M., Department of Pharmaceutics, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt, Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Helwan University, Cairo, 11790, Egypt; Cavalu S., Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, Oradea, 410087, Romania; Saber S., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt; Youssef M.E., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt; Abdelhamid A.M., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt; Elagamy H.I., Department of Pharmaceutics, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Kamal I., Department of Pharmaceutics, Faculty of Pharmacy, Port Said University, Port Said, Egypt; Gaafar A.G.A., Department of Pharmacology and Toxicology, Faculty of Pharmacy, Port Said University, Port Said, 42511, Egypt; El-Ahwany E., Department of Immunology, Theodor Bilharz Research Institute, Giza, Egypt; Amin N.A., Department of Haematology, Theodor Bilharz Research Institute, Giza, 12411, Egypt; Girgis S., Department of Pharmaceutics, Faculty of Pharmacy, Alsalam University, Egypt; El-Sandarosy R., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt; Mahmoud F., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt; Rizk H., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt; Mansour M., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt; Hasaballah A., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt; El-Rafi A.A., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt; El-Azez R.A., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt; Essam M., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt; Mohamed D., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt; Essam N., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt; Mohammed O.A., Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, 11566, Egypt, Department of Clinical Pharmacology, Faculty of medicine, Bisha University, Bisha, 61922, Saudi Arabia

Abstract

Ulcerative colitis is an idiopathic disease that is widely incident worldwide. Canagliflozin, antidiabetic agent, exhibited significant anti-inflammatory effects in a variety of animal models. Additionally, hyaluronic acid is considered one of the key players in the tissue regeneration process. It has been proven to modulate inflammation and cellular migration, which are the main phases of wound healing. The combination of hyaluronic acid with chitosan in microsphere fabrication was anticipated to reveal a synergistic muco-adhesiveness potential with additional advantage of the chitosan penetration enhancing effect. The current study aimed to explore the potential of canagliflozin-loaded chitosan-hyaluronic acid microspheres intrarectal administration to mitigate acetic acid-induced colitis in rats. Colon tissues were examined for macroscopic and microscopic pathological changes. ELISA and qRT-PCR techniques were applied for the detection of cytokines involved in the AMPK/NF-κB/NLRP3 axis. Intrarectal administration of this formula alleviated colitis severity, which was reflected by the reduced DAI, MES, colonic weight/length ratio and histopathological scoring values. Interestingly, canagliflozin-loaded chitosan-hyaluronic acid microspheres significantly enhanced AMPK phosphorylation and depressed NF-κB and NLRP3 expression leading to a subsequent reduction in caspase-1 cleavage and the inhibition of several inflammatory cytokines, including IL-1β, and IL-18. Overall, the current study revealed that the protective effects of the formula against acetic acid-induced colitis are primarily mediated via augmenting AMPK phosphorylation and its consequences of NF-κB inactivation. Since canagliflozin is not associated with hypoglycemic effects, clinical application of canagliflozin-loaded chitosan-hyaluronic acid microspheres represent a novel therapeutic option for the treatment of patients with ulcerative colitis. © 2022 The Authors

Keywords

AMPK/NFκB/NLRP3 axis; Canagliflozin; Chitosan; Hyaluronic acid; Microspheres; Ulcerative colitis; cryopyrin; Hermes antigen; interleukin 18; interleukin 1beta; interleukin 1beta converting enzyme; interleukin 6; microsphere; myeloperoxidase; protein Bax; protein bcl 2; reactive oxygen metabolite; sequestosome 1; toll like receptor 4; adult; AMPK signaling; animal experiment; animal model; antidiabetic activity; antiinflammatory activity; Article; body weight; colon tissue; controlled study; disease severity; dispersity; drug release; enzyme linked immunosorbent assay; histopathology; in vitro study; inflammatory cell; male; NF kB signaling; nonhuman; particle size; photon correlation spectroscopy; protein cleavage; protein phosphorylation; rat; real time polymerase chain reaction; transmission electron microscopy; ultrafiltration; water solubility; zeta potential

Citation Information

Scopus Citations: 49

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