The supportive role of NSC328382, a P2X7R antagonist, in enhancing the inhibitory effect of CRID3 on NLRP3 inflammasome activation in rats with dextran sodium sulfate-induced colitis

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Saber S.; Yahya G.; Gobba N.A.; Sharaf H.; Alshaman R.; Alattar A.; Amin N.A.; El-Shedody R.; Aboutouk F.H.; El-Galeel Y.A.; El-Hefnawy A.; Shabaka D.; Khalifa A.; Saleh R.; Osama D.; El-Zoghby A.; Youssef M.E.

Journal: Journal of Inflammation Research

Publisher: Dove Medical Press Ltd

Publication Date: July 2021

Volume / Issue: Volume 14

Pages: 3443–3463

ISSN: 11787031

DOI: 10.2147/JIR.S315938

Scopus: View on Scopus

Document Type: Article

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

Authors and Affiliations

Saber S., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Yahya G., Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Al Sharqia, Egypt; Gobba N.A., Department of Pharmacology and Toxicology, College of Pharmacy, Misr University for Science and Technology, Cairo, Egypt; Sharaf H., Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Alshaman R., Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia; Alattar A., Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia; Amin N.A., Department of Haematology, Theodor Bilharz Research Institute, Giza, Egypt; El-Shedody R., Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Aboutouk F.H., Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; El-Galeel Y.A., Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; El-Hefnawy A., Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Shabaka D., Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Khalifa A., Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Saleh R., Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Osama D., Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; El-Zoghby A., Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Youssef M.E., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt

Abstract

Purpose: The NLRP3 inflammasome is a substantial component of the inflammation process. The complex pathogenesis of and the implication of a vast number of components in the inflammasomeactivation pathway prompted us to search for compounds that have a wide therapeutic index and act at the level of multiple cellular targets. Although CRID3 blocks NLRP3 with high specificity in the laboratory, clinical trials of the compound reported weaker potency. Methods: We used NSC328382, a P2X7R antagonist, as an adjunctive therapy and generated a strategy to potentiate the effects of CRID3 in rats with DSS-induced colitis. Results: NSC328382/CRID3 combined therapy exhibited a significantly increased efficacy compared with either of the monotherapies. NSC328382/CRID3 was more efficient in 1) attenuating colon shortening and disease activity; 2) improving goblet cell density and both the macroscopic and microscopic scenario of the injured colon; 3) improving the antioxidant defense mechanisms of the inflamed colon against oxidative stress; and 4) mitigating the inflammation state by downregulating the proinflammatory cytokines. Pyroptotic cell death was also conspicuously restrained. Additionally, NSC328382 interrupted the MyD88/NF-κB axis. Moreover, NSC328382/CRID3 exhibited the ability to alter Th1/Th2 dominance. Conclusion: The clinical application of NSC328382/CRID3 may result in the generation of a novel approach for the treatment of IBDs. © 2021 Saber et al.

Keywords

Colitis; CRID3; MyD88/NF-κB; NSC328382; P2X7R/NLRP3; agents used in inflammatory bowel disease; caspase 3; CD11b antigen; crid 3; cryopyrin; digestive tract agent; glutathione; immunoglobulin enhancer binding protein; interleukin 10; interleukin 12p70; interleukin 18; interleukin 1beta; interleukin 1beta converting enzyme; interleukin 6; malonaldehyde; messenger RNA; myeloid differentiation factor 88; myeloperoxidase; nsc 328382; superoxide dismutase; transcription factor RelA; tumor necrosis factor; unclassified drug; adult; animal experiment; animal model; animal tissue; antioxidant activity; Article; CD4+ T lymphocyte; cell death; cell density; clinical effectiveness; combination drug therapy; controlled study; dextran sulfate sodium-induced colitis; disease activity; dose response; down regulation; drug effect; drug efficacy; drug mechanism; enzyme activity; flow cytometry; goblet cell; histology; male; monocyte; monotherapy; nonhuman; oxidative stress; protein expression; pyroptosis; rat; Th1 cell; Th2 cell; treatment outcome; Wistar rat

Citation Information

Scopus Citations: 34

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