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
Sameh Saber,1 Galal Yahya,2 Naglaa A Gobba,3 Hossam Sharaf,4 Reem Alshaman,5 Abdullah Alattar,5 Noha A Amin,6 Ruwyda El-Shedody,4 Farah H Aboutouk,4 Yumna Abd El-Galeel,4 Amr El-Hefnawy,4 Dina Shabaka,4 Arwa Khalifa,4 Renad Saleh,4 Donya Osama,4 Ghada El-Zoghby,4 Mahmoud E Youssef1 1Department of Ph...
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2021
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oai:doaj.org-article:f8d86ce274e94b90bbd443251d1214a32021-12-02T16:17:55ZThe 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 Colitis1178-7031https://doaj.org/article/f8d86ce274e94b90bbd443251d1214a32021-07-01T00:00:00Zhttps://www.dovepress.com/the-supportive-role-of-nsc328382-a-p2x7r-antagonist-in-enhancing-the-i-peer-reviewed-fulltext-article-JIRhttps://doaj.org/toc/1178-7031Sameh Saber,1 Galal Yahya,2 Naglaa A Gobba,3 Hossam Sharaf,4 Reem Alshaman,5 Abdullah Alattar,5 Noha A Amin,6 Ruwyda El-Shedody,4 Farah H Aboutouk,4 Yumna Abd El-Galeel,4 Amr El-Hefnawy,4 Dina Shabaka,4 Arwa Khalifa,4 Renad Saleh,4 Donya Osama,4 Ghada El-Zoghby,4 Mahmoud E Youssef1 1Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; 2Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Al Sharqia, Egypt; 3Department of Pharmacology and Toxicology, College of Pharmacy, Misr University for Science and Technology, Cairo, Egypt; 4Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; 5Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia; 6Department of Haematology, Theodor Bilharz Research Institute, Giza, EgyptCorrespondence: Mahmoud E Youssef; Sameh SaberDepartment of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Costal International Road, P.O. Box: +11152, Mansoura, Dakahlia, EgyptTel +2 50 2770140; +2 01033124949Fax +2 50 2770140Email mahmoodelsaid@hotmail.com; sampharm81@gmail.com; sameh.mohamed@deltauniv.edu.egPurpose: 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 inflammasome-activation 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.Keywords: NSC328382, CRID3, P2X7R/NLRP3, MyD88/NF-κB, ColitisSaber SYahya GGobba NASharaf HAlshaman RAlattar AAmin NAEl-Shedody RAboutouk FHAbd El-Galeel YEl-Hefnawy AShabaka DKhalifa ASaleh ROsama DEl-Zoghby GYoussef MEDove Medical Pressarticlensc328382crid3p2x7r/nlrp3myd88/nf-κbcolitisPathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 14, Pp 3443-3463 (2021) |
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nsc328382 crid3 p2x7r/nlrp3 myd88/nf-κb colitis Pathology RB1-214 Therapeutics. Pharmacology RM1-950 |
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nsc328382 crid3 p2x7r/nlrp3 myd88/nf-κb colitis Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Saber S Yahya G Gobba NA Sharaf H Alshaman R Alattar A Amin NA El-Shedody R Aboutouk FH Abd El-Galeel Y El-Hefnawy A Shabaka D Khalifa A Saleh R Osama D El-Zoghby G Youssef ME 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 |
| description |
Sameh Saber,1 Galal Yahya,2 Naglaa A Gobba,3 Hossam Sharaf,4 Reem Alshaman,5 Abdullah Alattar,5 Noha A Amin,6 Ruwyda El-Shedody,4 Farah H Aboutouk,4 Yumna Abd El-Galeel,4 Amr El-Hefnawy,4 Dina Shabaka,4 Arwa Khalifa,4 Renad Saleh,4 Donya Osama,4 Ghada El-Zoghby,4 Mahmoud E Youssef1 1Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; 2Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Al Sharqia, Egypt; 3Department of Pharmacology and Toxicology, College of Pharmacy, Misr University for Science and Technology, Cairo, Egypt; 4Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; 5Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia; 6Department of Haematology, Theodor Bilharz Research Institute, Giza, EgyptCorrespondence: Mahmoud E Youssef; Sameh SaberDepartment of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Costal International Road, P.O. Box: +11152, Mansoura, Dakahlia, EgyptTel +2 50 2770140; +2 01033124949Fax +2 50 2770140Email mahmoodelsaid@hotmail.com; sampharm81@gmail.com; sameh.mohamed@deltauniv.edu.egPurpose: 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 inflammasome-activation 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.Keywords: NSC328382, CRID3, P2X7R/NLRP3, MyD88/NF-κB, Colitis |
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| author |
Saber S Yahya G Gobba NA Sharaf H Alshaman R Alattar A Amin NA El-Shedody R Aboutouk FH Abd El-Galeel Y El-Hefnawy A Shabaka D Khalifa A Saleh R Osama D El-Zoghby G Youssef ME |
| author_facet |
Saber S Yahya G Gobba NA Sharaf H Alshaman R Alattar A Amin NA El-Shedody R Aboutouk FH Abd El-Galeel Y El-Hefnawy A Shabaka D Khalifa A Saleh R Osama D El-Zoghby G Youssef ME |
| author_sort |
Saber S |
| title |
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 |
| title_short |
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 |
| title_full |
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 |
| title_fullStr |
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 |
| title_full_unstemmed |
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 |
| title_sort |
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 |
| publisher |
Dove Medical Press |
| publishDate |
2021 |
| url |
https://doaj.org/article/f8d86ce274e94b90bbd443251d1214a3 |
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