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

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 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 gener-ated 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-Kappa B 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.