A novel benzo[d]imidazole derivate prevents the development of dextran sulfate sodium-induced murine experimental colitis via inhibition of NLRP3 inflammasome.

Biochem Pharmacol. 2013 May 15;85(10):1504-12.

Liu W, Guo W, Wu J, Luo Q, Tao F, Gu Y, Shen Y, Li J, Tan R, Xu Q, Sun Y.

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.

Abstract

NLRP3 inflammasome has been reported to be associated with various kinds of immunological diseases including colitis. However, there are few drug candidates targeting inflammasomes for the treatment of colitis. In the present study, we aimed at examining the effect of 1-ethyl-5-methyl-2-phenyl-1H-benzo[d]imidazole, a synthetic small molecular compound also named Fc11a-2, for the treatment of dextran sulfate sodium (DSS)-induced experimental colitis in mice via targeting NLRP3 inflammasome. Treatment with Fc11a-2 dose-dependently attenuated the loss of body weight and shortening of colon length induced by DSS. In addition, the disease activity index, histopathologic scores and myeloperoxidase activity were also significantly reduced by Fc11a-2 treatment. Moreover, protein and mRNA levels of DSS-induced proinflammatory cytokines in colon, including TNF-α, IL-1β, IL-18, IL-17A and IFN-γ, were markedly suppressed by Fc11a-2. Furthermore, a decreased CD11c⁺ macrophage infiltration in colons and inactivation of caspase-1 in peritoneal macrophages were detected in Fc11a-2-treated mice. The mechanism of action of Fc11a-2 was related to the inhibition of the cleavage of pro-caspase-1, pro-IL-1β and pro-IL-18 which in turn suppressed the activation of NLRP3 inflammasome. Taken together, our results demonstrate the ability of Fc11a-2 to inhibit NLRP3 inflammasome activation and its potential use in the treatment of inflammatory bowel diseases. Copyright © 2013 Elsevier Inc.

PMID: 23506741

 

Graphical abstract

Small molecular compound Fc11a-2 attenuates dextran sulfate sodium (DSS)-induced experimental colitis in mice through inhibiting NLRP3 inflammasome activation.

Qiang Xu or Yang Sun

Correspondence to

Qiang Xu, PhD, or Yang Sun, PhD, School of Life Sciences, Nanjing University, Nanjing 210093 China, Tel/Fax: +86-25-83597620; E-mail: molpharm@163.com (Q. Xu); yangsun@nju.edu.cn (Y. Sun)

Acknowledgments:

This work was supported by Science Fund for Creative Research Groups of NSFC (No. 81121062), National Natural Science Foundation of China (Nos. 81173070, 91229109, 90913023, 91129728 and 81101563), and National Science & Technology Major Project (No. 2012ZX09304-001).

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