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

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.

• Authors: Wen Liu, Wenjie Guo, Jing Wu, Qiong Luo, Feifei Tao, Yanhong Gu, Yan Shen, Jianxin Li, Renxiang Tan, Qiang Xu, Yang Sun
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 85 Issue 10 Pg. 1504-12 (May 15 2013) ISSN: 1873-2968 [Electronic] England
• PMID: 23506741 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Benzimidazoles
• Carrier Proteins
• Cytokines
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Dextran Sulfate
• Peroxidase
• Caspase 1

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, pharmacology)
• Benzimidazoles (chemical synthesis, pharmacology)
• Carrier Proteins (antagonists & inhibitors, genetics, metabolism)
• Caspase 1 (genetics, metabolism)
• Cell Line
• Colitis (chemically induced, pathology, prevention & control)
• Colon (drug effects, metabolism, pathology)
• Cytokines (biosynthesis)
• Dextran Sulfate
• Dose-Response Relationship, Drug
• Female
• Gene Expression (drug effects)
• Humans
• Inflammasomes (antagonists & inhibitors, genetics, metabolism)
• Macrophages, Peritoneal (drug effects, pathology)
• Mice
• Mice, Inbred C57BL
• NLR Family, Pyrin Domain-Containing 3 Protein
• Neutrophil Infiltration (drug effects)
• Neutrophils (drug effects, metabolism, pathology)
• Peroxidase (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship