3-(3-Pyridylmethylidene)-2-indolinone Reduces the Severity of Colonic Injury in a Murine Model of Experimental Colitis

Kun-Ping Wang,Shou-Guo Zhang,En-Dong Liu,Yi-Qun Zhan,Lan Dong,Peng Cao,Hui Chen,Xiao-Ming Yang,Chang-Yan Li,Miao Yu,Xiang-Zhen Kong,Chao Zhang,Xiao-Ming Dong,Ke Zhao,Chun-Ping Hu,Lin Wang,Chang-Hui Ge

doi:10.1155/2015/959253

Abstract

Nrf2 is the key transcription factor regulating the antioxidant response which is crucial for cytoprotection against extracellular stresses. Numerous in vivo studies indicate that Nrf2 plays a protective role in anti-inflammatory response. 3-(3-Pyridylmethylidene)-2-indolinone (PMID) is a synthesized derivative of 2-indolinone compounds. Our previous study suggested that PMID induces the activation of Nrf2/ARE pathway, then protecting against oxidative stress-mediated cell death. However, little is known regarding the anti-inflammatory properties of PMID in severe inflammatory phenotypes. In the present study we determined if PMID treatment protects mice from dextran sodium sulphate- (DSS-) induced colitis. The result suggests that treatment with PMID prior to colitis induction significantly reduced body weight loss, shortened colon length, and decreased disease activity index compared to control mice. Histopathological analysis of the colon revealed attenuated inflammation in PMID pretreated animals. The levels of inflammatory markers in colon tissue and serum were reduced associated with inhibition of NF-κB activation. The expression levels of Nrf2-dependent genes such as HO-1, NQO1, and Nrf2 were increased in PMID pretreated mice. However, PMID pretreatment did not prevent DSS-induced colitis in Nrf2 knockout mice. These data indicate that PMID pretreatment in mice confers protection against DSS-induced colitis in Nrf2-dependent manner, suggesting a potential role of PMID in anti-inflammatory response.

Highlights

Chronic inflammation has been identified as a potential risk factor for colorectal and other cancers
The model control mice showed reduced length of colon, while the colons of PMID pretreated mice were shortened to a greater extent (Figure 1(c))
Microscopic analysis of colon tissue showed that colitis mice pretreated with PMID had noticeably lower levels of inflammatory cell infiltration into their distal colon mucosa, loss of colonic crypts, and epithelial cell necrosis compared to Model control (MC) mice (Figure 1(d))

Summary

Introduction

Chronic inflammation has been identified as a potential risk factor for colorectal and other cancers. Nrf is the key transcription factor regulating the antioxidant response which is crucial for cytoprotection against extracellular stresses. Disruption of Nrf gene renders animals more susceptible to dextran sodium sulphate- (DSS-) induced colitis and to AOM-DSSinduced colon carcinogenesis [9,10,11]. Nrf pathway appears to mediate a strong anti-inflammatory response, besides induction of detoxification and antioxidant enzymes. Our previous study suggested that PMID induces the ARE-mediated genes expression through stabilization of Nrf protein and activation of Nrf2/ARE pathway and protects against oxidative stress-mediated cell death, indicating that PMID is a novel antioxidant agent by triggering the induction of antioxidant and defensive genes [12]. In the present study we determined if PMID treatment protects mice from dextran sodium sulphate- (DSS-) induced colitis

Materials and Methods

Results

Discussion

Conflict of Interests