BJ-1108, a 6-Amino-2,4,5-trimethylpyridin-3-ol analogue, ameliorates DSS-induced colitis in mice

Abstract

Background

Inflammatory bowel disease (IBD) is characterised by a chronic inflammation of gastrointestinal tract with unknown aetiology. Oxidative stress is one of contributing factors associated with the disease severity of IBD, and currently has been implicated as a therapeutic target. Previous studies showed that BJ-1108, a derivative of 6-amino-2,4,5-trimethylpyridin-3-ol, significantly inhibited reactive oxygen species (ROS) generation resulting in suppression of tumour growth in vitro. We therefore investigated the effects of BJ-1108 on dextran sulfate sodium (DSS)-induced experimental colitis in mice.

Methods

DSS-induced colitis was made by two cycles of DSS (2%) administration followed by 7-day water administration. The effect of BJ-1108 was also evaluated in vitro using Caco-2 cells.

Results

DSS-treated mice exhibited severe colitis, whereas mice administrated BJ-1108 improved the disease severity indicated by body weight, histological scores, spleen weight, T cell and macrophage infiltrates. BJ-1108 administration also inhibited colonic expression of NF-kB p65 and IL-1β in vivo. In addition, BJ-1108 treated mice had the enhanced epithelial barrier function indicated by in vivo intestinal permeability and the expression of tight junction proteins such as ZO-1, occludin, claudin-1 and claudin-3 in DSS-induced colitis model. Next, we used in vitro Caco-2 cells to confirm the effects of BJ-1108 on ROS generation and barrier function. As expected, BJ-1108 treated Caco-2 cells significantly ameliorated the cytokine-induced ROS generation in dose-dependent manner. In addition, BJ-1108 remarkably recovered in vitro injured-barrier functions assessed by transepithelial electrical resistance and tight junction protein expression in dose-dependent manner. Finally, we founded that BJ-1108 suppressed NF-kB p65 and PI3K/AKT pathway, and slightly p38/JNK pathway in time-dependent manner.

Conclusions

Collectively, these results provided that BJ-1108 had a therapeutic potential for IBD through reduction of ROS generation and inhibition of NF-kB and PI3K/AKT pathway.