A novel pyrazole-containing indolizine derivative suppresses NF-κB activation and protects against TNBS-induced colitis via a PPAR-γ-dependent pathway

The nuclear factor-kappa B (NF-kappa B)-mediated activation of macrophages plays a key role in mucosal immune responses in Crohn's disease (CD). Moreover, increasing evidence shows that the activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) exerts satisfactory anti-inflammatory effects in experimental colitis models, mostly by suppressing NF-kappa B-mediated macrophage activation. Therefore, exploring therapeutic strategies to activate PPAR-gamma and inhibit the NF-kappa B pathway in colonic macrophages holds great promise for the treatment of CD. In this study, five novel pyrazole-containing indolizine derivatives (B1, B2, B3, B4 and B5) were successfully synthesized and characterized, and their anti-inflammatory activities for CD treatment were also investigated. Among the five compounds, compound B4 effectively decreased the NF-kappa B-mediated production of the pro-inflammatory cytokine TNF-alpha in LPS-stimulated peritoneal macrophages. Moreover, compound B4 significantly ameliorated 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced mouse colitis symptoms, including body weight loss, colonic pathological damage and inflammatory cell infiltration. The results of western blotting and luciferase reporter assays indicated that compound B4 activated PPAR-gamma and subsequently suppressed NF-kappa B activation. Conversely, the addition of the PPAR-gamma antagonist GW9662 abrogated the anti-inflammatory effects of compound B4 both in vitro and in vivo. In summary, compound B4 activated the PPAR-gamma pathway to inhibit downstream NF-kappa B signaling, which alleviated experimental colitis. Thus, this compound may serve as a potential therapeutic agent for patients with CD. (C) 2017 Elsevier Inc. All rights reserved.