A derivative of 3-(1,3-diarylallylidene)oxindoles inhibits dextran sulfate sodium-induced colitis in mice

TL;DR

A new compound called IA-0130 was found to reduce inflammation and improve symptoms in mice with colitis, possibly by blocking harmful signaling pathways.

Contribution

The study is the first to demonstrate the therapeutic effects of IA-0130, a novel oxindole derivative, in treating colitis in mice.

Findings

IA-0130 reduced weight loss, bleeding, and colon shortening in mice with DSS-induced colitis.

The compound inhibited pro-inflammatory cytokines and maintained intestinal barrier integrity.

IA-0130 suppressed the gp130 signaling pathway and IL-6 expression in colonic tissues.

Abstract

IA-0130 is a derivative of 3-(1,3-diarylallylidene)oxindoles, which is a selective estrogen receptor modulator (SERM). A previous study demonstrated that SERM exhibits anti-inflammatory effects on colitis by promoting the anti-inflammatory phenotype of monocytes in murine colitis. However, the therapeutic effects of oxindole on colitis remain unknown. Therefore, we evaluated the efficacy of IA-0130 on dextran sulfate sodium (DSS)-induced mouse colitis.

The DSS-induced colitis mouse model was established by administration of 2.5% DSS for 5 days. Mice were orally administered with IA-0130 (0.01 mg/kg or 0.1 mg/kg) or cyclosporin A (CsA; 30 mg/kg). Body weight, disease activity index score and colon length of mice were calculated and histological features of mouse colonic tissues were analyzed using hematoxylin and eosin staining. The expression of inflammatory cytokines and tight junction (TJ) proteins were analyzed using quantitative real-time PCR and enzyme-linked immunosorbent assay. The expression of interleukin-6 (IL-6) signaling molecules in colonic tissues were investigated using Western blotting and immunohistochemistry (IHC).

IA-0130 (0.1 mg/kg) and CsA (30 mg/kg) prevented colitis symptom, including weight loss, bleeding, colon shortening, and expression of pro-inflammatory cytokines in colon tissues. IA-0130 treatment regulated the mouse intestinal barrier permeability and inhibited abnormal TJ protein expression. IA-0130 down-regulated IL-6 expression and prevented the phosphorylation of signaling molecules in colonic tissues.

This study demonstrated that IA-0130 suppressed colitis progression by inhibiting the gp130 signaling pathway and expression of pro-inflammatory cytokines, and maintaining TJ integrity.

The online version contains supplementary material available at 10.1007/s43440-024-00616-2.

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