Novel compound JOAB-40 decreases inflammation in vitro and colitis severity in vivo by using the murine Dextran Sulfate Sodium (DSS) model

Abstract

Abstract Crohn’s disease and ulcerative colitis are two disorders categorized as inflammatory bowel diseases (IBD). Patients with IBD may have inflammation extending the full thickness of the gut and non-gut organs mediated in part by Th-induced cytokines IL-1β, -2, -12, -13, -17, TNF-α, and IFN-Υ. To mimic this in vivo, DSS given in drinking water (3% w/v) can induce colitis in mice. Our previous work with novel anti-inflammatory enaminone E121 has shown that treating mice with E121 along with DSS-induced colitis (prophylactic approach) reduced colitis severity at gross and histological levels at the 30–60 mg/kg doses. Modifications made to E121 have resulted in new compounds (JOAB series) that include a piperazino ring which can not only decrease levels of pro-inflammatory cytokines but also inhibit chemokine signaling through CCR2. In vitro data suggest that JOAB-40 can reduce levels of TNF, IL-1, IL-6, and IL-12 in LPS-stimulated macrophages. Since JOAB-40 was successful in decreasing inflammation in a mouse model of hemarthrosis without toxicity, we assessed its efficacy in decreasing inflammation associated with colitis. Prophylactically, mice treated with JOAB-40 had a more profound reduction in severity of colitis at lower doses (1–10 mg/kg) than E121. At higher doses (30–60 mg/kg), both E121 and JOAB were equivalent in their potency in reducing colitis severity. When both agents were given after colitis induction (treatment approach), JOAB-40 reduced colitis severity at 10, 30, and 60 mg/kg doses (by 50% compared to vehicle), but E121 did not reduce colitis severity at histological level when used at similar dose range. These data suggest JOAB-40 is more effective in reducing colitis severity in mice compared to the parental E121 compound.