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.
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