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The enaminone E121 suppresses immune responses in vitro and in vivo Asthma is a chronic inflammatory disease of the airways. Current treatment is far from optimal and there is a need for novel therapeutic agents. The purpose of this study was to assess the anti-asthma effects of an enaminone, E121, and also its effects on human peripheral blood mononuclear cell (HPBMC) proliferation and cytokine release. The effects of E121 were assessed in an ovalbumin (OVA)-induced model of airway inflammation and airway hyperresponsiveness (AHR). In addition, the effects of E121 on phytohemagglutinin (PHA), anti-CD3 monoclonal antibody (mAb), and lipopolysaccharide (LPS)-induced HPBMC proliferation and cytokine release, respectively, were assessed. Treatment of mice with E121 (10, 60 and 100 mg/kg; i.p) dose-dependently decreased the OVA-induced influx of leukocytes into the airways, 24 h after last OVA challenge, compared to the control group (3.1 + 0.3 x 104, 2.6 + 0.7 x 104, 2.1 + 0.2 x 104 vs. 5.5 + 0.9 x 104 /ml, P<0.05) and decreased the percentage of eosinophils at 100 mg/kg compared to control animals (15.7 + 5.1 vs. 40.0 + 5.6 %, P<0.05). OVA challenge induced a significant increase in AHR to methacholine compared to control animals (5.3 + 0.6 vs. 2.4 + 0.2, P<0.05) and this was also inhibited by E121 (2.5 + 0.3 vs. 5.3 + 0.6, P<0.05). Treatment with E121 additionally significantly inhibited HPBMC proliferation induced by both PHA (9567.6 + 2422.6 vs. 39709.8 + 4356.5; P<0.05; relative inhibition 76 %) and anti-CD3 mAb (11461.6 + 1517.1 vs. 24844.8 + 3026.8; P<0.05; relative inhibition 54 %. E121 also inhibited PHA, anti-CD3 mAb, and LPS-induced cytokine release from HPBMC cultures. These findings indicate that E121 exhibits anti-inflammatory and immunosuppressive activities and may therefore represent a novel class of anti-asthma therapy.
Funded by Kuwait University grant # PT 0105 and the Swiss National Science Foundation.
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