A semisynthetic diterpenoid lactone inhibits NF-κB signalling to ameliorate inflammation and airway hyperresponsiveness in a mouse asthma model.
Andrographolide (AGP) and 14-deoxy-11,12-didehydroandrographolide (DDAG), two main diterpenoid constituents of Andrographis paniculata were previously shown to ameliorate asthmatic symptoms in a mouse model. However, due to inadequacies of both compounds in terms of drug-likeness, DDAG analogues were semisynthesised for assessment of their anti-asthma activity. A selected analogue, 3,19-diacetyl-14-deoxy-11,12-didehydroandrographolide (SRS27), was tested for inhibitory activity of NF-κB activation in TNF-α-induced A549 cells and was subsequently evaluated in a mouse model of ovalbumin (OVA)-induced asthma. Female BALB/c mice, 6-8weeks old were sensitized on days 0 and 14, and challenged on days 22, 23 and 24 with OVA. Compound or vehicle (3% dimethyl sulfoxide) was administered intraperitoneally 1h before and 11h after each OVA aerosol challenge. On day 25, pulmonary eosinophilia, airway hyperresponsiveness, mucus hypersecretion, inflammatory cytokines such as IL-4, -5 and -13 in BAL fluid, gene expression of inflammatory mediators such as 5-LOX, E-selectin, VCAM-1, CCL5, TNF-α, AMCase, Ym2, YKL-40, Muc5ac, CCL2 and iNOS in animal lung tissues, and serum IgE were determined. SRS27 at 30μM was found to suppress NF-κB nuclear translocation in A549 cells. In the ovalbumin-induced mouse asthma model, SRS27 at 3mg/kg displayed a substantial decrease in pulmonary eosinophilia, BAL fluid inflammatory cytokines level, serum IgE production, mucus hypersecretion and gene expression of inflammatory mediators in lung tissues. SRS27 is the first known DDAG analogue effective in ameliorating inflammation and airway hyperresponsiveness in the ovalbumin-induced mouse asthma model.
['Lim|J C-W|JC|', 'Goh|F-Y|FY|', 'Sagineedu|S-R|SR|', 'Yong|A C-H|AC|', 'Sidik|S M|SM|', 'Lajis|N H|NH|', 'Wong|W S F|WS|', 'Stanslas|J|J|']
D000072283:A549 Cells D000818:Animals D018927:Anti-Asthmatic Agents D000893:Anti-Inflammatory Agents D001249:Asthma D001992:Bronchoalveolar Lavage Fluid D002452:Cell Count D016207:Cytokines D004195:Disease Models, Animal D004224:Diterpenes D005260:Female D006801:Humans D007073:Immunoglobulin E D007074:Immunoglobulin G D007783:Lactones D008807:Mice, Inbred BALB C D016328:NF-kappa B D010047:Ovalbumin D015398:Signal Transduction
NF-κB Airway hyperresponsiveness Mouse asthma model Ovalbumin A549 cell line Andrographolide analogues Oxidative stress