A semisynthetic diterpenoid lactone inhibits NF-κB signalling to ameliorate inflammation and airway hyperresponsiveness in a mouse asthma model

• Published in: Toxicology and applied pharmacology Vol. 302; pp. 10 - 22
• Main Authors: Lim, J.C.-W., Goh, F.-Y., Sagineedu, S.-R., Yong, A.C.-H., Sidik, S.M., Lajis, N.H., Wong, W.S.F., Stanslas, J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2016
• Subjects: 60 APPLIED LIFE SCIENCES; A549 cell line; A549 Cells; AEROSOLS; Airway hyperresponsiveness; Andrographis paniculata; Andrographolide analogues; ANIMAL TISSUES; Animals; Anti-Asthmatic Agents - pharmacology; Anti-Asthmatic Agents - therapeutic use; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; ASTHMA; Asthma - blood; Asthma - drug therapy; Asthma - immunology; Asthma - physiopathology; Bronchoalveolar Lavage Fluid - chemistry; Bronchoalveolar Lavage Fluid - cytology; Cell Count; Cytokines - immunology; Disease Models, Animal; Diterpenes - pharmacology; Diterpenes - therapeutic use; DMSO; DRUGS; Female; GENES; Humans; Immunoglobulin E - blood; Immunoglobulin G - blood; INFLAMMATION; LACTONES; Lactones - pharmacology; Lactones - therapeutic use; LUNGS; LYMPHOKINES; MICE; Mice, Inbred BALB C; Mouse asthma model; NF-kappa B - antagonists & inhibitors; NF-kappa B - genetics; NF-kappa B - immunology; NF-κB; OVA; OVALBUMIN; OXIDATION; Oxidative stress; RESPIRATORY TRACT CELLS; Signal Transduction; TRANSLOCATION; SRS27; NF-κB; Ovalbumin; Oxidative stress; A549 cell line; DDAG; AGP; AHR; Andrographolide analogues; Mouse asthma model; Airway hyperresponsiveness
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2016.04.004

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. [Display omitted] •SRS27 was synthesised to overcome inadequacies of its parent compound in terms of drug-likeness.•SRS27 was tested in TNF-α-induced A549 lung cells and ovalbumin (OVA)-induced mouse asthma model.•SRS27 suppressed NF-κB nuclear translocation in A549 cells.•SRS27 alleviated lung inflammation and airway hyperresponsiveness in mouse asthma model.•SRS27 is the first known DDAG analogue tested positive in ameliorating asthma.