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
Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore.
Toxicol Appl Pharmacol. 2016 Jul 1;302:10-22. doi: 10.1016/j.taap.2016.04.004. Epub 2016 Apr 27.
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.
穿心莲内酯（AGP）和14-去氧-11,12-二脱氢穿心莲内酯（DDAG）是穿心莲的两种主要二萜类成分，先前已证明它们可改善小鼠模型中的哮喘症状。然而，由于这两种化合物在类药性方面存在不足，因此对DDAG类似物进行了半合成，以评估其抗哮喘活性。对一种选定的类似物3,19-二乙酰基-14-去氧-11,12-二脱氢穿心莲内酯（SRS27）进行了测试，以检测其在TNF-α诱导的A549细胞中对NF-κB激活的抑制活性，并随后在卵清蛋白（OVA）诱导的哮喘小鼠模型中进行了评估。6至8周龄的雌性BALB/c小鼠在第0天和第14天致敏，并在第22、23和24天用OVA进行激发。在每次OVA气雾剂激发前1小时和激发后11小时腹腔注射化合物或赋形剂（3%二甲基亚砜）。在第25天，测定肺嗜酸性粒细胞增多、气道高反应性、黏液分泌过多、BAL液中IL-4、-5和-13等炎性细胞因子、动物肺组织中5-LOX、E-选择素、VCAM-1、CCL5、TNF-α、AMCase、Ym2、YKL-40、Muc5ac、CCL2和iNOS等炎性介质的基因表达以及血清IgE。发现30μM的SRS能抑制A549细胞中NF-κB的核转位。在卵清蛋白诱导的小鼠哮喘模型中，3mg/kg的SRS27可使肺嗜酸性粒细胞增多、BAL液炎性细胞因子水平、血清IgE产生、黏液分泌过多以及肺组织中炎性介质的基因表达显著降低。SRS27是首个已知的在卵清蛋白诱导的小鼠哮喘模型中有效改善炎症和气道高反应性的DDAG类似物。
