Effects of MP-AzeFlu enhanced by activation of bitter taste receptor TAS2R
Effects of MP-AzeFlu enhanced by activation of bitter taste receptor TAS2R
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DOI：
10.1186/s13223-020-00438-w
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发表时间：
2020-06-03
影响因子：
2.7
通讯作者：
Cardell, Lars Olaf
中科院分区：
文献类型：
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作者：
Ekstedt, Sandra;Georen, Susanna Kumlien;Cardell, Lars Olaf
MP-AzeFlu是一种相对较新的药物，用于治疗变应性鼻炎。它由组胺H1受体拮抗剂盐酸氮卓斯汀(AZE)和皮质类固醇激素氟替卡松(FP)组成。它有点苦涩的味道(通常被认为是一种缺点)可以归因于AZE。我们在这里假设MP-AzeFlu可能通过激活苦味受体(Tas2R)而产生一些有益的效果，这是最近在人类呼吸道中描述的。在鼻子中，TAS2Rs诱导抗菌肽的分泌并增加纤毛活动，而在肺中，它们引起呼吸道平滑肌松弛。Tas2R介导的效应背后的机制尚不完全清楚。为探讨Tas2R在MP-AzeFlu所致效应中的作用，用组织浴法观察了不同药理拮抗剂或相应载体存在或不存在时，Balb/c小鼠预缩离呼吸道的舒缩反应。MP-AzeFlu对预收缩的呼吸道有明显的剂量依赖性松弛作用，这种作用可能是由其AZE组分介导的。MP-AzeFlu和AZE的扩张效应均与Tas2R激动剂氯喹的反应相似，但不依赖组胺受体(H1-、H2-和H3-)、前列腺素、cAMP和cGMP的参与，这些都是已知的常见的气道扩张途径。其他苦味的抗组胺药物(即奥洛他定和地氯雷他定)也使呼吸道节段松弛。这些数据支持MP-AzeFlu有能力以与氯喹相同的方式激活Tas2R的观点。这种作用似乎是由AZE介导的，而不是通过组胺受体。MP-AzeFlu激活Tas2R可能有助于在中/重度变应性鼻炎患者的对照临床试验中观察到其优于FP的疗效。
MP-AzeFlu is relatively new a pharmaceutical drug used in the treatment of allergic rhinitis. It is comprised of azelastine hydrochloride (AZE), a potent histamine-H1-receptor antagonist and fluticasone propionate (FP), corticosteroid. It's somewhat bitter taste (often considered a disadvantage) can be attributed to AZE. We here hypothesize that MP-AzeFlu may induce some of its beneficial effects through activation of bitter taste receptors (Tas2R), which have recently been described in human airways. In the nose Tas2Rs induce secretion of antimicrobial peptides and increase ciliary activity, while in the lung they cause airway smooth muscle relaxation. The mechanisms behind Tas2R-mediated effects are not yet fully known. In order to evaluate the role of Tas2R in the effects induced by MP-AzeFlu the dilatory response of pre-contracted isolated airways from Balb/c mice was investigated in tissue bath myographs in the presence or absence of various well-characterized pharmacological antagonists or their corresponding vehicles. MP-AzeFlu caused a potent dose- dependent relaxation of pre- contracted airways, an effect probably mediated by its AZE component. The dilatory effect of MP-AzeFlu and AZE both mimicked the response induced by the Tas2R agonist, chloroquine, but was independent of histamine receptor (H1-, H2- and H3-), prostaglandins, cAMP and cGMP involvement, all known to be common pathways for airway dilation. Other bitter-tasting antihistamines (i.e. olopatadine and desloratadine) also relaxed airway segments. These data support the notion that MP-AzeFlu has the ability to activate Tas2R in the same way as chloroquine. The effect appears to be mediated by AZE, but not via the histamine receptor. Activation of Tas2R by MP-AzeFlu may contribute to its superior efficacy over FP observed in controlled clinical trials in patients with moderate/severe allergic rhinitis.