Effects of MP-AzeFlu enhanced by activation of bitter taste receptor TAS2R

Abstract

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.

TAS2R supports odontoblastic differentiation of human dental pulp stem cells in the inflammatory microenvironment

“…TAS2R was found to be expressed in hDPSCs for the first time. TAS2R was initially identified in taste buds of the tongue and played a role in recognizing bitter taste, preventing the ingestion of toxic substances and performing self-defense functions [ 32 ]. There is increasing evidence that TAS2R has a variety of functions independent of taste in anti-inflammation [ 16 ], anti-infection [ 14 ], reduction airway hyper-responsiveness [ 33 ].…”

Bitter Taste Receptor as a Therapeutic Target in Orthopaedic Disorders

“… 65 Upon investigation towards the mechanism of MP-AzeFlu, Ekstedt et al (2020) discovered that the dilatory effects of MP-AzeFlu were independent of the common airway dilatory pathways involving histamine receptors (H1-, H2- and H3-), prostaglandins, cAMP and cGMP. 66 When examining pre-contracted murine airways, the authors found that MP-AzeFlu and AZE had dilatory effects similar to that of T2R agonists, suggesting that MP-AzeFlu functioned through bitter taste receptor activation.…”

Taste Receptors: The Gatekeepers of the Airway Epithelium

“…The interest in T1Rs and T2Rs is mainly because of their quick immune response (e.g., against inhaled harmful substances and their second messenger pathways that take a few seconds to minutes to be expressed) compared to other receptors expressed on the epithelium [ 50 , 72 , 73 ]. Activation of T2Rs using bitter taste agonists have been adopted to treat inflammation-linked respiratory diseases such as asthma, chronic obstructive pulmonary disease, CRS, and allergic rhinitis [ 47 , 69 , 74 , 75 ]. In addition, the T1R attenuation of T2R mediated anti-microbial peptide secretion may also have important clinical relevance.…”

“…Allergic rhinitis is a chronic airway disorder, clinically characterized by sneezing, nasal discharge, nasal obstruction, and nasal hyperreactivity [ 53 ]. In the study of Ekstedt et al, the authors investigated the involvement of T2Rs in the beneficial effect of MP-AzeFlu in the pre-contracted airway of Balb/c mice [ 75 ]. MP-AzeFlu is a drug used in the treatment of allergic rhinitis patients and consists of azelastine hydrochloride (AZE) and fluticasone propionate (FP).…”

“…MP-AzeFlu is a drug used in the treatment of allergic rhinitis patients and consists of azelastine hydrochloride (AZE) and fluticasone propionate (FP). In their study, they demonstrated that MP-AzeFlu caused airway dilatation, comparable to the effect induced by the T2R agonist, chloroquine [ 75 ]. Additionally, in the study of Kook et al, positive effects of T2R agonists were seen in allergic rhinitis patients [ 83 ].…”