Montelukast Reverses Β2-Adrenoceptor Tolerance in Airway Smooth Muscle and Shows a Synergic Effect in Vivo

The regular use of β2-adrenoceptor (β2-ARs) has been correlated to asthmatic-like changes and the risk of severe adverse reactions. Here, we investigated whether montelukast (MK), a cysteinyl leukotriene receptor antagonist, might improve β2-agonists responses in airways. The study has been conducted in vitro on isolated mouse bronchi and in vivo in an experimental model of asthma. For this aim, we have synthesized a salt montelukast/formoterol (MFS) that gave us the possibility to simultaneously administer β2-agonist formoterol and montelukast (MFS) in vivo. First, functional studies showed that MK did not affect the bronchial tone but prevented the homologous β2-AR-desensitization. Molecular studies confirmed the efficacy of MK in preserving the β2-agonists responses in airways by downregulating the protein kinase pathway. The MK effect on β2 desensitization was confirmed in vivo by using MFS. The pretreatment of OVA-sensitized mice showed an enhanced significant effect of MFS compared to MK or formoterol alone in modulating AHR. MFS also induced a dose-dependent reversion of β2-AR dysfunction by recovering bronchial relaxation in sensitized mice. Further, histological staining confirmed the beneficial effect of MFS in controlling other asthma features as the reduction in the mucus-producing cell. The therapeutic efficacy of MFS was also tested via nasal administration, confirming the effect of MSF on AHR modulation and inflammation. Thus, we demonstrated that the association of montelukast/formoterol might represent a promising therapeutic strategy to control asthma features such as AHR and lung inflammation ensuring a reduced risk of the β2 desensitization phenomenon.