Azelastine potentiates antiasthmatic dexamethasone effect on a murine asthma model

Abstract

Glucocorticoids are among the most effective drugs to treat asthma. However, the severe adverse effects associated generate the need for its therapeutic optimization. Conversely, though histamine is undoubtedly related to asthma development, there is a lack of efficacy of antihistamines in controlling its symptoms, which prevents their clinical application. We have reported that antihistamines potentiate glucocorticoids’ responses in vitro and recent observations have indicated that the coadministration of an antihistamine and a synthetic glucocorticoid has synergistic effects on a murine model of allergic rhinitis. Here, the aim of this work is to establish if this therapeutic combination could be beneficial in a murine model of asthma. We used an allergen‐induced model of asthma (employing ovalbumin) to evaluate the effects of the synthetic glucocorticoid dexamethasone combined with the antihistamine azelastine. Our results indicate that the cotreatment with azelastine and a suboptimal dose of dexamethasone can improve allergic lung inflammation as shown by a decrease in eosinophils in bronchoalveolar lavage, fewer peribronchial and perivascular infiltrates, and mucin‐producing cells. In addition, serum levels of allergen‐specific IgE and IgG1 were also reduced, as well as the expression of lung inflammatory‐related genes IL‐4, IL‐5, Muc5AC, and Arginase I. The potentiation of dexamethasone effects by azelastine could allow to reduce the effective glucocorticoid dose needed to achieve a therapeutic effect. These findings provide first new insights into the potential benefits of glucocorticoids and antihistamines combination for the treatment of asthma and grants further research to evaluate this approach in other related inflammatory conditions.

Imiquimod suppresses respiratory syncytial virus (RSV) replication via PKA pathway and reduces RSV induced-inflammation and viral load in mice lungs

“…Lung sections were assessed for severity of inflammation by two independent observers, Dr. María Virginia Gentilini and Dr. Carlos Bueno, blinded to treatment. An index of pathologic changes in hematoxylin and eosin (H&E) slides was obtained accordingly to Zappia et al (2019). Briefly, 20 consecutive airways per slide were examined at 400 × magnification and scoring the inflammatory infiltrates around the airways and vessels for severity (0, normal; 1, ≤3 cells diameter thick; 2, 4 to 10 cells diameter thick; 3, ≥10 cells diameter thick).…”

Ginsenoside F1 Attenuates Eosinophilic Inflammation in Chronic Rhinosinusitis by Promoting NK Cell Function

“…To assess the therapeutic effect of G-F1, mice were administered with an intraperitoneal injection of 50 mg/kg G-F1 or an intranasal injection of 3.5 mg/kg G-F1 three times a week during CRS modeling. Dexamethasone (Sigma-Aldrich) was used as a positive control at a dosage of 2 mg/kg intranasally as described in previous studies using murine model of ECRS and asthma [ 36 , 37 ]. After CRS development and treatment, nasal tissue sections were trimmed from euthanized mice and placed in 4% formaldehyde solution (Thermo Fisher Scientific, Waltham, MA).…”

Antihistamines Potentiate Dexamethasone Anti-Inflammatory Effects. Impact on Glucocorticoid Receptor-Mediated Expression of Inflammation-Related Genes

“…We discussed that the existence of cell types co-expressing H1R and GR suggests that our findings may have implications for regulation of inflammation in several systems, and the co-administration of corticoids and antihistamines could result in a reduction of the GC dose needed to achieve a therapeutic effect. As a proof-of-concept, we demonstrated an effective use for the treatment of asthma in an experimental murine model [25]. However, there is a need for a careful evaluation of the side effects of antihistamine and GC co-administration, because GCs' undesired effects could also be enhanced by antihistamines [26].…”

“…We have previously shown that the antihistamines mepyramine (MEP) and azelastine (AZE) potentiate dexamethasone (DEX) inhibition of NF-κB activity in vitro on an IL-6 promoter-driven luciferase reporter [24,25]. To extend this study we evaluated the effect of the different antihistamines mepyramine (MEP), trans-triprolidine (TRIP), cetirizine (CET), chlorpheniramine (CHLOR) and diphenhydramine (DIPH) using HEK-293T cells cotransfected with plasmids coding for GR, H1R and the aforementioned reporter.…”