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, 7 (6), e00531
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Azelastine Potentiates Antiasthmatic Dexamethasone Effect on a Murine Asthma Model

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Azelastine Potentiates Antiasthmatic Dexamethasone Effect on a Murine Asthma Model

Carlos D Zappia et al. Pharmacol Res Perspect.

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.

Keywords: antihistamines; asthma; azelastine; dexamethasone; glucocorticoids; histamine.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Azelastine enhances dexamethasone‐induced GR activity in vitro. (A) HEK293T cells cotransfected with the reporter TAT3‐Luc, H1 receptor, and GR coding plasmids were treated for 10 min with 10‐μmol/L azelastine (AZE) or not, as indicated, and incubated with 0.1 ‐nmol/L or 1‐nmol/L dexamethasone (DEX). (B) HEK293T cells were cotransfected with IL6‐Luc, H1 receptor, and GR coding plasmids and were pretreated with 10‐μmol/L azelastine (AZE) for 10 min and then with increasing concentrations of dexamethasone (DEX) for 4 h and finally treated with 2000 IU/mL TNFα for 18 h. Luciferase activity was determined as described in the methods section. Results are mean ± SD of five independent experiments performed in triplicates. *P < .01
Figure 2
Figure 2
Effect of cotreatment on allergen‐specific humoral response. Serum levels of OVA‐specific (A) IgE, (B) IgG1, and (C) IgG2a antibodies were quantified in all experimental groups. N: Naïve animals; OVA: animals sensitized and treated with vehicle; AZE: animals sensitized with OVA and intranasally treated with azelastine; SD: animals sensitized with OVA and intranasally treated with a 10‐fold dilution of optimal dexamethasone solution. OD: animals sensitized with OVA and intranasally treated with an optimal dose of dexamethasone. AD: animals sensitized with OVA and intranasally treated with a solution containing azelastine and a suboptimal dose of dexamethasone. Dots represent the individual values obtained and horizontal lines represent the mean ± SD. *P < .05
Figure 3
Figure 3
Effect of cotreatment on eosinophilia in bronchoalveolar lavage (BAL). BAL differential cell counts were performed on cytocentrifuge slides, fixed and stained with a modified Wright‐Giemsa stain. N: Naïve animals; OVA: animals sensitized and treated with vehicle; AZE: animals sensitized with OVA and intranasally treated with azelastine; SD: animals sensitized with OVA and intranasally treated with a 10‐fold dilution of optimal dexamethasone solution. OD: animals sensitized with OVA and intranasally treated with an optimal dose of dexamethasone. AD: animals sensitized with OVA and intranasally treated with a solution containing azelastine and a suboptimal dose of dexamethasone. Dots represent the individual values obtained and horizontal lines represent the mean ± SD. *P < .05
Figure 4
Figure 4
Effect of cotreatment on lung histopathology. (A‐F) Animal lungs treated as indicated were instilled and fixed with 10% buffered formalin. Following paraffin embedding, sections for microscopy were stained with Hematoxylin and PAS. Original magnification 400X. Black arrows point to prominent goblet cell hyperplasia and infiltration around airways and vessels. (G) An index of pathologic changes in H&E slides was obtained by scoring the inflammatory infiltrate around the airways and vessels for greatest severity. The Inflammation Index was calculated as the average of the airways’ index. (H) A histological goblet cell score was obtained in Periodic acid‐Schiff (PAS)‐stained lung sections by examining 20 consecutive airways from all groups of mice and categorized according to the abundance of PAS‐positive goblet. The Mucus Index was calculated as the average of the airways’ score. N: Naïve animals; OVA: Animals sensitized and treated with vehicle; AZE: animals sensitized with OVA and intranasally treated with azelastine; SD: animals sensitized with OVA and intranasally treated with a 10‐fold dilution of optimal dexamethasone solution. OD: animals sensitized with OVA and intranasally treated with an optimal dose of dexamethasone. AD: animals sensitized with OVA and intranasally treated with a solution containing azelastine and a suboptimal dose of dexamethasone. Dots represent the individual values obtained and horizontal lines represent the mean ± SD. *P < .05
Figure 5
Figure 5
Effect of cotreatment on asthma‐inflammatory genes expression. Transcriptional response of four asthma‐inflammatory genes (A) IL‐4, (B) IL‐5, (C) Muc5AC, and (D) ArgI from lungs of all experimental mice. mRNA levels were quantified by qPCR as described in the methods section. N: Naïve animals; OVA: animals sensitized and treated with vehicle; AZE: animals sensitized with OVA and intranasally treated with azelastine; SD: animals sensitized with OVA and intranasally treated with a 10‐fold dilution of optimal dexamethasone solution. OD: animals sensitized with OVA and intranasally treated with an optimal dose of dexamethasone. AD: animals sensitized with OVA and intranasally treated with a solution containing azelastine and a suboptimal dose of dexamethasone. Results are mean ± SD. *P < .05

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