Oral or intranasal angiotensin-(1-7) improves anxiety and depression-like behaviors in mice subjected to allergic pulmonary inflammation

Abstract

Allergic asthma is a chronic respiratory disease characterized by airway inflammation and hyperresponsiveness, that has a challenging management when associated with anxiety and depression, which affects around 50 % of patients with difficult-to-control asthma. Angiotensin-(1-7) [Ang-(1-7)], a key mediator of the renin-angiotensin system, has demonstrated the ability to attenuate airway remodeling, hyperreactivity and to promote resolution of lung inflammation. Furthermore, Ang-(1-7) exhibits anxiolytic and antidepressant effects when administered into the brain. Here we investigated whether peripheral administration of Ang-(1-7) by two different routes could alleviate depressive and anxiety-like behaviors and inflammation in asthmatic mice. Male Balb/c mice, 8–10 weeks old, underwent sensitization and challenge with ovalbumin. Asthmatic mice received either an oral or intranasal formulation of Ang-(1-7) included in hydroxypropyl-β-cyclodextrin (HPβCD). Both oral and intranasal Ang-(1-7) treatments induced reduction in lung inflammation, and effectively ameliorated depressive and anxiety-like behaviors, as shown in elevated plus maze, open field, and tail suspension tests. Notably, intranasal Ang-(1-7) decreased levels of TNF-α and IL-6 in the prefrontal cortex, and, regardless of treatment, there was an elevation in IL-10. Additionally, in other asthmatic animals, ICV administration of Ang-(1-7), which resulted in the expected attenuation in depressive and anxiety-like behaviors, did not significantly reduce lung inflammation, suggesting the improvement in behavioral tests following peripheral treatment with Ang-(1-7) cannot be solely attributed to a decrease in pulmonary inflammation. The data of the present study showed that both intranasal and oral administration of Ang-(1-7) not only alleviates pulmonary inflammation but also mitigates stress-coping behaviors, indicating this peptide as a promising therapeutic candidate for enhancing the treatment and quality of life for patients with asthma.