Efeito da Angiotensina-(1-7) sobre o comportamento ansioso em camundongos submetidos a inflamação pulmonar alérgica

Abstract

Allergic asthma is a chronic respiratory disease without a cure up to this time. One aspect that makes asthma control difficult is its association with anxiety and depression. These comorbidities are present in approximately 50% of patients with difficult-to-control asthma. Angiotensin-(1-7) [Ang-(1-7)], an important mediator of the renin-angiotensin system, attenuates airway remodeling and hyperreactivity, in addition to stimulating the resolution of the inflammatory process in an asthma model chronic. In addition, Ang-(1-7) also has an anxiolytic/antidepressant effect when administered into the central nervous system. The objective of the present study was to evaluate whether part of the beneficial effect induced by Ang-(1-7) for the restoration of pulmonary homeostasis in asthma could be related to an improvement in emotional behavior. Eight to 10 weeks old male Balb/c and C57BL/6J mice strains and Mas receptor knockout animals (Mas KO) were used. Animals were subjected to the experimental model of allergic asthma and to evaluations of anxious/depressive behaviors and lung inflammation parameters. In this work we showed that treatment of asthmatic mice with oral or intranasal Ang-(1-7) attenuated the anxiety- and depression-like behaviors in association to reduction in parameters indicative of pulmonary inflammation. We also showed that the beneficial effects of peripherally administered Ang-(1-7) were not altered by ICV infusion with the Mas antagonist, A-779. Furthermore, ICV infusion with Ang-(1-7) not only prevented anxiety- and depressive-like behaviors, but also partially attenuated lung inflammation. We also showed that asthmatic animals with Mas receptor deletion had attenuated inflammatory parameters, and still exhibited anxious/depressive behaviors. We also observed that the experimental model of asthma caused a reduction in the levels of noradrenaline, adrenaline and dopamine in the regions of the cortex and hippocampus, which was not modified by oral or intranasal treatments with Ang-(1-7). Finally, we observed that oral treatment with Ang-(1-7) prevented the increase in neuronal activity in regions related to emotional control, such as the paraventricular nucleus of the hypothalamus and the hippocampus. Taken together, these results indicate that Ang-(1-7) combines anti-inflammatory and anxiolytic and anti-depressive effects, reinforcing the interest in the development of new formulations based on Ang-(1-7) for the treatment of inflammatory diseases.