Estresse crônico moderado e imprevisível induz comportamento tipo depressivo em Drosophila melanogaster: ação terapêutica do γ-orizanol

Abstract

Depression is a serious, recurring disease and a disabling psychiatric condition that affects more than 350 million individuals worldwide. Chronic unpredictable mild stress is na experimental model that simulates the development and progression of clinical depression and serves as a protocol for testing the effectiveness of candidate compounds for antidepressants. γ-oryzanol is a promising antidepressant candidate because it is a natural compound obtained from rice bran oil and has biological effects previously described in the literature. The general objective of the work was to investigate whether chronic unpredictable mild stress induces depressive behavior in the Drosophila melanogaster and to evaluate the therapeutic action of γ-oryzanol in this model. At first (Scientific Article) we aimed to establish/standardize Drosophila melanogaster as a model to investigate the changes induced by chronic unpredictable mild stress that predict depressive behavior, since there was no data in the literature on behavior similar to depression in Drosophila triggered by chronic stress, nor using stressors that simulate the stress of daily life that employ extensive adaptive demandson the body. The results of this article demonstrated that flies exposed to the stress protocol for ten days had a longer immobility time in the forced swim test, anecdotal behavior in the sucrose preference test, a decrease in mating behavior and an aggressive behavior, in addition to of changes in monoamine levels involved in the development of depressive pathology. Thus, we conclude that although Drosophila melanogaster has its limitations as an animal model of depression, it is able to satisfy criteria for a valid animal model, such as good face and construction validity to test the effects of candidates for antidepressants. In addition, it meets the ethical precepts because it is an alternative model to the use of mammals in experimentation. Based on these results, we sought to investigate the therapeutic action of γ-oryzanol (Manuscript I) on flies subjected to depressive behavior, using the protocol we validated above. γ-oryzanol contains a mixture of ferulic acid esters, it is described as having a potent antioxidant effect, among others, but there is a lack of data on a possible XIII antidepressant effect of γ-oryzanol. In this study, γ-oryzanol was effective against the depressive-like signs developed by flies exposed to the chronic stress protocol assessed through predictive tests of depressive behavior, in addition to the regulation of their monoaminergic levels. Existing evidence suggests that chronic stress impairs the antioxidante tatus of brain tissue and may be related to the development of depression, therefore, the effect of γ-oryzanol on some parameters of oxidative stress (reactive species levels, lipid peroxidation) have been demonstrated (Results Preliminaries) where γ-oryzanol had a neuroprotective effect, possibly related to its antioxidant potential. Together, the results of this thesis contribute to making Drosophila a valid animal model for the development of depressive behavior and thus assist in understanding the behavioral responses and physiological mechanisms of this pathology. In addition, treatment with γ-oryzanol demonstrated a potential antidepressant effect and may be a therapeutic alternative for the treatment of depression.