Efeitos antidepressivos da cumarina no modelo de depressão induzido por corticosterona: envolvimento noradrenérgico, serotoninérgico, neuroinflamatório e antioxidante

Abstract

Depression is considered a major public health problem because it significantly interferes with people's quality of life. Pharmacological treatment of currently available depression is ineffective for about 30% of patients, has significant side effects and late onset of therapeutic response. In this context, there is a growing interest in studies of new bioactive substances that do not present those problems. Coumarin (1,2-benzopyrone) is an aromatic compound found in various plant species, with biological actions of this substance both in the periphery and in the central nervous system. The aim of this study was to study the antidepressant effects of coumarin in the animal model of resistant depression induced by repeated administration of corticosterone (CORT). For the study, male Swiss mice weighing between 25 and 30g were used, which received the following treatment protocol: a) Control group; b) CORT group; c) CORT and coumarin group [CORT 20 mg/kg for 14 days. Between the 15th and the 21st day, the mice received CORT + coumarin (0.5, 5 or 50 mg/kg.)]. On the last day of treatment, one hour after the administration of the substances, the animals were submitted to open field test, elevated plus maze test, forced swim test and sucrose preference test. To elucidate the mechanism of action of coumarin, pre-treatment with drugs related to the noradrenergic, dopaminergic and serotonergic systems was performed only in the forced swim test. Immediately after those tests, the animals were sacrificed and the brain areas [hippocampus (HC), prefrontal cortex (CPF) and striatum (EC)] of the animals were dissected for oxidative and neuroinflammatory stress tests. The results showed that the treatment with CORT caused an anxiogenic and depressant-like effects, as well as behavior of anhedonia type. The administration of coumarin, especially at the highest dose (50 mg/kg), was able to reverse the depressant effects of CORT, being this mechanism of action related to noradrenergic and serotonergic systems. As for the oxidative stress results, the animals treated with CORT showed an increase of malondialdehyde (MDA) and nitrite in all studied areas, being these effects reversed with all studied doses of coumarin. CORT increased expression of nuclear factor-kappa B (NF-κB) and tumor necrosis factor alpha (TNFα) in the hippocampus, being these effects reversed only by coumarin in the dose of 50 mg/kg. In conclusion, coumarin was able to reverse depressant-like behavior induced by repeated administration of corticosterone. The antidepressant effects of coumarin are related to the serotonergic and noradrenergic systems, as well as its antioxidant and anti-inflammatory actions of this compound. That way, it´s suggested that coumarin has a therapeutic potential that can be used in the treatment of depressive disorders.