Efeito do tipo antidepressivo do 7-flúor-1,3-difenilisoquinolina-1-amina em modelos de estresse em roedores

Abstract

Current treatments for depression are inadequate for many patients and progress in understanding of this psychiatric disease is slow. The isoquinoline is an important class of molecules with antidepressant-like effect in animal models, among them the 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI), has been reported to have an antidepressant-like action in mouse acute tests, involving different neurochemical systems. The aim of this study was to investigate the antidepressant-like effect of FDPI in depression models induced by acute and chronic stress in rodents. Firstly, the results of article 1 demonstrated that pre- and post-treatment with FDPI (10 mg/kg, intragastric) protected against depressive-like behavior induced by acute restraint stress in male Swiss mice. The antidepressant-like action of FDPI involves the modulation of oxidative stress and the monoaminergic system, increasing the serotonin uptake and inhibiting the monoamine oxidase (MAO) isoforms, MAO-A and MAO-B. The article 2 was carried out with the purpose of investigating the mechanisms of FDPI in the chronic unpredictable mild stress (CUMS) model. The FDPI treatment (0.1 and 1 mg/kg, intragastric) prevented against the depressive-like behavior induced by CUMS in male Swiss mice, possibly by regulation of nuclear factor (NF)-kB and pro-inflammatory cytokines levels and modulation of hypothalamic-pituitary-adrenal axis, serotonin uptake and the pro-brain derived neurotrophic factor (proBDNF)/ tyrosine kinase receptor (TrkB) signaling pathway altered by CUMS. Moreover, the results of article 3 showed that repeated FDPI treatment (25 mg/kg, intragastric), but not acute treatment, protected mice against stress-induced social avoidance through of modulation of neurotrophin signaling pathways in the prefrontal cortex of male Swiss mice. Lastly, in the article 4 it was demonstrated that FDPI treatment (5 mg/kg, intragastric) reversed the anhedonic behavior induced by maternal separation stress in male Wistar rats of different ages (PND 30 and 90) by modulating the glutamatergic/GABAergic systems. Together, the results of this thesis suggest that the antidepressant-like effect of FDPI is related to different mechanisms in the central nervous system. FDPI is a multi-target molecule interesting to the development of novel therapies for the treatment of depression.