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

• Autor(a) principal: Pesarico, Ana Paula
• Data de Publicação: 2018
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Manancial - Repositório Digital da UFSM
• Texto Completo: http://repositorio.ufsm.br/handle/1/15234
• topic: Isoquinolina; Depressão; Estresse oxidativo; Monoaminas; GABA; Glutamanto; Isoquinoline; Depression; Stress; Oxidative stress; Monoamines; Glutamate; CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA

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.