Efeitos comportamentais, metabólicos e circuitos neuronais do agonista de GLP-1 liraglutida, no modelo de depressão induzida por estresse crônico imprevisível

Abstract

Depression is an affective disorder characterized by feelings of sadness, indifference and discouragement, being one of the most common psychiatric disorders that affects the population at some point in life and affects 322 million people in the world. Liraglutide (LIRA) is a drug used to treat diabetes mellitus and has demonstrated neuroprotective action and induction of neurogenesis. The present study was proposed to evaluate the behavioral, metabolic and neurochemical effects of repeated administration of LIRA, a GLP-1 agonist, in an unpredictable chronic stress-induced depression (ECI) model that may produce an effect similar to clinical depression. Female Swiss mice (25-30g) submitted to 21 days of ECI were used, being added either LIRA (120 or 240 μg / kg subcutaneously) or FXT (10 mg / kg orally) from the 15th to 21st days of treatment. On the 22nd day the animals were submitted to forced swim test, splash test, open field, elevated maze, new object recognition, passive avoidance, Y-maze, behavioral tests. After the tests, the mice were euthanized and the adrenal and areas of the prefrontal cortex (CF) hippocampus (HC) were dissected to evaluate metabolic (adrenal weight, animal weight and glycemia) and neurochemical (oxidative stress, Brain-Derived Neurotrophic Factor-BDNF, corticosterone levels, adrenal cortex histology, glial fibrillary acid protein-GFAP, Golgi-Cox, synaptosomes and glucocorticoid receptor). The behavioral results showed that the ECI decreased the open arms entry percentage in the elevated cross maze test and increased the forced swimming immobility time. These effects were reversed by LIRA at the highest dose. Regarding the metabolism results it was observed that the ECI animals showed a 50% reduction in weight gain compared to the control group, being reversed by the two doses of LIRA. Regarding the study of oxidative stress, a decrease in GSH levels was observed only in HC, however LIRA or FXT were not able to reverse it. A decrease in BDNF concentrations was observed in HC and this effect was reversed by LIRA. An increase in GFAP activity was observed in the three hippocampal areas evaluated (CA1, CA3 and dentate gyrus). However no effect was observed after administration of LIRA or FXT on GFAP levels. ECI animals showed a reduction in synaptic density and in the number of glucocorticoid receptors not being reversed by treatment with LIRA. In conclusion, our results showed that animals undergoing ECI showed anxiogenic and depressive behaviors. These effects being reversed by LIRA. The adrenal cortical layer revealed hypertrophy that was reversed by the LILA at the highest dose. Although there was a relationship between behavioral study, increased oxidative stress and decreased BDNF levels in ECI animals, this relationship was not directly proportional to oxidative stress in animals undergoing LIRA treatment. The ECI model increased GFAP expression and density of hippocampal dendritic spines and increased glucocorticoid receptor intensity.