Envolvimento de fatores oxidativos e inflamatórios sobre a resistência ao tratamento com fluoxetina em um modelo de depressão em camundongos

Abstract

Major depression (DM) is among the most disabling mental disorders in the world. According to the World Health Organization (WHO), more than 300 million people are affected by DM. The disorder is characterized by a set of signs and symptoms, which include depressed mood, anhedonia, ideas of regret and guilt, eating and sleep disorders, among others. DM is highly related to suicide rates. Worryingly, a significant portion of patients with DM are refractory to available antidepressant agents (approximately 30 to 50%), and these are considered to have treatment-resistant depression (TRD). The pathophysiology of DM, as well as of TRD, is still not fully elucidated. However, oxidative stress and the inflammatory process may be important mechanisms involved in these processes. Thus, the aim of this study was to evaluate whether oxidative and inflammatory markers may be involved in resistance to fluoxetine treatment in mice submitted to a depressive-like behavior induction protocol. For this, the chronic corticosterone administration (ACC) model was used. To stratify the animals into treatment-responsive (fluoxetine) and non-responsive, the tail suspension test was used. In addition to this behavioral test, the animals were evaluated in the forced swim test, elevated plus maze and open field test. After the behavioral tests, the animals were sacrificed and blood samples and brain structures (hippocampus, prefrontal cortex and striatum) were taken for oxidative and inflammatory analyses. It was observed that the animals that had a worse response to fluoxetine in the tail suspension test, showed an anxious-like behavior in the elevated plus maze test and a longer fight time in the forced swim test. Furthermore, this same group of animals had higher levels of hydrogen peroxide (H2O2) and lower catalase activity in the hippocampus. It was also shown that animals resistant to fluoxetine had increased peripheral levels of IL-17 and INF-γ when compared to the levels of these cytokines in animals that had a good response to fluoxetine. Thus, it can be suggested that refractoriness to antidepressant treatment with fluoxetine may be related to a hippocampal oxidative imbalance, as well as an increase in peripheral interleukins.