Interrelação entre inflamação, estresse oxidativo e disfunção mitocondrial na depressão: desenvolvimento de um modelo tipo depressivo in vitro

Abstract

Depression is a mental disorder recognized worldwide as a public health problem. Among the symptoms, sleep disorders, decreased energy, anxiety, deep sadness, and loss of interest in performing activities that were previously considered pleasurable, stand out. Recent studies demonstrate a relationship between inflammation, oxidative stress, mitochondrial dysfunction in the pathophysiology of depression, generating physiological, psychological, and cognitive consequences. One of the hypotheses that explain the association between these processes is the kynurenine?s metabolism. Thus, the development of an in vitro depressive-type model is important to help understand the complex mechanism of this disease, as well as to test new drugs that can reduce the rates of refractory patients and also minimize the use of animals in studies that present numerous biases. Thus, the present work aimed to study the relationship between inflammatory processes and mitochondrial alterations triggered by kynurenine catabolites and to develop an in vitro model capable of mimicking some of the biochemical alterations reported in depressive patients. In addition, after establishing the model, with the objective of testing new drugs that can reduce the rates of refractory patients and increase adherence to treatment, reducing side effects in relation to conventional drugs, an extract rich in phenolic compounds obtained from Araucaria angustifolia (AAE) was tested. (EAA). To simulate the depressive-like condition, BV-2 microglial cells were treated with 10?g/mL of lipopolysaccharide (LPS), associated with kynurenine (KYN), a toxic catabolic, at a concentration of 1000?M, for 24 hours. The association of LPS + KYN reduced cell viability and increased apoptosis rates, in addition to generating mitochondrial dysfunction observed through reduced activities in complexes I and IV of the electron transport chain, levels of ATP, and mitochondrial proteins SIRT1, SIRT3, and NDUFS7 complex I subunit. We also observed an increase in the levels of NO, intracellular ROS and inflammatory markers such as COX, NF-?ß and p-NF-?ß, mimicking some biochemical and molecular events observed in a significant number of depressive patients. Pre-treatment of cells with EAA avoided all observed changes, except for inflammatory markers. Although more studies are needed, this work shows, for the first time, a depressive-like model capable of simultaneously inducing inflammation, mitochondrial dysfunction, oxidative stress, and apoptosis, in vitro. This model has the potential to be used to seek a greater understanding of the etiology of depression and also for the previous screening of potential new drugs or supplements for the treatment of depression. [resumo fornecido pelo autor]