Efeitos comportamentais e neuroquímicos de inibidores da enzima dipeptidilpetidase 4 em modelo de depressão induzida por reserpina em camundongos

Abstract

Depression is a mood disorder of high prevalence in the general population which is characterized by hypothymia, anhedonia and low energy. Inhibitors of the enzyme dipeptidylpeptidase 4 (DPP4) are drugs used to treat type 2 diabetes mellitus (DM2) which also have effects on the central nervous system (CNS). Therefore, we carried out this study with the objective of evaluating the behavioral, antioxidant and anti-inflammatory effects of the administration of sitagliptin, a DPP4 inhibitor, in a model of depression induced by reserpine in mice. Female Swiss mice weighing 25 to 30g were given a daily injection of reserpine (1mg / kg, subcutaneously) alone or in combination with sitagliptin (3 and 6 mg / kg, subcutaneously) for three days. On the third day of treatment, one hour after the last administration of the drugs, the animals were submitted to the following behavioral tests: open field, tail suspension, forced swimming, raised cross and perforated plate. After the behavioral tests, the animals were sacrificed by decapitation and the hippocampus, the prefrontal cortex and the striatum were dissected. The brain areas were used to perform the following neurochemical studies: levels of lipid peroxidation, reduced glutathione (GSH), superoxide dismutase (SOD) activity, myeloperoxidase activity, (MPO) concentration of interleukin-6 (IL-6) and interleukin-4 (IL-4). The results demonstrated that repeated administration of reserpine induced a depressed-like behavioral pattern by increasing the immobility time of the animals in both the tail suspension test and forced swimming without altering the locomotor activity of the animals. This action was reversed by the association with sitagliptin, mainly in the highest dose (6 mg / kg). Reserpine presented oxidative effects demonstrated by the increase of MDA, SOD and MPO and reduction of GSH in the cerebral areas studied. In our study, the administration of sitagliptin, mainly at the highest dose, was able to reverse reserpine-induced changes in lipid peroxidation, MPO activity and GSH levels. The association of sitagliptin with reserpine increased IL-6 levels and decreased IL-4 levels when compared to the reserpine group. From the results of our study, we conclude that, in an animal model of depression induced by reserpine, sitagliptin, especially at the dose of 6mg / kg, presents antidepressive, antioxidant and anti-inflammatory effects.