Efeitos terapêuticos do extrato de mirtilo em modelos de transtornos psiquiátricos em roedores

Abstract

Bipolar disorder and major depressive disorder are complex and chronic psychiatric disorders characterized by severe mood changes. Despite the negative impact of these pathologies, there is still a gap regarding the pathophysiological mechanisms and treatment. Therefore, it becomes crucial to better understand neurobiology, as well as to seek new therapeutic approaches for patients. In this context, blueberry (Vaccinium spp.) stands out, a fruit that contains polyphenols with neuroprotective action in its composition. Considering the above, the aim of this study was to investigate the effect of the blueberry extract administration on behavioral and biochemical parameters in mice submitted to experimental models of mania and depression. For the protocol of mania, adult male Wistar rats were orally treated with water, lithium (45 mg/kg, twice a day) or blueberry extract (200 mg/kg, once a day) for 14 days. From the 7th to the 14th day, the animals also received saline or ketamine intraperitoneally; on the 15th day, they received saline or ketamine (25 mg/kg) intraperitoneally and underwent the open field test. Subsequently, the animals were euthanized, where the cerebral cortex and hippocampus were collected. For the depression experimental protocol, adult male Swiss mice were used, these were treated for seven days with water, fluoxetine (20 mg/kg) or blueberry extract (100 or 200 mg/kg) once daily orally; on the 7th day received vehicle or lipopolysaccharide (LPS) (0.83 mg/kg) intraperitoneally and after 24 hours they were submitted to open field, tail suspension, forced swim and splash test. After the tests, the animals were euthanized, where the cerebral cortex, striatum and hippocampus were collected. The results obtained demonstrated that the administration of blueberry extract prevented the manic-like behavior (hyperlocomotion) induced by ketamine. Furthermore, ketamine induced a reduction in the activity of complex I and IV, citrate synthase and Ca2+ -ATPase in the brain structures. However, blueberry extract partially attenuated these changes. Regarding the protocol with mice, it was observed that the administration of LPS induced a depressive-like behavior, characterized by an increase in the immobility time in the tail suspension and forced swim tests, in addition to an increase in the latency for the beginning of self-cleaning and a reduction in total self-cleaning time in the splash test. Treatment with blueberry extract demonstrated antidepressant-like potential, as it prevented these changes. As for the biochemical analysis, it was observed that the administration of blueberry extract prevented the changes induced by LPS, as it reduced the levels of reactive e species, as well as increased the total thiol content and catalase activity. Blueberry extract also prevented the LPS-induced increase in tumor necrosis factor-α (TNF-α) levels. Furthermore, we found that the blueberry extract prevented the reduction in Na+ ,K+-ATPase and monoamine oxidase-A activities, as well as the increase in acetylcholinesterase activity induced by the experimental model. As for the results of relative expression of RNAm, we found that the administration of LPS induced an increase in the levels of TNF-α, interleukin (IL)-1β and IL-10 in cerebral cortex and hippocampus, however, the blueberry extract administration attenuated these changes in the cerebral cortex. Furthermore, the results showed that the administration of LPS did not induce significant changes in the relative expression of the brain-derived neurotrophic factor and the nuclear transcription factor kappa B. As for the results obtained in the molecular docking analysis, we found that the anthocyanins malvidin 3-galactoside and malvidin 3-glycoside show significant interactions with the enzyme indoleamine 2,3-dioxygenase. In view of the results obtained, we can conclude that the blueberry extract has antimanic and antidepressant-like potential, since it attenuated behavioral, biochemical and molecular changes induced by an experimental model of mania and depression. Furthermore, we can conclude that the blueberry extract has an excellent neuroprotective role.