Neuropharmacological properties of Euterpe oleracea: an in vitro study of the potential use at psychiatric illness treatment

Introduction: Neuropsychiatric diseases, as bipolar disorder (BD), have a very complex pathophysiology. Several times the diagnostic and to choose a correct treatment are difficult. Currently, have been developed studies related to mechanisms that can be associated with specific biomarkers present on mental illness. Some studies are describing an association between neuropsychiatric diseases and mitochondrial dysfunction and consequent cellular modifications. Additionally, some psychiatric illnesses are been associated with chronic inflammatory activation via pro-inflammatory cytokines production. In this sense, the search for drug development to treat psychiatric illness is very necessary. Euterpe oleracea, known as açaí, is an Amazonian fruit and a potential candidate for neuropharmacological study due to chemical matrix, including a variety of bioactive compounds with biological effects. There are molecules that could act at mitochondrial function and neurophysiology. Objective: to perform a literature review about the mitochondrial dysfunction impact at bipolar disorder and chemically analyse and evaluate the neupharmacological in vitro effect of açaí extract through mitochondrial function modulation and oxidative and inflammatory metabolisms. Methodology: initially we produced a review about the association between BD and cellular mitochondrial metabolism based on scientific articles published at last 20 years in different journals found at PUBMED-MEDLINE of American library. This review helped to create the ecperimental in vitro design of this study. After, we performed an in vitro experimental research using a cell line SH-SY5Y exposed to rotenone. SH-SY5Y cells were obtained from American Type Culture Collection (ATCC®), and treated with freeze-dried hydroalcoholic açaí extract which was analyzed by high performance liquid chromatography. Initially the açaí effect at cell viability was measured through different concentration-effect curves. We also induced mitochondrial complex I dysfunction using rotenone at 5, 15 and 30 nM. Before and after rotenone exposition 5 μg/mL of açaí extract was added to evaluate the potential effect of açaí to prevent and reverse rotenone damages. After all treatments were performed experimental assays to evaluate the mitochondrial transport chain, the mitochondrial complex I enzyme activity, the protein and gene expression of NDUFS7, S8, V1 and V2 of complex I, the total levels of reactive oxygen species and lipid peroxidation. For the third study we used RAW 264.7 macrophages from ATCC. Cells were activated with PHA and exposed to different concentrations of açaí extract during 72h. Using the most anti-inflammatory effective concentration of açaí extract, we developed all another experimental assays to evaluate oxidative metabolism parameters, cell cycle and protein expression of cytokines and NLRP3-inflammasome. The statistical analysis was performed by one way anova followed by Tukey or Dunnett post hoc. Results: the obtained results were organized in three scientific articles. The review paper was published at Canadian Journal of Psychiatry and indicated the relevance of studies that dentify plants with potential properties to modulate mitochondrial complex I. The obtained results of second study were published at Oxidative and Cellular Longevity journal where we observed that hydroalcoholic açaí extract presented high levels of orientin (8,05±0,03mg/g), p-cumaric acid (3,52±0,01mg/g) and apigenin (3,49±0,01mg/g). In vitro results related to mitochondrial dysfunction and oxidative stress showed that the most effective concentration of açaí extract was 5μg/mL after 48h of incubation. We observed that açaí extract at both experimental models presented protective effects under mitochondrial complex I and this effect was due to an increased protein and gene expression mainly for NDUFS7 and S8 subunits that form the active region of this complex. Despite, was observed a decreased rate of reactive oxygen species and of lipid peroxidation under açaí exposition. Results of third study were organized in a manuscript that will be submitted for publication at Inflammation Research journal. It was observed the anti-inflammatory activity of açaí in macrophage PHA-induced, where the effective concentration able to reduce 50% of cellular proliferation (EC50) 1 μg/mL. Complementary assays showed that this specific concentration is capable to decrease inflammatory markers as proliferation rate, cell cycle, ROS levels and nitric oxide. Açaí also reduced pro-inflammatory cytokines levels (IL-1β, IL-6, TNFα. INFγ), and the inflammasome NLRP3, increasing IL-10 levels. Conclusion: the results obtained until this moment are suggesting that açaí has neuropharmacological activity and is a potential candidate for drug development or food supplement for psychiatric diseases treatment, especially BD which is related to mitochondrial complex I dysfunction and chronic inflammatory activation.

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