Influência de fatores farmacológicos e nutricionais na resposta oxidativa-inflamatória in vitro induzida pela olanzapina

Abstract

Introduction: Olanzapine (OLZ) is a second generation antipsychotic (ASG) used in the treatment of schizophrenia, bipolar disorder and other neuropsychiatric conditions. The adverse effects of ASG include weight gain and metabolic changes that increase the risk of developing obesity, diabetes, and cardiovascular disorders. Studies have associated the metabolic adverse effects of ASG with a low-grade and chronic inflammatory state, involving immune system cells and oxidative stress. It is possible that oxidative and inflammatory responses caused by OLZ may be influenced by nutritional and pharmacological interactions. Lithium, a mood stabilizer, also used in schizophrenia and bipolar disorder, has shown pro or anti-inflammatory effects and therefore could modulate the inflammatory and oxidative response induced by OLZ. The açaí (Euterpe oleracea Mart.), an amazonian fruit, could also influence these effects caused by OLZ, because it exhibits antioxidant and anti-inflammatory properties. Objective: to evaluate in vitro the influence of pharmacological and nutritional factors on the oxidative and inflammatory response induced by OLZ. Methodology: The RAW 264.7 macrophage cell line was exposed in vitro for 72h at different concentrations of OLZ and cell proliferation was evaluated. An OLZ concentration was selected. In the same cell model, in a second experimental protocol, the selected OLZ concentration was associated with lithium (0.7 mEq / L) and in the third protocol the OLZ was associated with the hydroalcoholic extract of açaí. We evaluated: (1) cell proliferation rate (2) oxidative markers (3) inflammatory markers (4) apoptotic markers. Results: Different concentrations of OLZ indicated a hormetic effect on macrophage proliferation in 72h. The selected OLZ concentration (0.03 μg / mL) presented pro-oxidative effects with elevated superoxide anion (SA), nitric oxide (NO) and reactive oxygen species (ROS). OLZ presented pro-inflammatory effects with elevation of all pro- inflammatory cytokines (IL-1, IL-6, TNF-α) and reduction of the anti-inflammatory cytokine (IL-10). Exposure of lithium to macrophages per se also triggered an oxidative and inflammatory response, but with a slight elevation of cell proliferation, AS, ROS and IL-1β. However, the association of lithium with OLZ was able to attenuate the elevation of all oxidative and inflammatory markers induced by OLZ and attenuate the reduction of IL-10 levels. Açaí exposed to macrophages per se did not trigger increased cell proliferation or oxidative and inflammatory markers. The açaí (5 μg / mL) associated with OLZ attenuated the elevation of OLZ-induced levels of oxidative, inflammatory and apoptotic markers (caspases 1, 3 and 8), as well as attenuated the reduction of IL-10. Conclusion: Despite the limitations related to the in vitro studies, the results suggest that pharmacological and nutritional components could attenuate the pro-oxidative and pro-inflammatory action of OLZ on macrophages, such as lithium and açaí. Thus, pharmacological and nutritional interactions could be a relevant strategy to minimize the peripheral adverse effects of OLZ, due to the oxidative-inflammatory profile. Complementary in vivo studies will be needed to corroborate these findings.