The trypanocidal action of eupomatenoid-5 isolated from Piper regnellii var. pallescens may be related to an imbalance between the antioxidant system and ROS
Due to the severe side effects and variable efficacy, the current treatment for Chagas disease is still unsatisfactory. Natural compounds are good alternative chemotherapeutic agents for treatment of this infection . Our group has reported antiproliferative activity and morphological alterations of eupomatenoid-5 isolated from leaves of Piper regnellii var. pallescens against epimastigotes and intracellular amastigotes of T. cruzi . Here, we assessed the effects of eupomatenoid-5 on trypomastigotes, and investigated the possible mechanism of action of this compound on T. cruzi. Eupomatenoid-5 exhibited activity against trypomastigotes, where 50% of the cells were non-viable with 40.5µM of the compound. Ultrastructural analyses showed effects on the cytoplasmic membrane and vacuole formation. Treatment with eupomatenoid-5 for 24h, increased lipoperoxidation 6-fold in trypomastigotes and 2-fold in epimastigotes. Cytometry analysis of rhodamine 123-stained T. cruzi showed depolarization of mitochondrial membrane potential in 29.0 and 62.8% of epimastigotes treated with 34.0 and 51.0µM of eupomatenoid-5, respectively, after 96h of incubation. Eupomatenoid-5 also increased G6PD activity by 265, 1,403 and 3,601% after treatment with 34.0, 85.0 and 170.0µM for 24h, followed by an increase in H2O2 consumption in epimastigotes. Although T. cruzi possesses different ROS detoxifying mechanisms, they seem to be less efficient than those of mammals. Therefore, the parasite detoxifying systems may be considered a target for drug development. Our results indicate that the trypanocidal action of eupomatenoid-5 may be associated with the impairment of antioxidant systems, causing oxidative stress that can trigger destructive effects on biological molecules such as lipids and proteins, leading to parasite death.
Acknowledgements: This study was supported through grants from DECIT/SCTIE/MS and MCT by CNPq, FINEP, PRONEX/Fund. Araucária
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