TrypanocidalActivity of Natural Sesquiterpenoids Involves Mitochondrial Dysfunction, ROS Production and Autophagic Phenotype in Trypanosoma cruzi

Abstract

Chagas disease is a neglected tropical disease that is caused by the protozoan Trypanosoma cruzi and represents a serious health problem, especially in Latin America. The clinical treatment of Chagas disease is based on two nitroderivatives that present severe side effects and important limitations. In folk medicine, natural products, including sesquiterpenoids, have been employed for the treatment of different parasitic diseases. In this study, the trypanocidal activity of compounds isolated from the Chilean plants Drimys winteri, Podanthus mitiqui and Maytenus boaria on three T. cruzi evolutive forms (epimastigote, trypomastigote and amastigote) was evaluated. Total extracts and seven isolated sesquiterpenoids were assayed on trypomastigotes and epimastigotes. Polygodial (Pgd) from D. winteri, total extract from P. mitiqui (PmTE) and the germacrane erioflorin (Efr) from P. mitiqui were the most bioactive substances. Pgd, Efr and PmTE also presented strong effects on intracellular amastigotes and low host toxicity. Many ultrastructural effects of these substances, including reservosome disruption, cytosolic vacuolization, autophagic phenotype and mitochondrial swelling (in the case of Pgd), were observed. Flow cytometric analysis demonstrated a reduction in mitochondrial membrane potential in treated epimastigotes and an increase in ROS production and high plasma membrane permeability after treatment with Pgd. The promising trypanocidal activity of these natural sesquiterpenoids may be a good starting point for the development of alternative treatmentsforChagas disease.

Trypanocidal Mechanism of Action and in silico Studies of p-Coumaric Acid Derivatives

“…An increase in relative fluorescence was observed at both tested concentrations of compound 7 (5.164 μM, and 10.329 μM), as well as an increase in production of reactive oxygen species, inducing oxidative stress against the parasite. Thus, cells treated with compound 7 presented a reduction in the accumulation of rhodamine 123, causing loss of mitochondrial transmembrane potential [51,52]. Upon analysis of the images performed by scanning electron microscopy, alterations and loss of cellular integrity were observed in the groups treated with compound 7 ; this was confirmed by the flow cytometry data [53].…”

Comparative Study of Bioactivity and Safety Evaluation of Ethanolic Extracts of Zanthoxylum schinifolium Fruit and Pericarp

“…The observed cytotoxicity of the ZS extracts against WI-38 cells may be due to ROS-mediated oxidative stress or toxicity of the extract itself. Several phytochemicals, including sesquiterpenoids, glycosides, alkaloids, and coumarins, induce cell death via ROS generation [ 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ]. Therefore, ZS extracts, containing schinifolenol A, zanthoxyloside A, norchelerythrine, and auraptene, have the potential to induce oxidative stress-induced cell death [ 22 , 23 , 26 ].…”

Plant Terpenoids as Hit Compounds against Trypanosomiasis

“…Compound 80 was also previously isolated from the Chilean species Drimys winteri , and was tested on the same parasite forms with weak comparable results. On this work, the authors associated the trypanosomal activity of this compound with intracellular effects occurring in the parasite, namely, mitochondrial dysfunctions, ROS production and autophagic phenotype [ 79 ].…”