Trypanocidal action of eupomatenoid-5 is related to mitochondrion dysfunction and oxidative damage in Trypanosoma cruzi

Abstract

Because of its severe side effects and variable efficacy, the current treatment for Chagas disease is unsatisfactory. Natural compounds are good alternative chemotherapeutic agents for the treatment of this infection. Recently, our group reported the antiproliferative activity and morphological alterations in epimastigotes and intracellular amastigotes of Trypanosoma cruzi treated with eupomatenoid-5, a neolignan isolated from leaves of Piper regnellii var. pallescens. Here, we demonstrate that eupomatenoid-5 exhibited activity against trypomastigotes, the infective form of T. cruzi (EC₅₀ 40.5 μM), leading to ultrastructural alteration and lipoperoxidation in the cell membrane. Additionally, eupomatenoid-5 induced depolarization of the mitochondrial membrane, lipoperoxidation and increased G6PD activity in epimastigotes of T. cruzi. These findings support the possibility that different mechanisms may be targeted, according to the form of the parasite, and that the plasma membrane and mitochondria are the structures that are most affected in trypomastigotes and epimastigotes, respectively. Thus, the trypanocidal action of eupomatenoid-5 may be associated with mitochondrial dysfunction and oxidative damage, which can trigger destructive effects on biological molecules of T. cruzi, leading to parasite death.

Trypanocidal Action of (−)-Elatol Involves an Oxidative Stress Triggered by Mitochondria Dysfunction

“…In this view, the mitochondria might be the initial target organelle of (−)-elatol. This hypothesis agrees with many other studies and strengthens the idea that mitochondria might be a target for trypanocidal action of new compounds [9,14,32,33]. On the other hand, we could also speculate that the initial event induced by (−)-elatol would be the increase of mitochondrial ROS, induced for example by a decrease in the antioxidant enzyme activity of the parasite.…”

“…In fact, increasingly well documented papers have described trypanocidal compounds targeting parasite mitochondrial function [9,14]. …”

The Effects ofN-Butyl-1-(4-dimethylamino)phenyl-1,2,3,4-tetrahydro-β-carboline-3-carboxamide againstLeishmania amazonensisAre Mediated by Mitochondrial Dysfunction

“…The parasites were adhered on poly- l -lysine-coated coverslips, dehydrated in different concentrations of ethanol, critical-point dried with CO 2 , sputter coated with gold, and observed in a Shimadzu SS-550 scanning electron microscope [18]. …”

Mitochondria Superoxide Anion Production Contributes to Geranylgeraniol-Induced Death inLeishmania amazonensis

“…Promastigote forms (1 × 10 6 parasites/mL) in the absence or in the presence of 11  μ g/mL of geranylgeraniol for 48 h were washed with 0.01 M PBS and fixed in 2.5% glutaraldehyde in 0.1 M sodium cacodylate buffer at 4°C for 48 h. The parasites were adhered on the poly-L-lysine-coated coverslip, dehydrated in different concentrations of ethanol, critical point-dried with CO 2 , sputter-coated with gold, and observed in a Shimadzu SS-550 scanning electron microscope [18]. …”