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

Abstract

Natural compounds have shown good potential for the discovery of new chemotherapeutics for the treatment of Chagas’ disease. Recently, our group reported the effective trypanocidal activity of (−)-elatol, extracted from the red macroalgae Laurencia dendroidea present in the Brazilian coast against Trypanosoma cruzi. However, the mechanism of action of this compound has remained unclear. There are only hypotheses concerning its action on mitochondrial function. Here, we further investigated the mechanisms of action of (−)-elatol on trypomastigotes of T. cruzi. For this, we evaluated some biochemical alterations in trypomastigotes treated with (−)-elatol. Our results show that (−)-elatol induced depolarization of the mitochondrial membrane, an increase in the formation of mitochondrial superoxide anion and loss of cell membrane and DNA integrity. Additionally, (−)-elatol induced formation of autophagic vacuoles and a decrease in cell volume. All together, these results suggest that the trypanocidal action of (−)-elatol involves multiple events and mitochondria might be the initial target organelle. Our hypothesis is that the mitochondrial dysfunction leads to an increase of ROS production through the electron transport chain, which affects cell membrane and DNA integrity leading to different types of parasite death.

Miltefosine Increases Lipid and Protein Dynamics in Leishmania amazonensis Membranes at Concentrations Similar to Those Needed for Cytotoxicity Activity

“…The efficiency of incorporation and the uniformity of the probe distribution throughout the membrane can be verified on the basis of the EPR spectra immediately after labeling. For instance, spin-labeled lipids have been successfully incorporated into stratum corneum membranes (20), cellular membranes of coffee root tip segments (21), Trypanosoma cruzi protozoans (22), and fibroblasts (23). EPR spectroscopy has identified the presence of two populations of spin labels differing in molecular dynamics in cell membranes (24).…”

Electron paramagnetic resonance (EPR) spectral components of spin-labeled lipids in saturated phospholipid bilayers: effect of cholesterol

“…[8][9][10] The presence of the terpenes L-menthol and 1,8-cineole, two potent skin permeation enhancers, in stratum corneum at 1% (w/w) or DPPC vesicles at a terpene:lipid molar ratio of 0.7:1 drastically increased the lipid fluidity, especially by transferring the spin probes from a more to a less motionally restricted spectral component in the membranes. 9,10 More recently, EPR spectra of spin labels in membrane were simulated using two-component models to study effects of the anti antileishmanial drug miltefosine in stratum corneum intercellular membranes 11 and trypanocidal action of elatol 12 as well as the toxicity of terpenes in cultured fibroblasts. 13 Since the question of the spectral components in the EPR spectra of spin-labeled lipids in membrane models of simple bilayers has not been addressed in depth, we conducted an extensive experimental study with the spin probe methyl 5-doxyl-stearate (5-DMS) in vesicles of saturated phosphatidylcholines with acyl chain lengths ranging from 16 to 22 carbon atoms and temperatures in the 10 to 78 o C range.…”

Reduction of Toxoplasma gondii Development Due to Inhibition of Parasite Antioxidant Enzymes by a Dinuclear Iron(III) Compound

“…As previously described in the literature (49), iron may induce the production of free radicals, such as hydroxyl radicals, in biological systems; free radicals are often associated with DNA damage, lipid peroxidation, protein modifications, and other related effects that are characteristic of oxidative stress (50). Other parasites were recently described to be susceptible to chemical compounds that induce oxidative stress, such as miltefosine, which is used against Leishmania donovani (51); glabridin, which is used against Plasmodium falciparum and causes death, as evidenced by the depolarization of mitochondrial membrane potential, the activation of caspase-like proteases, and DNA fragmentation (52); and the compound elatol, which increases ROS production in treated T. cruzi trypomastigotes, leading to autophagy and apoptosis (53). T. gondii has evolved a robust antioxidant defense system (27), which is primarily based on the activity of the SOD (54) and CAT (53,55,56) antioxidant enzymes, enabling the parasite to deal with ROS produced by immune cells.…”

“…Other parasites were recently described to be susceptible to chemical compounds that induce oxidative stress, such as miltefosine, which is used against Leishmania donovani (51); glabridin, which is used against Plasmodium falciparum and causes death, as evidenced by the depolarization of mitochondrial membrane potential, the activation of caspase-like proteases, and DNA fragmentation (52); and the compound elatol, which increases ROS production in treated T. cruzi trypomastigotes, leading to autophagy and apoptosis (53). T. gondii has evolved a robust antioxidant defense system (27), which is primarily based on the activity of the SOD (54) and CAT (53,55,56) antioxidant enzymes, enabling the parasite to deal with ROS produced by immune cells. However, the parasite was unable to handle the increased intracellular oxidation that was generated in the host by the iron(III) compound.…”