Oxidative stress in mice treated with antileishmanial meglumine antimoniate

Bento, Diana Bittencourt; Souza, Bruna de; Steckert, Amanda V.; Dias, Ruella; Leffa, Daniela Dimer; Moreno, Susana Elisa; Petronilho, Fabrícia; Andrade, Vanessa Moraes de; Dal‐Pizzol, Felipe; Romão, Pedro Roosevelt Torres

doi:10.1016/j.rvsc.2013.08.004

Cited by 21 publications

(18 citation statements)

References 41 publications

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“…According to Singh et al (50), high ROS production, such as that observed in the oxidative burst, may lead to saturation of this antioxidant pathway due to the large consumption of GSH by GPx. These observations are in line with our results, especially because it has been shown that Sb III is able to impair the redox balance by promoting intracellular GSH depletion and glutathione reductase inhibition, thereby preventing GSH regeneration (14)(15)(16)(17)(18).…”

Section: Discussionsupporting

confidence: 93%

“…It should be noted that the animal dose used in this work was equivalent to approximately 1.5 mg/kg/day in humans, much lower than the regimen recommended by the WHO for humans, i.e., 20 mg/kg/day for 20 days (52). Nevertheless, the dose we used was able to cause oxidative stress-derived DNA damage, corroborating previous studies that demonstrated lipid peroxidation and protein carbonylation in animals receiving 20, 60, or 120 mg/kg/day of meglumine antimoniate for 3 days, with no difference in the resultant oxidative damage among doses (17).…”

Section: Discussionsupporting

confidence: 89%

“…Previous reports have found high CAT levels in Leishmania-infected animals (48), while others found lower enzymatic activity (47). Notwithstanding, Bento et al (17), studying uninfected animals receiving meglumine antimoniate, observed that CAT activity differs according to the organ evaluated. Once again, according to our data, Leishmania infection and meglumine antimoniate seem to independently promote oxidative stress, probably by acting on the same pathway, since there was no difference in the enzymes' activities when both conditions were present concomitantly.…”

Section: Discussionmentioning

confidence: 93%

“…Other studies suggest that both arsenic and antimony are responsible for inducing oxidative stress through the depletion of reducing agents, such as glutathione (GSH) (29,30). More recently, Bento et al (17) demonstrated that meglumine antimoniate causes protein carbonylation in the heart, spleen, and brain, besides lipid peroxidation in the livers and brains of CF-1 mice. Additionally, Kato et al (31) reported higher peroxidase enzyme activity in animals treated with meglumine antimoniate.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, studies have shown that antimonial compounds increase levels of reactive oxygen species (ROS)/reactive nitrogen species (RNS), altering enzyme activities related to the antioxidant defense system (15)(16)(17).…”

mentioning

confidence: 99%

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Meglumine Antimoniate (Glucantime) Causes Oxidative Stress-Derived DNA Damage in BALB/c Mice Infected by Leishmania (Leishmania) infantum

Moreira

Jesus

Soares

et al. 2017

Antimicrob Agents Chemother

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Leishmaniasis is a neglected tropical disease caused by Ͼ20 species of the protozoan parasite Leishmania. Meglumine antimoniate (Glucantime) is the firstchoice drug recommended by the World Health Organization for the treatment of all types of leishmaniasis. However, the mechanisms of action and toxicity of pentavalent antimonials, including genotoxic effects, remain unclear. Therefore, the mechanism by which meglumine antimoniate causes DNA damage was investigated for BALB/c mice infected by Leishmania (Leishmania) infantum and treated with meglumine antimoniate (20 mg/kg for 20 days). DNA damage was analyzed by a comet assay using mouse leukocytes. Furthermore, comet assays were followed by treatment with formamidopyrimidine-DNA glycosylase and endonuclease III, which remove oxidized DNA bases. In addition, the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in the animals' sera were assessed. To investigate mutagenicity, we carried out a micronucleus test. Our data demonstrate that meglumine antimoniate, as well as L. infantum infection, induces DNA damage in mammalian cells by the oxidation of nitrogenous bases. Additionally, the antileishmanial increased the frequency of micronucleated cells, confirming its mutagenic potential. According to our data, both meglumine antimoniate treatment and L. infantum infection promote oxidative stress-derived DNA damage, which promotes overactivation of the SOD-CAT axis, whereas the SOD-GPx axis is inhibited as a probable consequence of glutathione (GSH) depletion. Finally, our data enable us to suggest that a meglumine antimoniate regimen, as recommended by the World Health Organization, would compromise GPx activity, leading to the saturation of antioxidant defense systems that use thiol groups, and might be harmful to patients under treatment.

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