Mitochondrial disfunction and ROS production are essential for anti-Trypanosoma cruzi activity of β-lapachone-derived naphthoimidazoles

Bombaça, Ana Cristina S.; Viana, Paula Gonçalves; Santos, Augusto C. C.; Silva, Thaissa L.; Rodrigues, Aline Beatriz Mello; Guimarães, Ana Carolina Ramos; Goulart, Marília Oliveira Fonseca; Júnior, Eufrânio N. da Silva; Menna-Barreto, Rubem F.S.

doi:10.1016/j.freeradbiomed.2018.11.012

Cited by 35 publications

(15 citation statements)

References 42 publications

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“…The single mitochondria of trypanosomatids parasites presents a peculiar ultrastructure and functional plasticity that makes this organelle an excellent indicator of cell irreversible dysfunction and, consequently, an attractive therapeutic target for new therapeutic strategies . A critical event for the monitoring of the proper functioning of the mitochondrial respiratory chain of parasite is the determination of the mitochondrial membrane potential (ΔΨm) .…”

Section: Discussionmentioning

confidence: 99%

“…In trypanosomatids, autophagy is a biological process required for the maintenance of parasite life cycle, contributing to the regulation of cell density in the vectors and mammalian hosts, thus responding to the cell differentiation and modulation of host immunity . Despite its protective role, the exacerbation of this autophagic pathway can also lead to regulated cell death . To investigate the activation of this pathway of cell death caused by AR26 , the accumulation of autophagic vacuoles was evaluated by labelling with MDC.…”

Section: Discussionmentioning

confidence: 99%

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Resveratrol analogues present effective antileishmanial activity against promastigotes and amastigotes from distinct Leishmania species by multitarget action in the parasites

Antinarelli

Meinel

Coelho

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives The in vitro antileishmanial effect of analogues of resveratrol (AR) present in the N-aryl imines and N-aryl hydrazones series was investigated. In addition, possible parasite targets were evaluated. Methods Antipromastigote activity of Leishmania amazonensis, L. braziliensis and L. infantum, as well as the cytotoxicity on macrophages was determined by MTT assay and L. braziliensis-infected macrophages effect by Giemsa stain. After staining, effects on the parasite targets were analysed by flow cytometry or by fluorescence microscopy.Key-findings Among the tested compounds, the derivative AR26 showed the best effect against promastigotes of all Leishmania species (IC 50 < 3.0 µg/ml), being more active than miltefosine, the control drug. AR26 was also effective against amastigotes of L. braziliensis (IC 50 = 15.9 µg/ml), with low toxicity to mammalian cells. The evaluation of mechanism of action of AR26 on L. braziliensis promastigotes indicates mitochondrial potential depolarization, plasma membrane permeabilization, interference in the progression of the cell cycle and accumulation of autophagic vacuoles. In addition, any increase of the reactive oxygen species levels was detected in the treated L. braziliensis-macrophages.Conclusions Data indicate that the antileishmanial activity of AR26 is related to multitarget action, and the resveratrol analogues could be used in future studies as antileishmanial agent.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Resveratrol analogues present effective antileishmanial activity against promastigotes and amastigotes from distinct Leishmania species by multitarget action in the parasites

Antinarelli

Meinel

Coelho

et al. 2019

Journal of Pharmacy and Pharmacology

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“…Naphthoimidazoles are another class of molecules that target the mitochondrion. β-lapachone derivatives directly impair T. cruzi electron transport system, resulting in increased ROS production and parasite death (Bombaça et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

The Potent Trypanocidal Effect of LQB303, a Novel Redox-Active Phenyl-Tert-Butyl-Nitrone Derivate That Causes Mitochondrial Collapse in Trypanosoma cruzi

et al. 2021

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Chagas disease, which is caused by Trypanosoma cruzi, establishes lifelong infections in humans and other mammals that lead to severe cardiac and gastrointestinal complications despite the competent immune response of the hosts. Furthermore, it is a neglected disease that affects 8 million people worldwide. The scenario is even more frustrating since the main chemotherapy is based on benznidazole, a drug that presents severe side effects and low efficacy in the chronic phase of the disease. Thus, the search for new therapeutic alternatives is urgent. In the present study, we investigated the activity of a novel phenyl-tert-butyl-nitrone (PBN) derivate, LQB303, against T. cruzi. LQB303 presented trypanocidal effect against intracellular [IC50/48 h = 2.6 μM] and extracellular amastigotes [IC50/24 h = 3.3 μM] in vitro, leading to parasite lysis; however, it does not present any toxicity to host cells. Despite emerging evidence that mitochondrial metabolism is essential for amastigotes to grow inside mammalian cells, the mechanism of redox-active molecules that target T. cruzi mitochondrion is still poorly explored. Therefore, we investigated if LQB303 trypanocidal activity was related to the impairment of the mitochondrial function of amastigotes. The investigation showed there was a significant decrease compared to the baseline oxygen consumption rate (OCR) of LQB303-treated extracellular amastigotes of T. cruzi, as well as reduction of “proton leak” (the depletion of proton motive force by the inhibition of F1Fo ATP synthase) and “ETS” (maximal oxygen consumption after uncoupling) oxygen consumption rates. Interestingly, the residual respiration (“ROX”) enhanced about three times in LQB303-treated amastigotes. The spare respiratory capacity ratio (SRC: cell ability to meet new energy demands) and the ATP-linked OCR were also impaired by LQB303 treatment, correlating the trypanocidal activity of LQB303 with the impairment of mitochondrial redox metabolism of amastigotes. Flow cytometric analysis demonstrated a significant reduction of the ΔΨm of treated amastigotes. LQB303 had no significant influence on the OCR of treated mammalian cells, evidencing its specificity against T. cruzi mitochondrial metabolism. Our results suggest a promising trypanocidal activity of LQB303, associated with parasite bioenergetic inefficiency, with no influence on the host energy metabolism, a fact that may point to an attractive alternative therapy for Chagas disease.

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“…(12,13) Such mitochondrial susceptibility was confirmed by proteomic approaches, which also showed that trypanothione synthetase overexpression was induced by treatment. (15,16) Recently, we further investigated the mechanism of action of naphthoimidazoles, which revealed the oxidative misbalance derived from the direct effect on the mitochondrial electron transport chain (at least for N1) that leads to the production of high ROS levels to kill the parasite. (17) Other mechanistic proposals could not be discarded, especially in terms of explaining the action of N2 and N3.…”

Section: Discussionmentioning

confidence: 99%

“…Treated parasites showed high trypanothione reductase activity and were positioned in pockets of this enzyme, which was in line with the increase in trypanothione synthetase activity that was found in a previous proteomic study. (16)…”

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confidence: 99%

Antiparasitic and anti-inflammatory activities of ß-lapachone-derived naphthoimidazoles in experimental acute Trypanosoma cruzi infection

Cascabulho

Meuser-Batista

Moura

et al. 2020

Mem. Inst. Oswaldo Cruz

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BACKGROUND Chagas disease, which is caused by the protozoan Trypanosoma cruzi, is endemic to Latin America and mainly affects low-income populations. Chemotherapy is based on two nitrocompounds, but their reduced efficacy encourages the continuous search for alternative drugs. Our group has characterised the trypanocidal effect of naphthoquinones and their derivatives, with naphthoimidazoles derived from β-lapachone (N1, N2 and N3) being the most active in vitro. OBJECTIVES In the present work, the effects of N1, N2 and N3 on acutely infected mice were investigated. METHODS in vivo activity of the compounds was assessed by parasitological, biochemical, histopathological, immunophenotypical, electrocardiographic (ECG) and behavioral analyses. FINDINGS Naphthoimidazoles led to a decrease in parasitaemia (8 dpi) by reducing the number of bloodstream trypomastigotes by 25-50% but not by reducing mortality. N1 protected mice from heart injury (15 dpi) by decreasing inflammation. Bradycardia was also partially reversed after treatment with N1 and N2. Furthermore, the three compounds did not reverse hepatic and renal lesions or promote the improvement of other evaluated parameters. MAIN CONCLUSION N1 showed moderate trypanocidal and promising immunomodulatory activities, and its use in combination with benznidazole and/or anti-arrhythmic drugs as well as the efficacy of its alternative formulations must be investigated in the near future.

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Mitochondrial disfunction and ROS production are essential for anti-Trypanosoma cruzi activity of β-lapachone-derived naphthoimidazoles

Cited by 35 publications

References 42 publications

Resveratrol analogues present effective antileishmanial activity against promastigotes and amastigotes from distinct Leishmania species by multitarget action in the parasites

Resveratrol analogues present effective antileishmanial activity against promastigotes and amastigotes from distinct Leishmania species by multitarget action in the parasites

The Potent Trypanocidal Effect of LQB303, a Novel Redox-Active Phenyl-Tert-Butyl-Nitrone Derivate That Causes Mitochondrial Collapse in Trypanosoma cruzi

Antiparasitic and anti-inflammatory activities of ß-lapachone-derived naphthoimidazoles in experimental acute Trypanosoma cruzi infection

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