Mechanism of ascaridole activation in Leishmania

Geroldinger, Gerald; Tonner, Matthias; Bacher, Markus; Monzote, Lianet; Walter, Martín; Staniek, Katrin; Rosenau, Thomas; Gille, Lars

doi:10.1016/j.bcp.2017.02.023

Cited by 23 publications

(31 citation statements)

References 57 publications

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“…Asc, Car, and Caryo only slightly increased CM ● formation. At first view, it appears puzzling that Asc, which is known to trigger formation of carbon‐centered radicals (Geroldinger et al, ), does not trigger superoxide formation in this assay.…”

Section: Resultsmentioning

confidence: 89%

“…In a previous study, the major components of EO gave following IC 50 values: Asc, 0.6 ± 0.06 μM; Car, 101 ± 30 μM; and Caryo, 22.2 ± 10.4 μM against LaP (Monzote, Garcia, et al, ), which are particularly different for Asc and Car. Although qualitatively the iron‐dependent activation of Asc/EO was confirmed in LaP (Monzote, Garcia, et al, ) and LtP (Geroldinger et al, ), the quantitative outcome of viability assays may strongly depend on the cell number to drug ratio, detection method and even on assay medium and premature activation of Asc in media. Our current studies explore this systematically.…”

Section: Discussionmentioning

confidence: 98%

“…In a combinatorial study, it was shown that especially combinations of Asc:Car = 1:4 were most effective against lesion development in this cutaneous leishmaniasis model. In vitro studies using the L. tarentolae model showed that Asc is activated in Leishmania to a carbon‐centered radical species preferably by low molecular iron (Fe 2+ ) from the labile iron pool in Leishmania (Geroldinger et al, ). This was corroborated by the finding that IC 50 values for EO and Asc are strongly increased for L. amazonensis in the presence of iron chelators (Monzote, Garcia, et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…This was corroborated by the finding that IC 50 values for EO and Asc are strongly increased for L. amazonensis in the presence of iron chelators (Monzote, Garcia, et al, ). The selectivity of Asc/EO for Leishmania is based on their much higher labile iron pool compared with the labile iron pool of macrophage/monocyte host cells (Geroldinger et al, ). These data indicate that Asc is a nonmitochondrial radical generator in Leishmania .…”

Section: Discussionmentioning

confidence: 99%

“…In our study, besides whole LtP cells, Lainson & Shaw, 1987), and is not pathogenic for humans (Raymond et al, 2012). L. tarentolae has been widely used in pharmacological studies for (a) the screening of natural and synthetic products (Taylor et al, 2010), (b) the purification and characterization of proteins that are used for the screening of drugs with potential antileishmanial activity (Fritsche et al, 2007;Yakovich, Ragone, Alfonzo, Sackett, & Werbovetz, 2006), and (c) the amplification of genes involved in the resistance to certain antileishmanial drugs such as amphotericin B (Singh, Papadopoulou, & Ouellette, 2001) and sodium stibogluconate (Haimeur & Ouellette, 1998 (Monzote, Garcia, et al, 2014) and LtP (Geroldinger et al, 2017), the quantitative outcome of viability assays may strongly depend on the cell number to drug ratio, detection method and even on assay medium and premature activation of Asc in media. Our current studies explore this systematically.…”

Section: Discussionmentioning

confidence: 99%

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Interaction of ascaridole, carvacrol, and caryophyllene oxide from essential oil of Chenopodium ambrosioides L. with mitochondria in Leishmania and other eukaryotes

Monzote

Geroldinger

Tonner

et al. 2018

Phytotherapy Research

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The antileishmanial activity of the essential oil (EO) from Chenopodium ambrosioides L. has been demonstrated in vitro and in animal models, attributed to the major components of the EO. This study focused on the effects of the three major EO compounds carvacrol, caryophyllene oxide (Caryo), and the antileishmanial endoperoxide ascaridole (Asc) on mitochondrial functions in Leishmania tarentolae promastigotes (LtP). EO and Caryo were able to partially inhibit the leishmanial electron transport chain, whereas other components failed to demonstrate a direct immediate effect. Caryo demonstrated inhibition of complex III activity in LtP and in isolated complex III from other species. The formation of superoxide radicals was studied in Leishmania by electron spin resonance spectroscopy in the presence of iron chelators wherein selected compounds failed to trigger a significant immediate additional superoxide production in LtP. However, upon prolonged incubation of Leishmania with Asc and especially in the absence of iron chelators (allowing the activation of Asc), an increased superoxide radical production and significant impairment of mitochondrial coupling in Leishmania was observed. Prolonged incubation with all EO components resulted in thiol depletion. Taken together, the major components of EO mediate their leishmanicidal activity via different mitochondrial targets and time profiles. Further studies are required to elucidate possible synergistic effects of carvacrol and Asc and the influence of minor compounds.

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Section: Resultsmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Interaction of ascaridole, carvacrol, and caryophyllene oxide from essential oil of Chenopodium ambrosioides L. with mitochondria in Leishmania and other eukaryotes

Monzote

Geroldinger

Tonner

et al. 2018

Phytotherapy Research

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Repurposing topical triclosan for cutaneous leishmaniasis: Preclinical efficacy in a murine Leishmania (L.) amazonensis model

Mesquita

Romanelli

Trinconi

et al. 2020

Drug Development Research

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Leishmaniasis remains an important neglected tropical infection caused by the protozoan Leishmania and affects 12 million people in 98 countries. The treatment is limited with severe adverse effects. In the search for new therapies, the drug repositioning and combination therapy have been successfully applied to neglected diseases. The aim of the present study was to evaluate the in vitro and in vivo anti‐Leishmania (Leishmania) amazonensis potential of triclosan, an approved topical antimicrobial agent used for surgical procedures. in vitro phenotypic studies of drug‐treated parasites were performed to evaluate the lethal action of triclosan, accompanied by an isobolographic ex‐vivo analysis with the association of triclosan and miltefosine. The results showed that triclosan has activity against L. (L.) amazonensis intracellular amastigotes, with a 50% inhibitory concentration of 16 μM. By using fluorescent probes and transmission electron microscopy, a pore‐forming activity of triclosan toward the parasite plasma membrane was demonstrated, leading to depolarization of the mitochondrial membrane potential and reduction of the reactive oxygen species levels in the extracellular promastigotes. The in vitro interaction between triclosan and miltefosine in the combination therapy assay was classified as additive against intracellular amastigotes. Leishmania‐infected mice were treated with topical triclosan (1% base cream for 14 consecutive days), and showed 89% reduction in the parasite burden. The obtained results contribute to the investigation of new alternatives for the treatment of cutaneous leishmaniasis and suggest that the coadministration of triclosan and miltefosine should be investigated in animal models.

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Exploring Endoperoxides as Leishmanicidal Compounds

Sarkar

Chatterjee

2019

Oxidative Stress in Microbial Diseases

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Mechanism of ascaridole activation in Leishmania

Cited by 23 publications

References 57 publications

Interaction of ascaridole, carvacrol, and caryophyllene oxide from essential oil of Chenopodium ambrosioides L. with mitochondria in Leishmania and other eukaryotes

Interaction of ascaridole, carvacrol, and caryophyllene oxide from essential oil of Chenopodium ambrosioides L. with mitochondria in Leishmania and other eukaryotes

Repurposing topical triclosan for cutaneous leishmaniasis: Preclinical efficacy in a murine Leishmania (L.) amazonensis model

Exploring Endoperoxides as Leishmanicidal Compounds

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