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The sesquiterpene (−)-α-bisabolol is active against the causative agents of Old World cutaneous leishmaniasis through the induction of mitochondrial-dependent apoptosis

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Abstract

Cutaneous leishmaniasis treatment remains challenging due to the absence of a satisfactory treatment. The screening of natural compounds is a valuable strategy in the search of new drugs against leishmaniasis. The sesquiterpene (−)-α-bisabolol is effective in vivo against visceral leishmaniasis due to Leishmania infantum, but its mechanism of action remains elusive. The aim of this study is to validate this promising compound against the causative species of Old World cutaneous leishmaniasis and to get an insight into its antileishmanial mode of action. The compound was evaluated on L. tropica promastigotes and intracellular amastigotes using bone marrow-derived macrophages and its cytotoxicity was evaluated on L929 fibroblasts. The reactive oxygen species generation was evaluated using a sensitive probe. Mitochondrial depolarization was assessed evaluating the fluorescence due to rhodamine 123 in a flow cytometer. Apoptosis was investigated by measuring the fluorescence due to annexin V and propidium iodide in a flow cytometer. The ultrastructure of treated promastigotes and intracellular amastigotes was analysed through transmission electron microscopy. (−)-α-Bisabolol was active against L. tropica intracellular amastigotes displaying an inhibitory concentration 50 % of 25.2 µM and showing low cytotoxicity. This compound induced time and dose-dependent oxidative stress, mitochondrial depolarization and phosphatidilserine externalization (a marker of apoptosis). These effects were noticed at a low concentration and short exposure time. In the ultrastructural analyses, the treated parasites showed mitochondrial disruption, presence of electron-dense structures and chromatin condensation. These results suggest that this natural compound induces oxidative stress and mitochondrial-dependent apoptosis on Leishmania without disturbing the plasma membrane.

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Acknowledgments

The authors wish to thank Dr. Montserrat Gállego (University of Barcelona) and Dr. Pratlong (University of Montpellier) for kindly donating the Leishmania strains used in this work and the CIC (University of Granada) for facilitating the use of his transmission electron microscope and flow cytometer.

Funding

This work was supported by the Project PI14-01024, Ministry of Economy and Competitiveness, Instituto de Salud Carlos III, Madrid and Feder Funds for Regional Development from the European Union, “One way to make Europe”

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Authors and Affiliations

  1. Departamento de Parasitología, Facultad de Farmacia, Universidad de Granada, Campus de Cartuja s/n, 18071, Granada, Spain

    V. Corpas-López, G. Merino-Espinosa, V. Díaz-Sáez, F. Morillas-Márquez & J. Martín-Sánchez

  2. Departamento de Farmacología, Facultad de Farmacia, Universidad de Granada, Campus de Cartuja s/n, 18071, Granada, Spain

    M. C. Navarro-Moll

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  1. V. Corpas-López
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  2. G. Merino-Espinosa
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  3. V. Díaz-Sáez
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  4. F. Morillas-Márquez
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  5. M. C. Navarro-Moll
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  6. J. Martín-Sánchez
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Correspondence to V. Corpas-López.

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The authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Ethical approval

All applicable European guidelines for the care and use of animals were followed (Directive 2010/63/EU on the protection of animals used for scientific purposes). All experiments were approved by the Ethics Committee of Animal Experimentation of the University of Granada (CEEA 455-2013).

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Corpas-López, V., Merino-Espinosa, G., Díaz-Sáez, V. et al. The sesquiterpene (−)-α-bisabolol is active against the causative agents of Old World cutaneous leishmaniasis through the induction of mitochondrial-dependent apoptosis. Apoptosis 21, 1071–1081 (2016). https://doi.org/10.1007/s10495-016-1282-x

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