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The antidepressant clomipramine induces programmed cell death in Leishmania amazonensis through a mitochondrial pathway

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Abstract

Despite many efforts, the currently available treatments for leishmaniasis are not fully effective. To discover new medications, drug repurposing arises as a promising strategy. We present data that supports the use of the antidepressant clomipramine against Leishmania amazonensis. The drug presented selective activity at micromolar range against both the parasite forms and stimulated nitric oxide production in host macrophages. Regarding the mechanism of action, clomipramine led parasites do mitochondrial depolarization, which coupled with the inhibition of trypanothione reductase induced strong oxidative stress in the parasites. The effects observed in promastigotes included lipoperoxidation, plasma membrane permeabilization, and apoptosis hallmarks (i.e., DNA fragmentation, phosphatidylserine exposure, and cell shrinkage). The mechanism of action in both parasitic forms was quite similar, but amastigotes also exhibited energetic stress, reflected by a reduction of adenosine triphosphate levels. Such differential effects might be attributable to the metabolic particularities of each form of the parasitic. Ultrastructural alterations of the endomembrane system and autophagy were also observed, possibly indicating an adaptive response to oxidative stress. Our results suggest that clomipramine interferes with the redox metabolism of L. amazonensis. In spite of the cellular responses to recover the cellular homeostasis, parasites underwent programmed cell death.

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Acknowledgments

We thank all the staffs of the “Laboratório de Inovação Tecnológica no Desenvolvimento de Fármacos e Cosméticos” and the “Complexo de Centrais de Apoio à Pesquisa (COMCAP-UEM)”.

Funding

This study was supported by grants of Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes), Financiadora de Estudos e Projetos (FINEP) and Programa de Núcleos de Excelência (PRONEX/Fundação Araucária).

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Authors and Affiliations

  1. Programa de Pós-Graduação em Ciências Biológicas, Área de Concentração Biologia Celular e Molecular, Universidade Estadual de Maringá, Maringá, Paraná, Brazil

    Jean Henrique da Silva Rodrigues, Hélito Volpato & Celso Vataru Nakamura

  2. Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, Paraná, Brazil

    Nathielle Miranda & Tânia Ueda-Nakamura

  3. Laboratório de Inovação Tecnológica no Desenvolvimento de Fármacos e Cosméticos, Bloco B-08, Universidade Estadual de Maringá, Av. Colombo 5790, Maringá, Paraná, CEP 87020-900, Brazil

    Celso Vataru Nakamura

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  1. Jean Henrique da Silva Rodrigues
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  2. Nathielle Miranda
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  3. Hélito Volpato
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  4. Tânia Ueda-Nakamura
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  5. Celso Vataru Nakamura
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Correspondence to Celso Vataru Nakamura.

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da Silva Rodrigues, J.H., Miranda, N., Volpato, H. et al. The antidepressant clomipramine induces programmed cell death in Leishmania amazonensis through a mitochondrial pathway. Parasitol Res 118, 977–989 (2019). https://doi.org/10.1007/s00436-018-06200-x

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  • DOI: https://doi.org/10.1007/s00436-018-06200-x

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