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Parasitol Res. 2019 Mar;118(3):977-989. doi: 10.1007/s00436-018-06200-x. Epub 2019 Jan 29.

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

Author information

1
Programa de Pós-Graduação em Ciências Biológicas, Área de Concentração Biologia Celular e Molecular, Universidade Estadual de Maringá, Maringá, Paraná, Brazil.
2
Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, Paraná, Brazil.
3
Programa de Pós-Graduação em Ciências Biológicas, Área de Concentração Biologia Celular e Molecular, Universidade Estadual de Maringá, Maringá, Paraná, Brazil. cvnakamura@uem.br.
4
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. cvnakamura@uem.br.

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.

KEYWORDS:

Apoptosis; Intracellular amastigotes isolation; Leishmaniasis; Oxidative stress; Repositioning; Repurposing

PMID:
30694414
DOI:
10.1007/s00436-018-06200-x

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