Evaluation of antileishmanial potential of the antidepressant escitalopram in Leishmania infantum

Neglected tropical diseases (NTDs) such as visceral leishmaniasis (VL) present a limited and toxic therapeutic arsenal, and drug repositioning represents a safe and cost-effective approach. In this work, we investigated the antileishmanial potential and the mechanism of lethal action of the antidepressant escitalopram. The efficacy of escitalopram was determined ex-vivo using the intracellular Leishmania (L.) infantum amastigote model and the mammalian cytotoxicity was determined by the colorimetric MTT assay. The cellular and molecular alterations induced by the drug were investigated using spectrofluorimetry, a luminescence assay and flow cytometry. Our data revealed that escitalopram was active and selective against L. infantum parasites, with an IC50 value of 25 mu M and a 50% cytotoxic concentration (CC50) of 184 mu M. By using the fluorescent probes SYTOX (R) Green and DiSBAC(2)(3), the drug showed no alterations in the plasma membrane permeability nor in the electric potential of the membrane (Delta psi(p)); however, after a short-time incubation, the drug caused a dose-dependent up-regulation of the calcium levels, leading to the depolarization of the mitochondrial membrane potential Delta psi(m)) and a reduction of the ATP levels. No up regulation of reactive oxygen (ROS) was observed. In the cell cycle analysis, escitalopram induced a dose dependent increase of the parasites at the sub G(0)/G(1) stage, representing fragmented DNA. Escitalopram presented a selective antileishmanial activity, with disruption of single mitochondrion and interference in the cell cycle. Approved drugs such as escitalopram may represent a promising approach for NTDs and can be considered in future animal efficacy studies. (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

This study investigates the antileishmanial potential and mechanism of action of the antidepressant escitalopram. The results show that escitalopram selectively kills the parasite by disrupting mitochondria and interfering with the cell cycle.