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In vitro evaluation of the anti-leishmanial activity and toxicity of PK11195

BACKGROUND: Leishmaniasis, one of the most neglected diseases, is a serious public health problem in many countries, including Brazil. Currently available treatments require long-term use and have serious side effects, necessitating the development of new therapeutic interventions. Because transloca...

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Autores principales: Guedes, Carlos Eduardo Sampaio, Dias, Beatriz Rocha Simões, Petersen, Antonio Luis de Oliveira Almeida, Cruz, Kercia Pinheiro, Almeida, Niara de Jesus, Andrade, Daniela Rodrigues, de Menezes, Juliana Perrone Bezerra, Borges, Valéria de Matos, Veras, Patricia Sampaio Tavares
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Instituto Oswaldo Cruz, Ministério da Saúde 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851033/
https://www.ncbi.nlm.nih.gov/pubmed/29412342
http://dx.doi.org/10.1590/0074-02760170345
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author Guedes, Carlos Eduardo Sampaio
Dias, Beatriz Rocha Simões
Petersen, Antonio Luis de Oliveira Almeida
Cruz, Kercia Pinheiro
Almeida, Niara de Jesus
Andrade, Daniela Rodrigues
de Menezes, Juliana Perrone Bezerra
Borges, Valéria de Matos
Veras, Patricia Sampaio Tavares
author_facet Guedes, Carlos Eduardo Sampaio
Dias, Beatriz Rocha Simões
Petersen, Antonio Luis de Oliveira Almeida
Cruz, Kercia Pinheiro
Almeida, Niara de Jesus
Andrade, Daniela Rodrigues
de Menezes, Juliana Perrone Bezerra
Borges, Valéria de Matos
Veras, Patricia Sampaio Tavares
author_sort Guedes, Carlos Eduardo Sampaio
collection PubMed
description BACKGROUND: Leishmaniasis, one of the most neglected diseases, is a serious public health problem in many countries, including Brazil. Currently available treatments require long-term use and have serious side effects, necessitating the development of new therapeutic interventions. Because translocator protein (TSPO) levels are reduced in Leishmania amazonensis-infected cells and because this protein participates in apoptosis and immunomodulation, TSPO represents a potential target for Leishmania chemotherapy. The present study evaluated PK11195, a ligand of this protein, as an anti-leishmanial agent. OBJECTIVE: To evaluate the leishmanicidal activity of PK11195 against L. amazonensis in infected CBA mouse macrophages in vitro. METHODS: The viability of axenic L. amazonensis, Leishmania major, and Leishmania braziliensis promastigotes was assessed after 48 h treatment with PK11195 (0.2-400 µM). Additionally, intracellular parasite viability was evaluated to determine IC(50) values and the number of viable parasites in infected macrophages treated with PK11195 (50-100 µM). Infected macrophages were then treated with PK11195 (25-100 µM) to determine the percentage of L. amazonensis-infected cells and the number of parasites per infected cell. Electron microscopy was used to investigate morphological changes caused by PK11195. The production of free oxygen radicals, nitric oxide, and pro-inflammatory cytokines was also evaluated in infected macrophages treated with PK11195 and primed or not primed with IFN-γ. FINDINGS: Median IC(50) values for PK11195 were 14.2 µM for L. amazonensis, 8.2 µM for L. major, and 3.5 µM for L. braziliensis. The selective index value for L. amazonensis was 13.7, indicating the safety of PK11195 for future testing in mammals. Time- and dose-dependent reductions in the percentage of infected macrophages, the number of parasites per infected macrophage, and the number of viable intracellular parasites were observed. Electron microscopy revealed some morphological alterations suggestive of autophagy. Interestingly, MCP-1 and superoxide levels were reduced in L. amazonensis-infected macrophages treated with PK11195. MAIN CONCLUSIONS: PK11195 causes the killing of amastigotes in vitro by mechanisms independent of inflammatory mediators and causes morphological alterations within Leishmania parasites, suggestive of autophagy, at doses that are non-toxic to macrophages. Thus, this molecule has demonstrated potential as an anti-leishmanial agent.
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spelling pubmed-58510332018-03-20 In vitro evaluation of the anti-leishmanial activity and toxicity of PK11195 Guedes, Carlos Eduardo Sampaio Dias, Beatriz Rocha Simões Petersen, Antonio Luis de Oliveira Almeida Cruz, Kercia Pinheiro Almeida, Niara de Jesus Andrade, Daniela Rodrigues de Menezes, Juliana Perrone Bezerra Borges, Valéria de Matos Veras, Patricia Sampaio Tavares Mem Inst Oswaldo Cruz Original Article BACKGROUND: Leishmaniasis, one of the most neglected diseases, is a serious public health problem in many countries, including Brazil. Currently available treatments require long-term use and have serious side effects, necessitating the development of new therapeutic interventions. Because translocator protein (TSPO) levels are reduced in Leishmania amazonensis-infected cells and because this protein participates in apoptosis and immunomodulation, TSPO represents a potential target for Leishmania chemotherapy. The present study evaluated PK11195, a ligand of this protein, as an anti-leishmanial agent. OBJECTIVE: To evaluate the leishmanicidal activity of PK11195 against L. amazonensis in infected CBA mouse macrophages in vitro. METHODS: The viability of axenic L. amazonensis, Leishmania major, and Leishmania braziliensis promastigotes was assessed after 48 h treatment with PK11195 (0.2-400 µM). Additionally, intracellular parasite viability was evaluated to determine IC(50) values and the number of viable parasites in infected macrophages treated with PK11195 (50-100 µM). Infected macrophages were then treated with PK11195 (25-100 µM) to determine the percentage of L. amazonensis-infected cells and the number of parasites per infected cell. Electron microscopy was used to investigate morphological changes caused by PK11195. The production of free oxygen radicals, nitric oxide, and pro-inflammatory cytokines was also evaluated in infected macrophages treated with PK11195 and primed or not primed with IFN-γ. FINDINGS: Median IC(50) values for PK11195 were 14.2 µM for L. amazonensis, 8.2 µM for L. major, and 3.5 µM for L. braziliensis. The selective index value for L. amazonensis was 13.7, indicating the safety of PK11195 for future testing in mammals. Time- and dose-dependent reductions in the percentage of infected macrophages, the number of parasites per infected macrophage, and the number of viable intracellular parasites were observed. Electron microscopy revealed some morphological alterations suggestive of autophagy. Interestingly, MCP-1 and superoxide levels were reduced in L. amazonensis-infected macrophages treated with PK11195. MAIN CONCLUSIONS: PK11195 causes the killing of amastigotes in vitro by mechanisms independent of inflammatory mediators and causes morphological alterations within Leishmania parasites, suggestive of autophagy, at doses that are non-toxic to macrophages. Thus, this molecule has demonstrated potential as an anti-leishmanial agent. Instituto Oswaldo Cruz, Ministério da Saúde 2018-02-05 /pmc/articles/PMC5851033/ /pubmed/29412342 http://dx.doi.org/10.1590/0074-02760170345 Text en https://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Guedes, Carlos Eduardo Sampaio
Dias, Beatriz Rocha Simões
Petersen, Antonio Luis de Oliveira Almeida
Cruz, Kercia Pinheiro
Almeida, Niara de Jesus
Andrade, Daniela Rodrigues
de Menezes, Juliana Perrone Bezerra
Borges, Valéria de Matos
Veras, Patricia Sampaio Tavares
In vitro evaluation of the anti-leishmanial activity and toxicity of PK11195
title In vitro evaluation of the anti-leishmanial activity and toxicity of PK11195
title_full In vitro evaluation of the anti-leishmanial activity and toxicity of PK11195
title_fullStr In vitro evaluation of the anti-leishmanial activity and toxicity of PK11195
title_full_unstemmed In vitro evaluation of the anti-leishmanial activity and toxicity of PK11195
title_short In vitro evaluation of the anti-leishmanial activity and toxicity of PK11195
title_sort in vitro evaluation of the anti-leishmanial activity and toxicity of pk11195
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851033/
https://www.ncbi.nlm.nih.gov/pubmed/29412342
http://dx.doi.org/10.1590/0074-02760170345
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