Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/25026
Title: In vitro evaluation of the anti-leishmanial activity and toxicity of PK11195
Authors: Guedes, Carlos Eduardo Sampaio
Dias, Beatriz Rocha Simões
Petersen, Antonio Luis de Oliveira Almeida
Cruz, Kercia Pinheiro
Almeida, Niara de Jesus
Andrade, Daniela Rodrigues
Menezes, Juliana Perrone Bezerra de
Borges, Valéria de Matos
Veras, Patricia Sampaio Tavares
Affilliation: Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Patologia e Biointervenção. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Patologia e Biointervenção. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Patologia e Biointervenção. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Patologia e Biointervenção. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Patologia e Biointervenção. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório Integrado de Microbiologia e Imunoregulação. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Patologia e Biointervenção. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório Integrado de Microbiologia e Imunoregulação. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Patologia e Biointervenção. Salvador, BA, Brasil
Abstract: 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 IC50 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 IC50 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.
Keywords: PK11195
Leishmania amazonensis -
Macrophages
Chemotherapy
keywords: PK11195
Leishmania amazonensis
Macrófagos
Quimioterapia
Issue Date: 2018
Publisher: Instituto Oswaldo Cruz
Citation: GUEDES, C. E. S. et al. In vitro evaluation of the anti-leishmanial activity and toxicity of PK11195. Memórias do Instituto Oswaldo Cruz, v. 113, n. 4, p. e170345, 2018.
DOI: 10.1590/0074-02760170345
ISSN: 0074-0276
Copyright: open access
Appears in Collections:BA - IGM - Artigos de Periódicos

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