title: Treatment of murine visceral leishmaniasis using an 8-hydroxyquinoline-containing polymeric micelle system.
abstract: New therapeutics are urgently needed to treat visceral leishmaniasis (VL). Due to the fact that drug discovery is a long and expensive process, the development of delivery systems to carry old and toxic drugs could be considered, as well as the evaluation of new molecules that have already shown to present biological activity. In this context, the present study evaluated the in vitro and in vivo antileishmanial activity of an 8-hydroxyquinoline (8-HQN)-containing polymeric micelle (8-HQN/M) system against Leishmania infantum, the main causative agent of VL in the Americas. The experimental strategy used was based on the evaluation of the parasite load by a limiting-dilution technique in the spleen, liver, bone marrow and draining lymph nodes of the infected and treated animals, as well as by a quantitative PCR (qPCR) technique to also assess the splenic parasite load. The immune response developed was evaluated by the production of IFN-γ, IL-4, IL-10, IL-12 and GM-CSF cytokines, as well as by antileishmanial nitrite dosage and antibodies production. Hepatic and renal enzymes were also investigated to verify cellular injury as a result of treatments toxicity. In the results, 8-HQN/M-treated mice, when compared to the other groups: saline, free amphotericin B (AmpB, as a drug control), 8-HQN and B-8-HQN/M (as a micelle control) showed more significant reductions in their parasite burden in all evaluated organs. These animals also showed an antileishmanial Th1 immunity, which was represented by high levels of IFN-γ, IL-12, GM-CSF and nitrite, associated with a low production of IL-4 and IL-10 and anti-Leishmania IgG1 isotype antibodies. In addition, any hepatic or renal damage was found in these treated animals. In conclusion, 8-HQN/M was effective in treating L. infantum-infected BALB/c mice, and can be considered alone, or combined with other drugs, as an alternative treatment for VL.
authors.affiliation: Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brazil; Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Minas Gerais, Brazil.
authors.forename: Mariana Costa
authors.initials: MC
authors.lastname: Duarte
authors.affiliation: Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brazil.
authors.forename: Letícia Martins Dos Reis
authors.initials: LM
authors.lastname: Lage
authors.affiliation: Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Minas Gerais, Brazil.
authors.forename: Daniela Pagliara
authors.initials: DP
authors.lastname: Lage
authors.affiliation: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brazil.
authors.forename: Vívian Tamietti
authors.initials: VT
authors.lastname: Martins
authors.affiliation: Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brazil.
authors.forename: Ana Maria Ravena Severino
authors.initials: AM
authors.lastname: Carvalho
authors.affiliation: Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brazil.
authors.forename: Bruno Mendes
authors.initials: BM
authors.lastname: Roatt
authors.affiliation: Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brazil; Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Minas Gerais, Brazil.
authors.forename: Daniel
authors.initials: D
authors.lastname: Menezes-Souza
authors.affiliation: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brazil.
authors.forename: Carlos Alberto Pereira
authors.initials: CA
authors.lastname: Tavares
authors.affiliation: Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brazil.
authors.forename: Ricardo José
authors.initials: RJ
authors.lastname: Alves
authors.affiliation: Departamento de Farmácia, Escola de Farmácia, Universidade Federal de Ouro Preto, Ouro Preto 35400-000, Minas Gerais, Brazil; Laboratório de Tecnologia Farmacêutica, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas. Campus Capão do Leão, S/N, 96900-010 Pelotas, RS, Brazil.
authors.forename: José Mário
authors.initials: JM
authors.lastname: Barichello
authors.affiliation: Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brazil; Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Minas Gerais, Brazil. Electronic address: eduardoferrazcoelho@yahoo.com.br.
authors.forename: Eduardo Antonio Ferraz
authors.initials: EA
authors.lastname: Coelho
mesh_terms: D000666:Amphotericin B / Q000627:therapeutic use; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D000977:Antiparasitic Agents / Q000627:therapeutic use*; D004337:Drug Carriers / Q000627:therapeutic use*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D018314:Leishmania infantum / Q000187:drug effects* / Q000276:immunology; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D015125:Oxyquinoline / Q000627:therapeutic use*; D059208:Parasite Load
chemical_list: D000913:Antibodies, Protozoan; D000977:Antiparasitic Agents; D004337:Drug Carriers; D007074:Immunoglobulin G; D008823:Micelles; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D015125:Oxyquinoline; D000666:Amphotericin B; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: 8-Hydroxyquinoline; Leishmania infantum; Poloxamer P407; Toxicity; Treatment; Visceral leishmaniasis