Flau-A, a naphthoquinone derivative, is a promising therapeutic candidate against visceral leishmaniasis: A preliminary study
Flau-A, a naphthoquinone derivative, is a promising therapeutic candidate against visceral leishmaniasis: A preliminary study
Visceral leishmaniasis (VL) is a neglected tropical disease found in tropical and subtropical regions in the world. The therapeutics used for the treatment against disease presents problems, mainly related to drug toxicity, route of administration, high cost and/or by emergence of resistant strains. In this context, the search for alternative antileishmanial candidates is desirable. Recently, a naphthoquinone derivative namely 2-(2,3,4-tri-O-acetyl-6-deoxy-β-L-galactopyranosyloxy)-1,4-naphthoquinone or Flau-A showed an effective in vitro biological action against Leishmania infantum. In the present study, the efficacy of this naphthoquinone derivative was evaluated in an in vivo infection model. BALB/c mice (n = 12 per group) were infected and later received saline or were treated with empty micelles (B/Mic), free Flau-A or it incorporated in Poloxamer 407-based micelles (Flau-A/Mic). The products were administered subcutaneously in the infected animals, which were then euthanized one (n = 6 per group) and 15 (n = 6 per group) days post-therapy, when immunological and parasitological evaluations were performed. Results showed that animals treated with Flau-A or Flau-A/Mic produced significantly higher levels of antileishmanial IFN-γ, IL-12, TNF-α, GM-CSF, nitrite and IgG2a isotype antibody, when compared to data found in the control (saline and B/Mic) groups; which showed significantly higher levels of parasite-specific IL-4, IL-10 and IgG1 antibody. In addition, animals receiving free Flau-A or Flau-A/Mic presented also significant reductions in the parasite load in their spleens, livers, bone marrows and draining lymph nodes, when compared to the controls. A low hepatic and renal toxicity was also found. Overall, Flau-A/Mic showed better immunological and parasitological results, when compared to the use of free molecule. In conclusion, preliminary data suggest that this composition could be considered in future studies as promising therapeutic candidate against VL.
Animals, Antiprotozoal Agents/chemistry, Female, Leishmania infantum/drug effects, Leishmaniasis, Visceral/drug therapy, Mice, Mice, Inbred BALB C, Micelles, Naphthoquinones/chemistry, Parasite Load, Real-Time Polymerase Chain Reaction, Spleen/parasitology
108205
Mendonça, Débora V.C.
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Tavares, Grasiele S.V.
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Pereira, Isabela A.G.
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Oliveira-da-Silva, João A
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Ramos, Fernanda F.
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Lage, Daniela P.
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Machado, Amanda S.
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Carvalho, Lívia M.
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Reis, Thiago A.R.
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Carvalho, Ana Maria R.S.
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Ottoni, Flaviano M.
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Ludolf, Fernanda
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Freitas, Camila S.
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Martins, Vívian T.
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Chávez-Fumagalli, Miguel A.
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Duarte, Mariana C.
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Humbert, Maria V.
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Roatt, Bruno M.
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Menezes-Souza, Daniel
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Alves, Ricardo J.
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Coelho, Eduardo A.F.
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February 2022
Mendonça, Débora V.C.
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Tavares, Grasiele S.V.
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Pereira, Isabela A.G.
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Oliveira-da-Silva, João A
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Ramos, Fernanda F.
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Lage, Daniela P.
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Machado, Amanda S.
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Carvalho, Lívia M.
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Reis, Thiago A.R.
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Carvalho, Ana Maria R.S.
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Ottoni, Flaviano M.
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Ludolf, Fernanda
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Freitas, Camila S.
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Martins, Vívian T.
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Chávez-Fumagalli, Miguel A.
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Duarte, Mariana C.
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Humbert, Maria V.
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Roatt, Bruno M.
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Menezes-Souza, Daniel
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Alves, Ricardo J.
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Coelho, Eduardo A.F.
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Mendonça, Débora V.C., Tavares, Grasiele S.V., Pereira, Isabela A.G., Oliveira-da-Silva, João A, Ramos, Fernanda F., Lage, Daniela P., Machado, Amanda S., Carvalho, Lívia M., Reis, Thiago A.R., Carvalho, Ana Maria R.S., Ottoni, Flaviano M., Ludolf, Fernanda, Freitas, Camila S., Martins, Vívian T., Chávez-Fumagalli, Miguel A., Duarte, Mariana C., Humbert, Maria V., Roatt, Bruno M., Menezes-Souza, Daniel, Alves, Ricardo J. and Coelho, Eduardo A.F.
(2022)
Flau-A, a naphthoquinone derivative, is a promising therapeutic candidate against visceral leishmaniasis: A preliminary study.
Experimental Parasitology, 233, , [108205].
(doi:10.1016/j.exppara.2021.108205).
Abstract
Visceral leishmaniasis (VL) is a neglected tropical disease found in tropical and subtropical regions in the world. The therapeutics used for the treatment against disease presents problems, mainly related to drug toxicity, route of administration, high cost and/or by emergence of resistant strains. In this context, the search for alternative antileishmanial candidates is desirable. Recently, a naphthoquinone derivative namely 2-(2,3,4-tri-O-acetyl-6-deoxy-β-L-galactopyranosyloxy)-1,4-naphthoquinone or Flau-A showed an effective in vitro biological action against Leishmania infantum. In the present study, the efficacy of this naphthoquinone derivative was evaluated in an in vivo infection model. BALB/c mice (n = 12 per group) were infected and later received saline or were treated with empty micelles (B/Mic), free Flau-A or it incorporated in Poloxamer 407-based micelles (Flau-A/Mic). The products were administered subcutaneously in the infected animals, which were then euthanized one (n = 6 per group) and 15 (n = 6 per group) days post-therapy, when immunological and parasitological evaluations were performed. Results showed that animals treated with Flau-A or Flau-A/Mic produced significantly higher levels of antileishmanial IFN-γ, IL-12, TNF-α, GM-CSF, nitrite and IgG2a isotype antibody, when compared to data found in the control (saline and B/Mic) groups; which showed significantly higher levels of parasite-specific IL-4, IL-10 and IgG1 antibody. In addition, animals receiving free Flau-A or Flau-A/Mic presented also significant reductions in the parasite load in their spleens, livers, bone marrows and draining lymph nodes, when compared to the controls. A low hepatic and renal toxicity was also found. Overall, Flau-A/Mic showed better immunological and parasitological results, when compared to the use of free molecule. In conclusion, preliminary data suggest that this composition could be considered in future studies as promising therapeutic candidate against VL.
Text
Flau-A accepted manuscript
- Accepted Manuscript
More information
Accepted/In Press date: 25 December 2021
e-pub ahead of print date: 28 December 2021
Published date: February 2022
Additional Information:
Funding Information:
This work was supported by grant APQ-408675/2018–7 from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and by grant APQ-02167-21 from the Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) , Brazil. The authors also thank the Brazilian agencies Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and CNPq for the student scholarships.
Publisher Copyright:
© 2021 Elsevier Inc.
Keywords:
Animals, Antiprotozoal Agents/chemistry, Female, Leishmania infantum/drug effects, Leishmaniasis, Visceral/drug therapy, Mice, Mice, Inbred BALB C, Micelles, Naphthoquinones/chemistry, Parasite Load, Real-Time Polymerase Chain Reaction, Spleen/parasitology
Identifiers
Local EPrints ID: 456041
URI: http://eprints.soton.ac.uk/id/eprint/456041
ISSN: 0014-4894
PURE UUID: 7dfb9425-1de6-41e9-b372-aebd6e7fa395
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Date deposited: 12 Apr 2022 16:50
Last modified: 17 Mar 2024 07:12
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Contributors
Author:
Débora V.C. Mendonça
Author:
Grasiele S.V. Tavares
Author:
Isabela A.G. Pereira
Author:
João A Oliveira-da-Silva
Author:
Fernanda F. Ramos
Author:
Daniela P. Lage
Author:
Amanda S. Machado
Author:
Lívia M. Carvalho
Author:
Thiago A.R. Reis
Author:
Ana Maria R.S. Carvalho
Author:
Flaviano M. Ottoni
Author:
Fernanda Ludolf
Author:
Camila S. Freitas
Author:
Vívian T. Martins
Author:
Miguel A. Chávez-Fumagalli
Author:
Mariana C. Duarte
Author:
Maria V. Humbert
Author:
Bruno M. Roatt
Author:
Daniel Menezes-Souza
Author:
Ricardo J. Alves
Author:
Eduardo A.F. Coelho
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