The University of Southampton
University of Southampton Institutional Repository

Acarbose presents in vitro and in vivo antileishmanial activity against Leishmania infantum and is a promising therapeutic candidate against visceral leishmaniasis

Acarbose presents in vitro and in vivo antileishmanial activity against Leishmania infantum and is a promising therapeutic candidate against visceral leishmaniasis
Acarbose presents in vitro and in vivo antileishmanial activity against Leishmania infantum and is a promising therapeutic candidate against visceral leishmaniasis

Treatment against visceral leishmaniasis (VL) is mainly hampered by drug toxicity, long treatment regimens and/or high costs. Thus, the identification of novel and low-cost antileishmanial agents is urgent. Acarbose (ACA) is a specific inhibitor of glucosidase-like proteins, which has been used for treating diabetes. In the present study, we show that this molecule also presents in vitro and in vivo specific antileishmanial activity against Leishmania infantum. Results showed an in vitro direct action against L. infantum promastigotes and amastigotes, and low toxicity to mammalian cells. In addition, in vivo experiments performed using free ACA or incorporated in a Pluronic ® F127-based polymeric micelle system called ACA/Mic proved effective for the treatment of L. infantum-infected BALB/c mice. Treated animals presented significant reductions in the parasite load in their spleens, livers, bone marrows and draining lymph nodes when compared to the controls, as well as the development of antileishmanial Th1-type humoral and cellular responses based on high levels of IFN-γ, IL-12, TNF-α, GM-CSF, nitrite and IgG2a isotype antibodies. In addition, ACA or ACA-treated animals suffered from low organ toxicity. Treatment with ACA/Mic outperformed treatments using either Miltefosine or free ACA based on parasitological and immunological evaluations performed one and 15 days post-therapy. In conclusion, data suggest that the ACA/Mic is a potential therapeutic agent against L. infantum and merits further consideration for VL treatment.

Acarbose, Drug repositioning, Leishmania infantum, Miltefosine, Treatment, Visceral leishmaniasis
133-147
Costa, Rafaella R
79f68a36-2d38-421b-b555-d33c2cafbd06
Oliveira-da-Silva, Joao A
4f01f951-9cb5-4276-bd77-454ce43edf42
Reis, Thiago A.R.
d686af7d-6970-47ba-ac0c-fe4d796edb23
Tavares, Grasiele S.V.
fc7d96b8-844a-4ed9-8828-a3b97c891e05
Mendonca, Debora V.C.
8a2037ac-d816-49a4-9a10-add64485a340
Freitas, Camila S.
de050131-f325-4793-920c-db2bc3b13c5d
Lage, Daniela P
7748210f-98a7-4cc0-8d81-a06157865ab7
Martins, Vivian T.
e98e64d9-a3a0-4bfb-8ad3-a39144a7c607
Antinarelli, Luciana M.R.
7e416030-b50f-4f4e-89e7-30990eea9370
Sanchez Machado, Amanda
c8ade693-7d20-4447-be3f-cde9b9784bc1
Bandeira, Raquel S
19354e60-f553-4402-8bcf-b4b018d6f2d6
Ludolf, Fernanda
0e932908-e3e2-4d45-8c76-b2d860dcc115
Santos, Thais T.O.
3ce71063-c658-41d7-96a5-d0f1237b4e90
Brito, Rory C.F.
c417614b-f907-4e41-898a-ee3dd3651e55
Humbert, Maria
82134d25-24b8-4fdd-bd1c-461683b5322e
Menezes-Souza, Daniel
75a3d802-9ed2-4979-8997-8257c7d04824
Duarte, Mariana C
28152341-ffee-4906-8b8c-3ecc8e949bea
Chavez-Fumagalli, Miguel A
3c304c5d-f941-4fe7-98c7-fdabbbc1f504
Roatt, Bruno M.
83d5162d-a48a-4f4e-89e4-b6167ae34b7d
Coimbra, Elaine S
30ac4c4d-fde6-4a29-a60a-96e47c12822b
Ferraz Coelho, Eduardo Antonio
5e5a4bbe-2ad1-499d-aae2-bf3697f72924
Costa, Rafaella R
79f68a36-2d38-421b-b555-d33c2cafbd06
Oliveira-da-Silva, Joao A
4f01f951-9cb5-4276-bd77-454ce43edf42
Reis, Thiago A.R.
d686af7d-6970-47ba-ac0c-fe4d796edb23
Tavares, Grasiele S.V.
fc7d96b8-844a-4ed9-8828-a3b97c891e05
Mendonca, Debora V.C.
8a2037ac-d816-49a4-9a10-add64485a340
Freitas, Camila S.
de050131-f325-4793-920c-db2bc3b13c5d
Lage, Daniela P
7748210f-98a7-4cc0-8d81-a06157865ab7
Martins, Vivian T.
e98e64d9-a3a0-4bfb-8ad3-a39144a7c607
Antinarelli, Luciana M.R.
7e416030-b50f-4f4e-89e7-30990eea9370
Sanchez Machado, Amanda
c8ade693-7d20-4447-be3f-cde9b9784bc1
Bandeira, Raquel S
19354e60-f553-4402-8bcf-b4b018d6f2d6
Ludolf, Fernanda
0e932908-e3e2-4d45-8c76-b2d860dcc115
Santos, Thais T.O.
3ce71063-c658-41d7-96a5-d0f1237b4e90
Brito, Rory C.F.
c417614b-f907-4e41-898a-ee3dd3651e55
Humbert, Maria
82134d25-24b8-4fdd-bd1c-461683b5322e
Menezes-Souza, Daniel
75a3d802-9ed2-4979-8997-8257c7d04824
Duarte, Mariana C
28152341-ffee-4906-8b8c-3ecc8e949bea
Chavez-Fumagalli, Miguel A
3c304c5d-f941-4fe7-98c7-fdabbbc1f504
Roatt, Bruno M.
83d5162d-a48a-4f4e-89e4-b6167ae34b7d
Coimbra, Elaine S
30ac4c4d-fde6-4a29-a60a-96e47c12822b
Ferraz Coelho, Eduardo Antonio
5e5a4bbe-2ad1-499d-aae2-bf3697f72924

Costa, Rafaella R, Oliveira-da-Silva, Joao A, Reis, Thiago A.R., Tavares, Grasiele S.V., Mendonca, Debora V.C., Freitas, Camila S., Lage, Daniela P, Martins, Vivian T., Antinarelli, Luciana M.R., Sanchez Machado, Amanda, Bandeira, Raquel S, Ludolf, Fernanda, Santos, Thais T.O., Brito, Rory C.F., Humbert, Maria, Menezes-Souza, Daniel, Duarte, Mariana C, Chavez-Fumagalli, Miguel A, Roatt, Bruno M., Coimbra, Elaine S and Ferraz Coelho, Eduardo Antonio (2021) Acarbose presents in vitro and in vivo antileishmanial activity against Leishmania infantum and is a promising therapeutic candidate against visceral leishmaniasis. Medical Microbiology and Immunology, 210 (2-3), 133-147. (doi:10.1007/s00430-021-00707-4).

Record type: Article

Abstract

Treatment against visceral leishmaniasis (VL) is mainly hampered by drug toxicity, long treatment regimens and/or high costs. Thus, the identification of novel and low-cost antileishmanial agents is urgent. Acarbose (ACA) is a specific inhibitor of glucosidase-like proteins, which has been used for treating diabetes. In the present study, we show that this molecule also presents in vitro and in vivo specific antileishmanial activity against Leishmania infantum. Results showed an in vitro direct action against L. infantum promastigotes and amastigotes, and low toxicity to mammalian cells. In addition, in vivo experiments performed using free ACA or incorporated in a Pluronic ® F127-based polymeric micelle system called ACA/Mic proved effective for the treatment of L. infantum-infected BALB/c mice. Treated animals presented significant reductions in the parasite load in their spleens, livers, bone marrows and draining lymph nodes when compared to the controls, as well as the development of antileishmanial Th1-type humoral and cellular responses based on high levels of IFN-γ, IL-12, TNF-α, GM-CSF, nitrite and IgG2a isotype antibodies. In addition, ACA or ACA-treated animals suffered from low organ toxicity. Treatment with ACA/Mic outperformed treatments using either Miltefosine or free ACA based on parasitological and immunological evaluations performed one and 15 days post-therapy. In conclusion, data suggest that the ACA/Mic is a potential therapeutic agent against L. infantum and merits further consideration for VL treatment.

Text
Final manuscript - Accepted Manuscript
Download (247kB)

More information

Submitted date: 16 September 2020
Accepted/In Press date: 3 April 2021
Published date: 18 April 2021
Additional Information: Funding Information: This work was supported by Grant MR/R005850/1 from the Medical Research Council (VAccine deveLopment for complex Intracellular neglecteD pAThogEns—VALIDATE), UK, and Grant APQ-408675/2018-7 from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil. The authors also thank the Brazilian agencies Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), CNPq and the Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) for the student scholarships. Funding Information: This work was supported by Grant MR/R005850/1 from the Medical Research Council (VAccine deveLopment for complex Intracellular neglecteD pAThogEns?VALIDATE), UK, and Grant APQ-408675/2018-7 from the Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (CNPq), Brazil. The authors also thank the Brazilian agencies Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES), CNPq and the Funda??o de Amparo ? Pesquisa do Estado de Minas Gerais (FAPEMIG) for the student scholarships. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Keywords: Acarbose, Drug repositioning, Leishmania infantum, Miltefosine, Treatment, Visceral leishmaniasis

Identifiers

Local EPrints ID: 449965
URI: http://eprints.soton.ac.uk/id/eprint/449965
PURE UUID: b35fd1ed-ca90-4580-9a7b-f443a92ac6c6
ORCID for Maria Humbert: ORCID iD orcid.org/0000-0002-5728-6981

Catalogue record

Date deposited: 30 Jun 2021 16:31
Last modified: 17 Mar 2024 06:38

Export record

Altmetrics

Contributors

Author: Rafaella R Costa
Author: Joao A Oliveira-da-Silva
Author: Thiago A.R. Reis
Author: Grasiele S.V. Tavares
Author: Debora V.C. Mendonca
Author: Camila S. Freitas
Author: Daniela P Lage
Author: Vivian T. Martins
Author: Luciana M.R. Antinarelli
Author: Amanda Sanchez Machado
Author: Raquel S Bandeira
Author: Fernanda Ludolf
Author: Thais T.O. Santos
Author: Rory C.F. Brito
Author: Maria Humbert ORCID iD
Author: Daniel Menezes-Souza
Author: Mariana C Duarte
Author: Miguel A Chavez-Fumagalli
Author: Bruno M. Roatt
Author: Elaine S Coimbra
Author: Eduardo Antonio Ferraz Coelho

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×