Leishmanicidal activity in vivo of a miltefosine derivative in Mesocricetus auratus
Visceral leishmaniasis (VL) is a chronic and systemic disease; if untreated, it can cause death in a large number of cases. The therapy is based on the use of antimonials, which have been used for over 50 years. However, cases of resistance have been reported in some countries. In this context, milt...
| Autores: | , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2020 |
| País: | Brasil |
| Institución: | Universidade Federal de Minas Gerais (UFMG) |
| Repositorio: | Repositório Institucional da UFMG |
| Idioma: | inglés |
| OAI Identifier: | oai:repositorio.ufmg.br:1843/72580 |
| Acceso en línea: | https://doi.org/10.1016/j.actatropica.2020.105539 http://hdl.handle.net/1843/72580 https://orcid.org/0000-0003-2628-0357 https://orcid.org/0000-0003-1674-818X https://orcid.org/0000-0002-4920-072X https://orcid.org/0000-0001-6974-3724 https://orcid.org/0000-0003-0546-2549 https://orcid.org/0000-0002-1596-9709 https://orcid.org/0000-0002-1080-2440 https://orcid.org/0000-0003-3459-3169 |
| Access Level: | acceso abierto |
| Palabra clave: | Miltefosine derivative Experimental treatment Visceral leishmaniasis Immune response Química farmacêutica Leishmaniose visceral Resposta imune |
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Leishmanicidal activity in vivo of a miltefosine derivative in Mesocricetus auratusMiltefosine derivativeExperimental treatmentVisceral leishmaniasisImmune responseQuímica farmacêuticaLeishmaniose visceralResposta imuneVisceral leishmaniasis (VL) is a chronic and systemic disease; if untreated, it can cause death in a large number of cases. The therapy is based on the use of antimonials, which have been used for over 50 years. However, cases of resistance have been reported in some countries. In this context, miltefosine (MIL) was introduced to treat antimonial unresponsive cases. Nonetheless, in recent years MIL unresponsive and relapse cases of VL have increasingly been reported. In the current study, the therapeutic potential of compound 5-(4-(3-methanesulfonatepropyl)-1H-1,2,3-triazol-1-yl)dodecyl methanesulfonate (C11), an MIL derivative, was assessed in an experimental VL hamster model. For this purpose, golden hamsters (Mesocricetus auratus) were infected with Leishmania (L.) infantum chagasi and treated daily for 10 days with C11 and MIL administered orally; in addition, Glucantime (GLU), peritoneal route, were administered at 15, 10, 50 mg/kg body weight/day, respectively. Twenty four hours after the end of treatment the animals were euthanatized; and the specimens were collected to evaluate the relative mRNA expression of cytokines IFN-γ, TNF-α, IL-17, TGF-β, IL-4 and IL-10 in fragments of the spleen and liver; moreover, the parasitism in these organs was evaluated as well as the main histopathological alterations. The C11-treated animals showed greater expression of IL-17 and TNF-α cytokines and reduced expression of IL-10 in the spleen in comparison to the infected untreated group (UTG) (p <0.05). The C11 and GLU groups showed a significant reduction in the IgG levels in comparison to the UTG group (p <0.05). Moreover, the C11-treated animals had fewer parasites in the spleen than the UTG animals (reduction of 95.9%), as well as a greater preservation of white pulp architecture in the spleen than the UTG, GLU and MIL groups (p <0.05). For the liver, the animals from the C11 and MIL groups showed a significant increase in TNF-α relative expression in comparison to the UTG animals, which would explain the increase in the number of granulomas and the reduction in the parasitic load (p <0.05). Combined, these findings indicate that C11 is an interesting compound that should be considered for the development of new drugs against VL, mainly due to its leishmanicidal effect and immunostimulating action.CNPq - Conselho Nacional de Desenvolvimento Científico e TecnológicoFAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas GeraisCAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorINCT – Instituto nacional de ciência e tecnologia (Antigo Instituto do Milênio)Universidade Federal de Minas GeraisBrasilICX - DEPARTAMENTO DE QUÍMICAUFMG2024-08-05T14:48:09Z2024-08-05T14:48:09Z2020info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlepdfapplication/pdfhttps://doi.org/10.1016/j.actatropica.2020.1055391873-6254http://hdl.handle.net/1843/72580https://orcid.org/0000-0003-2628-0357https://orcid.org/0000-0003-1674-818Xhttps://orcid.org/0000-0002-4920-072Xhttps://orcid.org/0000-0001-6974-3724https://orcid.org/0000-0003-0546-2549https://orcid.org/0000-0002-1596-9709https://orcid.org/0000-0002-1080-2440https://orcid.org/0000-0003-3459-3169engActa Tropicainfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGJoana C. da SilvaJuliana Barbosa NunesVanessa Silva GontijoVanessa Silva GontijoRossimiriam Pereira de FreitasRosemeire Brondi AlvesFábio Antônio ColomboMarcia Dalastra LaurentiMarcos José Marques2024-08-05T14:48:10Zoai:repositorio.ufmg.br:1843/72580Repositório InstitucionalPUBhttps://repositorio.ufmg.br/oairepositorio@ufmg.bropendoar:2024-08-05T14:48:10Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false |
| dc.title.none.fl_str_mv |
Leishmanicidal activity in vivo of a miltefosine derivative in Mesocricetus auratus |
| title |
Leishmanicidal activity in vivo of a miltefosine derivative in Mesocricetus auratus |
| spellingShingle |
Leishmanicidal activity in vivo of a miltefosine derivative in Mesocricetus auratus Joana C. da Silva Miltefosine derivative Experimental treatment Visceral leishmaniasis Immune response Química farmacêutica Leishmaniose visceral Resposta imune |
| title_short |
Leishmanicidal activity in vivo of a miltefosine derivative in Mesocricetus auratus |
| title_full |
Leishmanicidal activity in vivo of a miltefosine derivative in Mesocricetus auratus |
| title_fullStr |
Leishmanicidal activity in vivo of a miltefosine derivative in Mesocricetus auratus |
| title_full_unstemmed |
Leishmanicidal activity in vivo of a miltefosine derivative in Mesocricetus auratus |
| title_sort |
Leishmanicidal activity in vivo of a miltefosine derivative in Mesocricetus auratus |
| dc.creator.none.fl_str_mv |
Joana C. da Silva Juliana Barbosa Nunes Vanessa Silva Gontijo Vanessa Silva Gontijo Rossimiriam Pereira de Freitas Rosemeire Brondi Alves Fábio Antônio Colombo Marcia Dalastra Laurenti Marcos José Marques |
| author |
Joana C. da Silva |
| author_facet |
Joana C. da Silva Juliana Barbosa Nunes Vanessa Silva Gontijo Rossimiriam Pereira de Freitas Rosemeire Brondi Alves Fábio Antônio Colombo Marcia Dalastra Laurenti Marcos José Marques |
| author_role |
author |
| author2 |
Juliana Barbosa Nunes Vanessa Silva Gontijo Rossimiriam Pereira de Freitas Rosemeire Brondi Alves Fábio Antônio Colombo Marcia Dalastra Laurenti Marcos José Marques |
| author2_role |
author author author author author author author |
| dc.subject.por.fl_str_mv |
Miltefosine derivative Experimental treatment Visceral leishmaniasis Immune response Química farmacêutica Leishmaniose visceral Resposta imune |
| topic |
Miltefosine derivative Experimental treatment Visceral leishmaniasis Immune response Química farmacêutica Leishmaniose visceral Resposta imune |
| description |
Visceral leishmaniasis (VL) is a chronic and systemic disease; if untreated, it can cause death in a large number of cases. The therapy is based on the use of antimonials, which have been used for over 50 years. However, cases of resistance have been reported in some countries. In this context, miltefosine (MIL) was introduced to treat antimonial unresponsive cases. Nonetheless, in recent years MIL unresponsive and relapse cases of VL have increasingly been reported. In the current study, the therapeutic potential of compound 5-(4-(3-methanesulfonatepropyl)-1H-1,2,3-triazol-1-yl)dodecyl methanesulfonate (C11), an MIL derivative, was assessed in an experimental VL hamster model. For this purpose, golden hamsters (Mesocricetus auratus) were infected with Leishmania (L.) infantum chagasi and treated daily for 10 days with C11 and MIL administered orally; in addition, Glucantime (GLU), peritoneal route, were administered at 15, 10, 50 mg/kg body weight/day, respectively. Twenty four hours after the end of treatment the animals were euthanatized; and the specimens were collected to evaluate the relative mRNA expression of cytokines IFN-γ, TNF-α, IL-17, TGF-β, IL-4 and IL-10 in fragments of the spleen and liver; moreover, the parasitism in these organs was evaluated as well as the main histopathological alterations. The C11-treated animals showed greater expression of IL-17 and TNF-α cytokines and reduced expression of IL-10 in the spleen in comparison to the infected untreated group (UTG) (p <0.05). The C11 and GLU groups showed a significant reduction in the IgG levels in comparison to the UTG group (p <0.05). Moreover, the C11-treated animals had fewer parasites in the spleen than the UTG animals (reduction of 95.9%), as well as a greater preservation of white pulp architecture in the spleen than the UTG, GLU and MIL groups (p <0.05). For the liver, the animals from the C11 and MIL groups showed a significant increase in TNF-α relative expression in comparison to the UTG animals, which would explain the increase in the number of granulomas and the reduction in the parasitic load (p <0.05). Combined, these findings indicate that C11 is an interesting compound that should be considered for the development of new drugs against VL, mainly due to its leishmanicidal effect and immunostimulating action. |
| publishDate |
2020 |
| dc.date.none.fl_str_mv |
2020 2024-08-05T14:48:09Z 2024-08-05T14:48:09Z |
| dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
| dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
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article |
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publishedVersion |
| dc.identifier.uri.fl_str_mv |
https://doi.org/10.1016/j.actatropica.2020.105539 1873-6254 http://hdl.handle.net/1843/72580 https://orcid.org/0000-0003-2628-0357 https://orcid.org/0000-0003-1674-818X https://orcid.org/0000-0002-4920-072X https://orcid.org/0000-0001-6974-3724 https://orcid.org/0000-0003-0546-2549 https://orcid.org/0000-0002-1596-9709 https://orcid.org/0000-0002-1080-2440 https://orcid.org/0000-0003-3459-3169 |
| url |
https://doi.org/10.1016/j.actatropica.2020.105539 http://hdl.handle.net/1843/72580 https://orcid.org/0000-0003-2628-0357 https://orcid.org/0000-0003-1674-818X https://orcid.org/0000-0002-4920-072X https://orcid.org/0000-0001-6974-3724 https://orcid.org/0000-0003-0546-2549 https://orcid.org/0000-0002-1596-9709 https://orcid.org/0000-0002-1080-2440 https://orcid.org/0000-0003-3459-3169 |
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1873-6254 |
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eng |
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eng |
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Acta Tropica |
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info:eu-repo/semantics/openAccess |
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openAccess |
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pdf application/pdf |
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Universidade Federal de Minas Gerais Brasil ICX - DEPARTAMENTO DE QUÍMICA UFMG |
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Universidade Federal de Minas Gerais Brasil ICX - DEPARTAMENTO DE QUÍMICA UFMG |
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reponame:Repositório Institucional da UFMG instname:Universidade Federal de Minas Gerais (UFMG) instacron:UFMG |
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Universidade Federal de Minas Gerais (UFMG) |
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UFMG |
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Repositório Institucional da UFMG |
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Repositório Institucional da UFMG |
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Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG) |
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repositorio@ufmg.br |
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