Cyclobenzaprine Raises ROS Levels in Leishmania infantum and Reduces Parasite Burden in Infected Mice.
The leishmanicidal action of tricyclic antidepressants has been studied and evidences have pointed that their action is linked to inhibition of trypanothione reductase, a key enzyme in the redox metabolism of pathogenic trypanosomes. Cyclobenzaprine (CBP) is a tricyclic structurally related to the a...
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ftdoajarticles:oai:doaj.org/article:28c6132da48d4a5bbb3836defb2f027e 2023-05-15T15:18:21+02:00 Cyclobenzaprine Raises ROS Levels in Leishmania infantum and Reduces Parasite Burden in Infected Mice. Edézio Ferreira Cunha-Júnior Valter Viana Andrade-Neto Marta Lopes Lima Thais Alves da Costa-Silva Andres J Galisteo Junior Maria A Abengózar Coral Barbas Luis Rivas Elmo Eduardo Almeida-Amaral Andre Gustavo Tempone Eduardo Caio Torres-Santos 2017-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0005281 https://doaj.org/article/28c6132da48d4a5bbb3836defb2f027e EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC5234845?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0005281 https://doaj.org/article/28c6132da48d4a5bbb3836defb2f027e PLoS Neglected Tropical Diseases, Vol 11, Iss 1, p e0005281 (2017) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2017 ftdoajarticles https://doi.org/10.1371/journal.pntd.0005281 2022-12-31T16:29:37Z The leishmanicidal action of tricyclic antidepressants has been studied and evidences have pointed that their action is linked to inhibition of trypanothione reductase, a key enzyme in the redox metabolism of pathogenic trypanosomes. Cyclobenzaprine (CBP) is a tricyclic structurally related to the antidepressant amitriptyline, differing only by the presence of a double bond in the central ring. This paper describes the effect of CBP in experimental visceral leishmaniasis, its inhibitory effect in trypanothione reductase and the potential immunomodulatory activity.In vitro antileishmanial activity was determined in promastigotes and in L. infantum-infected macrophages. For in vivo studies, L. infantum-infected BALB/c mice were treated with CBP by oral gavage for five days and the parasite load was estimated. Trypanothione reductase activity was assessed in the soluble fraction of promastigotes of L. infantum. For evaluation of cytokines, L. infantum-infected macrophages were co-cultured with BALB/c splenocytes and treated with CBP for 48 h. The supernatant was analyzed for IL-6, IL-10, MCP-1, IFN-γ and TNF-α. CBP demonstrated an IC50 of 14.5±1.1μM and an IC90 of 74.5±1.2 μM in promastigotes and an IC50 of 12.6±1.05 μM and an IC90 of 28.7±1.3 μM in intracellular amastigotes. CBP also reduced the parasite load in L. infantum-infected mice by 40.4±10.3% and 66.7±10.5% in spleen at 24.64 and 49.28 mg/kg, respectively and by 85.6±5.0 and 89.3±4.8% in liver at 24.64 and 49.28mg/kg, after a short-term treatment. CBP inhibited the trypanothione reductase activity with a Ki of 86 ± 7.7 μM and increased the ROS production in promastigotes. CBP inhibited in 53% the production of IL-6 in infected macrophages co-culture.To the best of our knowledge, this study is the first report of the in vivo antileishmanial activity of the FDA-approved drug CBP. Modulation of immune response and induction of oxidative stress in parasite seem to contribute to this efficacy. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 11 1 e0005281 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Edézio Ferreira Cunha-Júnior Valter Viana Andrade-Neto Marta Lopes Lima Thais Alves da Costa-Silva Andres J Galisteo Junior Maria A Abengózar Coral Barbas Luis Rivas Elmo Eduardo Almeida-Amaral Andre Gustavo Tempone Eduardo Caio Torres-Santos Cyclobenzaprine Raises ROS Levels in Leishmania infantum and Reduces Parasite Burden in Infected Mice. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
The leishmanicidal action of tricyclic antidepressants has been studied and evidences have pointed that their action is linked to inhibition of trypanothione reductase, a key enzyme in the redox metabolism of pathogenic trypanosomes. Cyclobenzaprine (CBP) is a tricyclic structurally related to the antidepressant amitriptyline, differing only by the presence of a double bond in the central ring. This paper describes the effect of CBP in experimental visceral leishmaniasis, its inhibitory effect in trypanothione reductase and the potential immunomodulatory activity.In vitro antileishmanial activity was determined in promastigotes and in L. infantum-infected macrophages. For in vivo studies, L. infantum-infected BALB/c mice were treated with CBP by oral gavage for five days and the parasite load was estimated. Trypanothione reductase activity was assessed in the soluble fraction of promastigotes of L. infantum. For evaluation of cytokines, L. infantum-infected macrophages were co-cultured with BALB/c splenocytes and treated with CBP for 48 h. The supernatant was analyzed for IL-6, IL-10, MCP-1, IFN-γ and TNF-α. CBP demonstrated an IC50 of 14.5±1.1μM and an IC90 of 74.5±1.2 μM in promastigotes and an IC50 of 12.6±1.05 μM and an IC90 of 28.7±1.3 μM in intracellular amastigotes. CBP also reduced the parasite load in L. infantum-infected mice by 40.4±10.3% and 66.7±10.5% in spleen at 24.64 and 49.28 mg/kg, respectively and by 85.6±5.0 and 89.3±4.8% in liver at 24.64 and 49.28mg/kg, after a short-term treatment. CBP inhibited the trypanothione reductase activity with a Ki of 86 ± 7.7 μM and increased the ROS production in promastigotes. CBP inhibited in 53% the production of IL-6 in infected macrophages co-culture.To the best of our knowledge, this study is the first report of the in vivo antileishmanial activity of the FDA-approved drug CBP. Modulation of immune response and induction of oxidative stress in parasite seem to contribute to this efficacy. |
format |
Article in Journal/Newspaper |
author |
Edézio Ferreira Cunha-Júnior Valter Viana Andrade-Neto Marta Lopes Lima Thais Alves da Costa-Silva Andres J Galisteo Junior Maria A Abengózar Coral Barbas Luis Rivas Elmo Eduardo Almeida-Amaral Andre Gustavo Tempone Eduardo Caio Torres-Santos |
author_facet |
Edézio Ferreira Cunha-Júnior Valter Viana Andrade-Neto Marta Lopes Lima Thais Alves da Costa-Silva Andres J Galisteo Junior Maria A Abengózar Coral Barbas Luis Rivas Elmo Eduardo Almeida-Amaral Andre Gustavo Tempone Eduardo Caio Torres-Santos |
author_sort |
Edézio Ferreira Cunha-Júnior |
title |
Cyclobenzaprine Raises ROS Levels in Leishmania infantum and Reduces Parasite Burden in Infected Mice. |
title_short |
Cyclobenzaprine Raises ROS Levels in Leishmania infantum and Reduces Parasite Burden in Infected Mice. |
title_full |
Cyclobenzaprine Raises ROS Levels in Leishmania infantum and Reduces Parasite Burden in Infected Mice. |
title_fullStr |
Cyclobenzaprine Raises ROS Levels in Leishmania infantum and Reduces Parasite Burden in Infected Mice. |
title_full_unstemmed |
Cyclobenzaprine Raises ROS Levels in Leishmania infantum and Reduces Parasite Burden in Infected Mice. |
title_sort |
cyclobenzaprine raises ros levels in leishmania infantum and reduces parasite burden in infected mice. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2017 |
url |
https://doi.org/10.1371/journal.pntd.0005281 https://doaj.org/article/28c6132da48d4a5bbb3836defb2f027e |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 11, Iss 1, p e0005281 (2017) |
op_relation |
http://europepmc.org/articles/PMC5234845?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0005281 https://doaj.org/article/28c6132da48d4a5bbb3836defb2f027e |
op_doi |
https://doi.org/10.1371/journal.pntd.0005281 |
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PLOS Neglected Tropical Diseases |
container_volume |
11 |
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1 |
container_start_page |
e0005281 |
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