TY - JOUR
T1 - In vitro and in vivo antileishmanial activity of β-acetyl-digitoxin, a cardenolide of Digitalis lanata potentially useful to treat visceral leishmaniasis
AU - Freitas, Camila S.
AU - Lage, Daniela P.
AU - Oliveira-Da-Silva, João A.
AU - Costa, Rafaella R.
AU - Mendonça, Débora V.C.
AU - Martins, Vívian T.
AU - Reis, Thiago A.R.
AU - Antinarelli, Luciana M.R.
AU - Machado, Amanda S.
AU - Tavares, Grasiele S.V.
AU - Ramos, Fernanda F.
AU - Brito, Rory C.F.
AU - Ludolf, Fernanda
AU - Chávez-Fumagalli, Miguel A.
AU - Roatt, Bruno M.
AU - Ramos, Gabriela S.
AU - Munkert, Jennifer
AU - Ottoni, Flaviano M.
AU - Campana, Priscilla R.V.
AU - Duarte, Mariana C.
AU - Gonçalves, Denise U.
AU - Coimbra, Elaine S.
AU - Braga, Fernão C.
AU - Pádua, Rodrigo M.
AU - Coelho, Eduardo A.F.
N1 - Publisher Copyright:
© C.S. Freitas et al., published by EDP Sciences, 2021.
PY - 2021
Y1 - 2021
N2 - Current treatments of visceral leishmaniasis face limitations due to drug side effects and/or high cost, along with the emergence of parasite resistance. Novel and low-cost antileishmanial agents are therefore required. We report herein the antileishmanial activity of β-acetyl-digitoxin (b-AD), a cardenolide isolated from Digitalis lanata leaves, assayed in vitro and in vivo against Leishmania infantum. Results showed direct action of b-AD against parasites, as well as efficacy for the treatment of Leishmania-infected macrophages. In vivo experiments using b-AD-containing Pluronic® F127 polymeric micelles (b-AD/Mic) to treat L. infantum-infected mice showed that this composition reduced the parasite load in distinct organs in more significant levels. It also induced the development of anti-parasite Th1-type immunity, attested by high levels of IFN-γ, IL-12, TNF-α, GM-CSF, nitrite and specific IgG2a antibodies, in addition to low IL-4 and IL-10 contents, along with higher IFN-γ-producing CD4+ and CD8+ T-cell frequency. Furthermore, low toxicity was found in the organs of the treated animals. Comparing the therapeutic effect between the treatments, b-AD/Mic was the most effective in protecting animals against infection, when compared to the other groups including miltefosine used as a drug control. Data found 15 days after treatment were similar to those obtained one day post-therapy. In conclusion, the results obtained suggest that b-AD/Mic is a promising antileishmanial agent and deserves further studies to investigate its potential to treat visceral leishmaniasis.
AB - Current treatments of visceral leishmaniasis face limitations due to drug side effects and/or high cost, along with the emergence of parasite resistance. Novel and low-cost antileishmanial agents are therefore required. We report herein the antileishmanial activity of β-acetyl-digitoxin (b-AD), a cardenolide isolated from Digitalis lanata leaves, assayed in vitro and in vivo against Leishmania infantum. Results showed direct action of b-AD against parasites, as well as efficacy for the treatment of Leishmania-infected macrophages. In vivo experiments using b-AD-containing Pluronic® F127 polymeric micelles (b-AD/Mic) to treat L. infantum-infected mice showed that this composition reduced the parasite load in distinct organs in more significant levels. It also induced the development of anti-parasite Th1-type immunity, attested by high levels of IFN-γ, IL-12, TNF-α, GM-CSF, nitrite and specific IgG2a antibodies, in addition to low IL-4 and IL-10 contents, along with higher IFN-γ-producing CD4+ and CD8+ T-cell frequency. Furthermore, low toxicity was found in the organs of the treated animals. Comparing the therapeutic effect between the treatments, b-AD/Mic was the most effective in protecting animals against infection, when compared to the other groups including miltefosine used as a drug control. Data found 15 days after treatment were similar to those obtained one day post-therapy. In conclusion, the results obtained suggest that b-AD/Mic is a promising antileishmanial agent and deserves further studies to investigate its potential to treat visceral leishmaniasis.
KW - Drug repositioning
KW - Miltefosine
KW - Toxicity
KW - Treatment
KW - Visceral leishmaniasis
KW - β-acetyl-digitoxin
UR - http://www.scopus.com/inward/record.url?scp=85104268221&partnerID=8YFLogxK
U2 - 10.1051/parasite/2021036
DO - 10.1051/parasite/2021036
M3 - Article
C2 - 33851916
AN - SCOPUS:85104268221
SN - 1252-607X
VL - 28
JO - Parasite
JF - Parasite
M1 - 200128
ER -