In vitro and in vivo antileishmanial activity of β-acetyl-digitoxin, a cardenolide of Digitalis lanata potentially useful to treat visceral leishmaniasis

Freitas C.S.; Lage D.P.; Oliveira-Da-Silva J.A.; Costa R.R.; Mendonça D.V.C.; Martins V.T.; Reis T.A.R.; Antinarelli L.M.R.; Machado A.S.; Tavares G.S.V.; Ramos F.F.; Brito R.C.F.; Ludolf F.; Chávez-Fumagalli M.A.; Roatt B.M.; Ramos G.S.; Munkert J.; Ottoni F.M.; Campana P.R.V.; Duarte M.C.; Gonçalves D.U.; Coimbra E.S.; Braga F.C.; Pádua R.M.; Coelho E.A.F. · Parasite (2021) · DOI: 10.1051/parasite/2021036

Resumen

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. © C.S. Freitas et al., published by EDP Sciences, 2021.

Instituciones: Universidad Católica de Santa María