TY - JOUR
T1 - Acarbose presents in vitro and in vivo antileishmanial activity against Leishmania infantum and is a promising therapeutic candidate against visceral leishmaniasis
AU - Costa, Rafaella R.
AU - Oliveira-da-Silva, João A.
AU - Reis, Thiago A.R.
AU - Tavares, Grasiele S.V.
AU - Mendonça, Débora V.C.
AU - Freitas, Camila S.
AU - Lage, Daniela P.
AU - Martins, Vívian T.
AU - Antinarelli, Luciana M.R.
AU - Machado, Amanda S.
AU - Bandeira, Raquel S.
AU - Ludolf, Fernanda
AU - Santos, Thaís T.O.
AU - Brito, Rory C.F.
AU - Humbert, Maria V.
AU - Menezes-Souza, Daniel
AU - Duarte, Mariana C.
AU - Chávez-Fumagalli, Miguel A.
AU - Roatt, Bruno M.
AU - Coimbra, Elaine S.
AU - Coelho, Eduardo A.F.
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
KW - Acarbose
KW - Drug repositioning
KW - Leishmania infantum
KW - Miltefosine
KW - Treatment
KW - Visceral leishmaniasis
UR - http://www.scopus.com/inward/record.url?scp=85104872696&partnerID=8YFLogxK
U2 - 10.1007/s00430-021-00707-4
DO - 10.1007/s00430-021-00707-4
M3 - Article
C2 - 33870453
AN - SCOPUS:85104872696
SN - 0300-8584
VL - 210
SP - 133
EP - 147
JO - Medical Microbiology and Immunology
JF - Medical Microbiology and Immunology
IS - 2-3
ER -