Efficacy of Spironolactone Treatment in Murine Models of Cutaneous and Visceral Leishmaniasis

TY - JOUR

T1 - Efficacy of Spironolactone Treatment in Murine Models of Cutaneous and Visceral Leishmaniasis

AU - Andrade-Neto, Valter Viana

AU - da Silva Pacheco, Juliana

AU - Inácio, Job Domingos

AU - Almeida-Amaral, Elmo Eduardo

AU - Torres-Santos, Eduardo Caio

AU - Cunha-Junior, Edezio Ferreira

N1 - This work was supported by Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) through fellowships E-26/202.348/2017 awarded to VVAN and E-26/202.371/2019 awarded to EFCJ (pós-doutorado nota 10), grant E-26/202.918/2018 awarded to ECTS (Cientista do Nosso Estado), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) grant 438858/2018-2 awarded to EFCJ, and Fundação Oswaldo Cruz (FIOCRUZ). E.E.A-A. was the recipient of a research fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). J.D.F.I. was a recipient of a postdoctoral fellowship from Fundação Oswaldo Cruz (FIOCRUZ). All funders are governmental non-profit foundations that support research in Brazil.

PY - 2021/4/13

Y1 - 2021/4/13

N2 - Translational studies involving the reuse and association of drugs are approaches that can result in higher success rates in the discovery and development of drugs for serious public health problems, including leishmaniasis. If we consider the number of pathogenic species in relation to therapeutic options, this arsenal is still small, and each drug possesses a disadvantage in terms of toxicity, efficacy, price, or treatment regimen. In the search for new drugs, we performed a drug screening of L. amazonensis promastigotes and intracellular amastigotes of fifty available drugs belonging to several classes according to their pharmacophoric group. Spironolactone, a potassium-sparing diuretic, proved to be the most promising drug candidate. After demonstrating the in vitro antileishmanial activity, we evaluated the efficacy on a murine experimental model with L. amazonensis and L. infantum. The treatment controlled the cutaneous lesion and reduced the parasite burden of L. amazonensis significantly, as effectively as meglumine antimoniate. The treatment of experimental visceral leishmaniasis was effective in reducing the parasite load on the main affected organs (spleen and liver) via high doses of spironolactone. The association between spironolactone and meglumine antimoniate promoted better control of the parasite load in the spleen and liver compared to the group treated with meglumine antimoniate alone. These results reveal a possible benefit of the concomitant use of spironolactone and meglumine antimoniate that should be studied more in depth for the future possibility of repositioning for leishmaniasis co-therapy.

AB - Translational studies involving the reuse and association of drugs are approaches that can result in higher success rates in the discovery and development of drugs for serious public health problems, including leishmaniasis. If we consider the number of pathogenic species in relation to therapeutic options, this arsenal is still small, and each drug possesses a disadvantage in terms of toxicity, efficacy, price, or treatment regimen. In the search for new drugs, we performed a drug screening of L. amazonensis promastigotes and intracellular amastigotes of fifty available drugs belonging to several classes according to their pharmacophoric group. Spironolactone, a potassium-sparing diuretic, proved to be the most promising drug candidate. After demonstrating the in vitro antileishmanial activity, we evaluated the efficacy on a murine experimental model with L. amazonensis and L. infantum. The treatment controlled the cutaneous lesion and reduced the parasite burden of L. amazonensis significantly, as effectively as meglumine antimoniate. The treatment of experimental visceral leishmaniasis was effective in reducing the parasite load on the main affected organs (spleen and liver) via high doses of spironolactone. The association between spironolactone and meglumine antimoniate promoted better control of the parasite load in the spleen and liver compared to the group treated with meglumine antimoniate alone. These results reveal a possible benefit of the concomitant use of spironolactone and meglumine antimoniate that should be studied more in depth for the future possibility of repositioning for leishmaniasis co-therapy.

KW - spironolactone

KW - drug repositioning

KW - leishmania

KW - visceral leishmaniasis

KW - pentavalent antimonial

UR - https://www.scopus.com/pages/publications/85104937045

U2 - 10.3389/fphar.2021.636265

DO - 10.3389/fphar.2021.636265

M3 - Article

C2 - 33927619

SN - 1663-9812

VL - 12

JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

M1 - 636265

ER -