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Anti-parasitic effect of the diuretic and Na+-ATPAse inhibitor furosemide in cutaneous leishmaniasis

Published online by Cambridge University Press:  06 June 2017

N. ARRUDA-COSTA
Affiliation:
Instituto de Biofísica Carlos Chagas Filho, Av Carlos Chagas Filho 373, 21941-901 Rio de Janeiro, Brazil
D. ESCRIVANI
Affiliation:
Instituto de Biofísica Carlos Chagas Filho, Av Carlos Chagas Filho 373, 21941-901 Rio de Janeiro, Brazil
E. E. ALMEIDA-AMARAL
Affiliation:
Fundação Oswaldo Cruz, Av Brazil 4365, 21040-900, Manguinhos, Rio de Janeiro, Brazil
J. R. MEYER-FERNANDES
Affiliation:
Instituto de Bioquímica Médica Leopoldo de Meis, Av Carlos Chagas Filho 373, 21941-901 Rio de Janeiro, Brazil
B. ROSSI-BERGMANN
Affiliation:
Instituto de Biofísica Carlos Chagas Filho, Av Carlos Chagas Filho 373, 21941-901 Rio de Janeiro, Brazil
Corresponding
E-mail address:

Summary

Leishmania amazonensis promastigotes are known to express furosemide (Lasix®)-sensitive P-type membrane Na+-ATPase. In the present study, furosemide activity was studied in intracellular amastigotes and infected BALB/c mice to investigate its efficacy in cutaneous leishmaniasis (CL). Intracellular parasites, but not macrophages, were found to be sensitive to killing by furosemide (IC50 = 87 µ m vs CC50 ≫ 1000 µ m, respectively). Although furosemide did not induce nitric oxide production or intracellular pH changes in infected macrophages, it led to a significant reactive oxygen species (ROS) burst. Freshly isolated tissue parasites expressed a high degree of Na+-ATPase activity that decreased with culture, indicative of a higher enzyme expression in amastigotes than in promastigotes. Both intraperitoneal and oral treatment of L. amazonensis-infected mice with furosemide dosages equivalent to that prescribed as a diuretic significantly reduced the parasite's growth compared with the situation in untreated mice. Combination with oral furosemide increased the efficacy and safety of intraperitoneal treatment with sodium stibogluconate (SSG). To summarize, furosemide control of intracellular leishmanial growth by means of parasite Na+-ATPase inhibition, and macrophage ROS activation may help explain its sole and SSG-combined therapeutic effect against murine CL.

Type
Research Article
Copyright
Copyright © Cambridge University Press 2017 

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