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

Abstract

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.

Cutaneous leishmaniasis: new oral therapeutic approaches under development

“…In a target‐based approach, a study investigated the diuretic drug furosemide, an Na + K ATPase inhibitor, as a potential treatment for CL caused by L. amazonensis 38 . This drug was showed to be active in vitro against intracellular amastigote forms (IC 50 87 μ m ) and exhibited higher selectivity to parasites than host macrophages.…”

The Functioning of Na+-ATPases from Protozoan Parasites: Are These Pumps Targets for Antiparasitic Drugs?

“…Although furosemide can inhibit the function of several transporters, the drug acts as an inhibitor of Na + -ATPase in L. amazonensis and disturbs cell proliferation, which could modify the cell volume as consequence of an increased intracellular Na + concentration [ 32 ]. The potential therapeutic effect of furosemide as anti-leishmanial agent has been suggested more recently, with the advantage that furosemide has since become one of the most frequently prescribed medications globally in diuretic therapy [ 33 ].…”

P-type transport ATPases inLeishmaniaandTrypanosoma

“…donovani is required for miltefosine transport and miltefosine inhibits the Na + -ATPase of T . cruzi [6, 13, 73, 104, 114, 125, 146]. Moving forward, the exploitation of P-type ATPase inhibitors as new therapeutic options in treating Leishmania and trypanosome infections should be a priority.…”