Experimental leishmaniasis: Synergistic effect of ion channel blockers and interferon-gamma on the clearance of Leishmania major by macrophages

Abstract

We have previously shown that cultured Leishmania promastigotes are sensitive to drugs blocking K+ and Na+ channels and Na+/H+ transport systems and that the percentage of parasite-infected macrophages decreases significantly in the presence of the drugs. In the present work, we analyzed whether this drug susceptibility of intracellular amastigotes is associated with the activation of macrophage microbicidal mechanisms. Pre-treatment of the cells with glibenclamide (GLIB) increased their resistance to infection with Leishmania, an effect that may be mediated by calcium fluxes since it was reversed by EGTA. Notably, in infected macrophages post-treated with the drugs, the clearance of parasites was strongly enhanced when the cells were treated simultaneously with GLIB and interferon-gamma this effect correlated with an increased production of reactive nitrogen intermediates. In conclusion, the data suggest that GLIB treatment increases the resistance of macrophages to infection with Leishmania and potentiate the interferon-gamma stimulated clearance of parasites via the induction of nitric-oxide.