An experimental model system for leishmaniasis. Effects of porphyrin-compounds and menadione on Leishmania parasites engulfed by cultured macrophages

In order to facilitate studies on the effects of chemotherapeutic agents on the host-parasite interactions in leishmaniasis, we have developed an experimental model for infecting human monocyte-derived- and mouse peritoneal macrophages in culture with recently-isolated Leishmania donovani promastigots (LDP). The chemotherapeutic agents studied were protoporphyrin, hematoporphyrin, menadione, and combinations of hematoporphyrin plus menadione. Since the Leishmania donovani amastigotes survived poorly in mouse macrophages and protoporphyrin was quite toxic to the latter, our investigations were focused on the effects of hematoporphyrin and menadione on amastigotes engulfed by human macrophages. Treatment of Leishmania donovani amastigotes-infested human macrophages with either 50 μM hematoporphyrin or 10 μM menadione did not influence significantly the survival of either Leishmania donovani amastigotes or the macrophages themselves. Larger individual doses of hematoporphyrin and menadione were toxic to both parasites and macrophages. The combination of 50 μM hematoporphyrin and 10 μM menadione, however, caused the destruction of the parasites without affecting the host macrophage. The enhanced deleterious effect from combined low doses of hematoporphyrin and menadione is discussed in terms of the production of reactive oxygen species, such as superoxide anion radical and hydrogen peroxide, originating from cellular redox cycling of manadione, and followed by decomposition of the formed hydrogen peroxide by hematoporphyrin to produce the more reactive hydroxyl radical.