ANTIMALARIAL EFFECTS OF C18 FATTY-ACIDS ON PLASMODIUM-FALCIPARUM IN CULTURE AND ON PLASMODIUM-VINCKEI-PETTERI AND PLASMODIUM-YOELII-NIGERIENSIS IN-VIVO

Following the demonstration of the antimalarial effect of the long chain saturated alcohol n-hentriacontanoi ((CH2)(29)CH2OH), isolated from the Bolivian endemic solanaceous plant Cuatresia sp., we have tested the effect of the C18 fatty acids oleic, elaidic, linoleic, and linoleic on malaria parasites. These fatty acids inhibited the parasitemic development in mice infected with Plasmodiurn vinckei petteri or with Plasmodium yoelii nigeriensis in a 4-day suppressive test. To gain a deeper discernment of the antimalarial mode of action, the effects of these compounds were evaluated on Plasmodiun falciparum growth in culture. Whereas n-hentriacontanol did not show any inhibition of this parasite, on the contrary, the C18 acids displayed a considerable inhibitory activity at less than or equal to 200 mu g/ml both in intact infected cells and in free parasites. In order to understand the mechanism of their antimalarial action, several tests were performed. No hemolysis of infected cells could be observed up to 500 mu g/ml. No effect on the lipid peroxidation, ATP levels, transport through the parasite-induced permeabiIity pathways, or on the phagocytosis of the infected cells could be observed. The cytotoxic effect of the fatty acids was very rapid: full inhibition of nucleic acids and protein syntheses was observed in less than 30 min. This inhibition was not relieved by the addition of deferrioxamine or FeCl3, indicating that fatty acids (FA) do not act by facilitating the transport of iron. Inhibition was relieved in neither the presence of erotic acid or its methyl ester, indicating that FA do not act at the mitochondrial level of pyrimidine synthesis. Inhibition was not relieved when cells were incubated in high potassium medium, implying that FA did not act by depleting the parasite of this physiologically important cation. Vitamin E had no protective effect and no evidence for Lipid peroxidation could be obtained, suggesting that the inhibitory effect of FA was not due to lipid peroxidation. These results suggest that octadecenoic acids may have a specific target(s) inside the parasite. Further investigations are warranted since soybean lipid emulsions used for parenteral nutrition show similar inhibition of parasite propagation in vivo and in culture. (C) 1995 Academic Press, Inc.