title: Implication of glutathione in the in vitro antiplasmodial mechanism of action of ellagic acid.
abstract: The search for new antimalarial chemotherapy has become increasingly urgent due to parasite resistance to current drugs. Ellagic acid (EA) is a polyphenol, recently found in various plant products, that has effective antimalarial activity in vitro and in vivo without toxicity. To further understand the antimalarial mechanism of action of EA in vitro, we evaluated the effects of EA, ascorbic acid and N-acetyl-L-cysteine (NAC), alone and/or in combination on the production of reactive oxygen species (ROS) during the trophozoite and schizonte stages of the erythrocytic cycle of P. falciparum. The parasitized erythrocytes were pre-labelled with DCFDA (dichlorofluorescein diacetate). We showed that NAC had no effect on ROS production, contrary to ascorbic acid and EA, which considerably reduced ROS production. Surprisingly, EA reduced the production of the ROS with concentrations (6.6×10(-9) - 6.6×10(-6) M) ten-fold lower than ascorbic acid (113×10(-6) M). Additionally, the in vitro drug sensitivity of EA with antioxidants showed that antiplasmodial activity is independent of the ROS production inside parasites, which was confirmed by the additive activity of EA and desferrioxamine. Finally, EA could act by reducing the glutathione content inside the Plasmodium parasite. This was consolidated by the decrease in the antiplasmodial efficacy of EA in the murine model Plasmodium yoelii- high GSH strain, known for its high glutathione content. Given its low toxicity and now known mechanism of action, EA appears as a promising antiplasmodial compound.
authors.affiliation: CNRS, Laboratoire de Chimie de Coordination (LCC), Toulouse, France. sohnjomnang@yahoo.fr
authors.forename: Patrice
authors.initials: P
authors.lastname: Njomnang Soh
authors.forename: Benoit
authors.initials: B
authors.lastname: Witkowski
authors.forename: Amandine
authors.initials: A
authors.lastname: Gales
authors.forename: Eric
authors.initials: E
authors.lastname: Huyghe
authors.forename: Antoine
authors.initials: A
authors.lastname: Berry
authors.forename: Bernard
authors.initials: B
authors.lastname: Pipy
authors.forename: Françoise
authors.initials: F
authors.lastname: Benoit-Vical
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D001205:Ascorbic Acid / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D004357:Drug Synergism; D004610:Ellagic Acid / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D010084:Oxidation-Reduction; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D010967:Plasmodium yoelii / Q000187:drug effects; D017382:Reactive Oxygen Species; D017262:Siderophores / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D000975:Antioxidants; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D017262:Siderophores; D004610:Ellagic Acid; D019328:Buthionine Sulfoximine; D005978:Glutathione; D003676:Deferoxamine; D001205:Ascorbic Acid; D000111:Acetylcysteine