Implication of glutathione in the in vitro antiplasmodial mechanism of action of ellagic acid

• Published in: PloS one Vol. 7; no. 9; p. e45906
• Main Authors: Njomnang Soh, Patrice, Witkowski, Benoit, Gales, Amandine, Huyghe, Eric, Berry, Antoine, Pipy, Bernard, Benoit-Vical, Françoise
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28.09.2012; Public Library of Science (PLoS)
• Subjects: Acetylcysteine; Acetylcysteine - pharmacology; Acids; Analysis; Animal models; Animals; Antimalarial activity; Antimalarial agents; Antimalarials - pharmacology; Antioxidants; Antioxidants - metabolism; Antioxidants - pharmacology; Antioxidants - physiology; Antiprotozoal agents; Ascorbic acid; Ascorbic Acid - pharmacology; Biocompatibility; Biology; Buthionine Sulfoximine - pharmacology; Cancer; Cells, Cultured; Chemistry; Chemotherapy; Consolidation; Deferoxamine; Deferoxamine - pharmacology; Diagnosis; Drug resistance; Drug Synergism; Drugs; Ellagic acid; Ellagic Acid - pharmacology; Enzyme Inhibitors - pharmacology; Erythrocytes; Erythrocytes - drug effects; Erythrocytes - metabolism; Erythrocytes - parasitology; Glutathione; Glutathione - metabolism; Glutathione - pharmacology; Glutathione - physiology; Health aspects; Humans; Inhibitory Concentration 50; Life Sciences; Malaria; Medicine; Mice; N-Acetyl-L-cysteine; Oxidation-Reduction; Oxygen; Parasite resistance; Parasites; Plasmodium; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - growth & development; Plasmodium falciparum - metabolism; Plasmodium yoelii - drug effects; Polyphenols; Prevention; Public health; Reactive Oxygen Species; Red blood cells; Risk factors; Rodents; Sabatier, Paul (1854-1941); Siderophores - pharmacology; Toxicity; Urology; France; Antioxidants; Plasmodium; Red blood cells; Parasitic diseases; Vitamin C; Antimalarials; Plasmodium yoelii; Glutathione
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0045906

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.