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Implication of glutathione in the in vitro antiplasmodial mechanism of action of ellagic acid.
- Source :
-
PloS one [PLoS One] 2012; Vol. 7 (9), pp. e45906. Date of Electronic Publication: 2012 Sep 28. - Publication Year :
- 2012
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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.
- Subjects :
- Acetylcysteine pharmacology
Animals
Antioxidants metabolism
Antioxidants physiology
Ascorbic Acid pharmacology
Buthionine Sulfoximine pharmacology
Cells, Cultured
Deferoxamine pharmacology
Drug Synergism
Enzyme Inhibitors pharmacology
Erythrocytes drug effects
Erythrocytes metabolism
Erythrocytes parasitology
Glutathione metabolism
Glutathione pharmacology
Humans
Inhibitory Concentration 50
Mice
Oxidation-Reduction
Plasmodium falciparum growth & development
Plasmodium falciparum metabolism
Plasmodium yoelii drug effects
Reactive Oxygen Species
Siderophores pharmacology
Antimalarials pharmacology
Antioxidants pharmacology
Ellagic Acid pharmacology
Glutathione physiology
Plasmodium falciparum drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 7
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 23029306
- Full Text :
- https://doi.org/10.1371/journal.pone.0045906