Ellagic Acid Induces in vitro Alkalinisation of the Digestive Vacuole in Drug-Sensitive Plasmodium falciparum Strain

Abstract

Background: Malaria is one of the leading causes of death worldwide caused by parasites of the genus Plasmodium. The reduced efficacy of the mainstay antimalarial drugs due to the widespread of drug-resistant Plasmodium falciparum (P. falciparum) necessitates an effort to develop novel antimalarial drugs with new targets. The effects of a phenolic compound, ellagic acid, against the malaria parasite have previously been reported. This present study aimed to evaluate the effect of ellagic acid on pH of the P. falciparum digestive vacuole. Methods: The antimalarial potential of ellagic acid against the chloroquine-sensitive strain (3D7) of P. falciparum was assessed by using a malarial SYBR Green 1 fluorescence-based (MSF) assay. The effect of different concentrations of ellagic acid on the pH of the parasite’s digestive vacuole at mid-trophozoite stage was examined by using a ratiometric pH indicator, fluorescein isothiocyanate (FITC)-dextran on the flow cytometry. Results: The result of the MSF assay showed that ellagic acid has an antimalarial activity (half-maximal inhibitory concentration [IC50] = 1.85 ± 4.57 nM) at par with a standard drug, artemisinin (IC50 = 1.91 ± 5.41 nM). The pH of the digestive vacuole of ellagic acid-treated parasites was significantly changed (pH values ranged from 6.11 to 6.74) in a concentration-dependent manner as compared to untreated parasites (P < 0.001). A similar effect was shown by the parasites treated with a standard proton pump inhibitor, concanamycin A. Conclusion: These findings suggest that ellagic acid might have altered the digestive vacuole pH through the inhibition of proton pumps that regulate the acidification of this organelle. Overall, this study provides a valuable insight into the potential of ellagic acid as a promising antimalarial candidate with a novel mechanism of action.

Efficacy of artesunate combined with Atractylodes lancea or Prabchompoothaweep remedy extracts as adjunctive therapy for the treatment of cerebral malaria

“…Furthermore, Soh et al reported that ellagic acid suppresses parasitemia in a dose-dependent manner with 100% suppression in mice treated with 50 and 100 mg/kg via the intraperitoneal route [ 62 ]. Previous studies supported the idea that ellagic acid altered the pH of the digestive vacuole through the prevention of proton pumps that control the acidification of this organelle [ 63 ]. In conclusion, the ethanolic extracts of A. lancea and Prabchopoothaweep remedy monotherapy inhibit parasitemia progression, whereas a combination of artesunate (standard drug) and crude extracts from Prabchompoothaweep remedy significantly exerts a potent synergistic effect in the antimalarial property.…”

Phytochemical Profiling and Biological Activities of Quercus sp. Galls (Oak Galls): A Systematic Review of Studies Published in the Last 5 Years

“…New findings confirmed these results. Hence, ellagic acid, the phenolic compound found in oak galls, presented strong antimalarial activity similar to a standard drug, artemisinin, while the pH of the digestive vacuole of ellagic-acid-treated parasites was significantly altered (pH = 6.11 to 6.74, p < 0.001) in a concentration-dependent manner versus untreated parasites [107].…”

Targeting Myeloperoxidase Activity and Neutrophil ROS Production to Modulate Redox Process: Effect of Ellagic Acid and Analogues

“…A recent study by Muchtar et al [23] reported one of the mechanisms of action of ellagic acid as acting through the pH of the P. falciparum digestive vacuole. Our group recently reported that polyphenolic derivatives, analogues of ellagic acid, constitute a promising scaffold that could play crucial role in malaria treatment through a currently unknown mode of action [24].…”