Suppressive effects of the anti-oxidant N-acetylcysteine on the anti-malarial activity of artesunate

Arreesrisom, Peera; Dondorp, Arjen M.; Udomsangpetch, Rachanee

doi:10.1016/j.parint.2007.04.004

Cited by 22 publications

(15 citation statements)

References 15 publications

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“…17) Antioxidants such as vitamin E promote the growth of malaria parasites, 18) and vitamin E deficiency increases the antimalarial activity of artemisinin in vivo. 19) Thus, our results are in agreement with the reports on oxidative stress as an essential process of artemisinin action.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Heme Enhances the Antimalarial Activity of Artemisinin

Tangnitipong

Thaptimthong

Srihirun

et al. 2012

Biological & Pharmaceutical Bulletin

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Artemisinin exerts the antimalarial activity through activation by heme. The hemolysis in malaria results in the elevated levels of plasma heme which may affect the activity of artemisinin. We hypothesized that the extracellular heme would potentiate the antimalarial activity of artemisinin. Hemin (ferric heme) at the pathologic concentrations enhanced the activity of artemisinin against Plasmodium falciparum in vitro and increased the levels of the lipid peroxidation products in the presence of artemisinin. The antimalarial activity of artemisinin and potentiation by hemin was decreased by vitamin E. Hemin had no effect on the activity of quinoline drugs (chloroquine, quinine and mefloquine). Furthermore, the oxidative effect of hemin in the presence of artemisinin or quinoline drugs was studied using low-density lipoprotein (LDL) oxidation as a model. Artemisinin enhanced the effects of hemin on lipid peroxidation and a decrease of tryptophan fluorescence in LDL whereas the quinoline drugs inhibited the oxidation by hemin. In conclusion, the extracellular hemin enhances the antimalarial activity of artemisinin as a result of the increasing oxidative effect of hemin.

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Section: Discussionmentioning

confidence: 99%

Extracellular Heme Enhances the Antimalarial Activity of Artemisinin

Tangnitipong

Thaptimthong

Srihirun

et al. 2012

Biological & Pharmaceutical Bulletin

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“…Ellagic acid could act as both a pro-and antioxidant in the same way as several polyphenols such as curcumin (14,22). It could be useful to carry out experiments to verify the pro-oxidant effects of ellagic acid, given that another antimalarial molecule (artesunate) seems to act by oxidative effects (2). A clinical report has shown that a molecule with the dual activities of antioxidant and antimalarial was interesting in the case of severe malaria (30).…”

Section: Discussionmentioning

confidence: 99%

“…The modulating effects of N-acetyl-L-cysteine (NAC) (Sigma, France) on the antimalarial activity of ellagic acid were assessed using strain FcM29. The experimental procedures were adapted from the protocol described previously by Arreesrisom et al (2). The final concentration of NAC used without an effect on parasitic growth was 0.87 M. The final concentration in the culture medium of ellagic acid was 0.18 M (IC 50 of ellagic acid for strain FcM29).…”

Section: Methodsmentioning

confidence: 99%

In Vitro and In Vivo Properties of Ellagic Acid in Malaria Treatment

Soh

Witkowski

Olagnier

et al. 2009

Antimicrob Agents Chemother

133

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Malaria is one of the most significant causes of infectious disease in the world. The search for new antimalarial chemotherapies has become increasingly urgent due to the parasites' resistance to current drugs. Ellagic acid is a polyphenol found in various plant products. In this study, antimalarial properties of ellagic acid were explored. The results obtained have shown high activity in vitro against all Plasmodium falciparum strains whatever their levels of chloroquine and mefloquine resistance (50% inhibitory concentrations ranging from 105 to 330 nM). Ellagic acid was also active in vivo against Plamodium vinckei petteri in suppressive, curative, and prophylactic murine tests, without any toxicity (50% effective dose by the intraperitoneal route inferior to 1 mg/kg/day). The study of the point of action of its antimalarial activity in the erythrocytic cycle of Plasmodium falciparum demonstrated that it occurred at the mature trophozoite and young schizont stages. Moreover, ellagic acid has been shown to potentiate the activity of current antimalarial drugs such as chloroquine, mefloquine, artesunate, and atovaquone. This study also proved the antioxidant activity of ellagic acid and, in contrast, the inhibitory effect of the antioxidant compound N-acetyl-L-cysteine on its antimalarial efficacy. The possible mechanisms of action of ellagic acid on P. falciparum are discussed in light of the results. Ellagic acid has in vivo activity against plasmodia, but modification of the compound could lead to improved pharmacological properties, principally for the oral route.New drugs against malaria are urgently needed, and traditional methods of malaria treatment could be a promising source of new antimalarial compounds (5). We have recently initiated several collaborative programs with West African countries aimed at selecting, by ethnopharmacological methods, plants largely used by traditional healers and the local populations for malaria treatment. The in vitro antiplasmodial activities of the crude extracts and fractions (from bioguided fractionation of the promising crude extracts of plants) enabled us to identified ellagic acid as one of the active ingredients. The in vitro antimalarial activity of this molecule was previously reported by other researchers (3,10). In this study, we clarify the high level of in vitro and in vivo antiplasmodial properties of ellagic acid, its antioxidant activity, and its potential pro-oxidant effect and gain a deeper understanding of its mechanisms of action. MATERIALS AND METHODSCompounds. Ellagic acid hydrate (Fig. 1) was obtained from Acros Organics (Belgium), with a molecular weight 302.19 g/mol. The following other reagents were also obtained: chloroquine diphosphate salt (Sigma, France), mefloquine hydrochloride (Hoffmann-La Roche, Switzerland), artesunate (Sanofi-Synthelabo, France), artemisinin (Sigma, Germany), and atovaquone (GlaxoSmithKline, United Kingdom).In vitro antiplasmodial activity. Five strains (W2-Indochina, FcM29-Cameroon, FcB1-Colombia, F32-Tanzania, and D...

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“…Artesunate is recommended by the World Health Organization because several clinical studies involving malaria patients have shown that treatment with this drug is well-tolerated and has few side effects [Hien et al, 1992]. According to Arreesrisom et al, (2007), artesunate acts by inducing free radicals in the presence of the Fe 12 that is released by malarial parasites during the process of heme degradation.…”

Section: Introductionmentioning

confidence: 99%

In vitro evaluation of the genotoxic and cytotoxic effects of artesunate, an antimalarial drug, in human lymphocytes

Mota

Cardoso

Gomes

et al. 2011

Environ and Mol Mutagen

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Artesunate is one of the main antimalarial drugs used in several countries. It is a semisynthetic compound derived from artemisinin, a substance extracted from the Chinese plant, Artemisia annua L. Despite the widespread use of artesunate as an antimalarial drug, there is a lack of data regarding its genotoxic effects in human lymphocytes. Therefore, in this study, we used the comet assay and micronucleus test to evaluate the possible genotoxic effects of artesunate in cultured human lymphocytes. In addition, cell death by necrosis and apoptosis was also assessed. Cells exposed to different concentrations of artesunate showed a significant concentration-dependent increase (P < 0.05) in DNA damage index and micronuclei frequency. A significant increase in the frequency of apoptotic and necrotic cells was also observed. Our results showed that artesunate is a genotoxic and cytotoxic compound in cultured human lymphocytes.

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Suppressive effects of the anti-oxidant N-acetylcysteine on the anti-malarial activity of artesunate

Cited by 22 publications

References 15 publications

Extracellular Heme Enhances the Antimalarial Activity of Artemisinin

Extracellular Heme Enhances the Antimalarial Activity of Artemisinin

In Vitro and In Vivo Properties of Ellagic Acid in Malaria Treatment

In vitro evaluation of the genotoxic and cytotoxic effects of artesunate, an antimalarial drug, in human lymphocytes

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