Activity of divicine in <i>Plasmodium vinckei</i>‐infected mice has implications for treatment of favism and epidemiology of G‐6‐PD deficiency

Clark, Ian A.; Cowden, W. B.; Hunt, Nicholas H.; Maxwell, Lesley; Mackie, Eleanor J.

doi:10.1111/j.1365-2141.1984.tb02922.x

Cited by 51 publications

(29 citation statements)

References 18 publications

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“…The increased vitamin E content in parasitized or unparasitized RBC from mice ill with malaria may be a similar response and is consistent with our earlier suggestion (9) that host tissues may come under free radical-induced oxidative attack from leucocytes as the disease progresses. This interpretation is strengthened by our recent experiments (unpublished data) showing that the exposure of normal mice to divicine, a source of free radicalinduced oxidative stress (24), increases vitamin E in their plasma and RBC. As the parasite load increases within the RBC, up to 80% of the total hemoglobin is digested (Table 3).…”

Section: Discussionmentioning

confidence: 75%

Oxidative stress and protective mechanisms in erythrocytes in relation to Plasmodium vinckei load.

Stocker¹,

Hunt²,

Buffinton³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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The protection of mouse erythrocytes (RBC) parasitized with Plasmodium vinckei vinckei against activated oxygen species was examined in relation to the intraerythrocytic parasite load. RBC from highly infected annials were separated by density gradient centrifugation into six bands with increasing parasite content and with parasitemias ranging from 17% to 100%. Increase in parasite load was accompanied by a decrease in the activities of the enzymes superoxide dismutase (EC 1.15.1.1), catalase (EC 1.11.1.6), glutathione peroxidase (EC 1.11.1.9), glutathione reductase [NAD(P)HJ (EC 1.6.4.2), and NADlI-methemoglobin reductase (EC 1.6.2.2; NADHNferricytochrome b5 oxidot-eductase) in the RBC lysates. In contrast, the total amount of reduced glutathione increased in the highly parasitized bands. Furthermore, the vitamin E content of all RBC bands, including the one that contained mainly nonparasitized erythrocytes, was 3-to 5-fold higher than that of control noniinfected RBC. Increasing parasite load was accompanied by an increase in the production of malonyldialdehyde, indicating enhanced lipid peroxidation.Our results indicate that oxidative stress is experienced by all RBC during a malarial infection and is accompanied by a variety of changes in the antioxidant defense mechanisms of the host and the parasite. Furthermore, it appears that the plasma membrane of the host cell is better protected against oxidative injury than are the membranes surrounding the parasite.Malarial infection is accompanied by a variety of biological responses on the part of the host, including the activation of its cellular immune system. Experiments with Plasmodium falciparum and Plasmodium berghei in vitro suggest that phagocytic cells from spleen (1), pentoneal cavity (1, 2), and peripheral blood (3-6) ingest parasitized erythrocytes (PRBC) or free merozoites as part of their role in cell-mediated immunity. Phagocytosis by macrophages and polymorphonuclear leukocytes is accompanied by a respiratory burst, which gives rise to the production of reactive oxygen species (ROS) (7,8) (16,17), but the effect of parasitemia upon the full range of antioxidant systems has yet to be explored.In this study RBC from the blood of highly parasitized mice were separated on the basis of parasite load and examined for their antioxidant'activities. Our results are consistent with the exposure of unparasitized RBC to oxidative stress and show that, with increased parasite content, complex changes occur in the antioxidant defense mechanisms within the PRBC. METHODSMale CBA/Cai mice, 6-10 weeks old, were infected by i.p. injection of 106 Plasmodium vinckei subsp. vinckei PRBC (9).Blood from control of infected mice, the latter showing 70-90%o parasitemia, was collected into sodium heparin (20 units/ml of blood). RBC from infected mice were separated as described by others (18). Briefly, 1-2 ml of infected blood was layered onto discontinuous gradients of Dextran T 40 (Pharmacia) in phosphate-buffered saline/5 mM glucose, pH 7.2, containing 4 ml of 40...

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Section: Discussionmentioning

confidence: 75%

Oxidative stress and protective mechanisms in erythrocytes in relation to Plasmodium vinckei load.

Stocker¹,

Hunt²,

Buffinton³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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“…The explanation offered here, like the traditional one, is based on the lack of reduced glutathione, but in the present formulation, there is no need to invoke a co-existant oxidative stress; the reduction in GSH content has serious and pervasive deleterious consequences for parasite growth without requiring the cataclysmic destruction which is seen when oxidant drugs are given to malaria-bearing animals (26). A mechanism ofthis type has the advantage of being continuously active under all circumstances for each growth cycle of the parasite.…”

Section: Discussionmentioning

confidence: 91%

“…The traditional interpretations rely on a decline in GSH content based on the inability of G6PD-deficient red cells to generate NADPH-an event which, in red cells, requires an intact pentose shunt together with an overwhelming oxidant stress. A significant oxidative stress, either created by the parasite itself or by some exogenous material, is always postulated, but rarely demonstrated (26). We and others have previously described a number of findings in normal infected red cells which suggest that the parasite/red cell unit is well protected against oxidative stress by enrichment with vitamin E and host superoxide dismutase as well as enhanced GSH stability (27,28).…”

Section: Discussionmentioning

confidence: 99%

Ribose metabolism and nucleic acid synthesis in normal and glucose-6-phosphate dehydrogenase-deficient human erythrocytes infected with Plasmodium falciparum.

Röth¹,

Ruprecht²,

Schulman³

et al. 1986

J. Clin. Invest.

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The metabolism of pentose-phosphate was investigated in Plasmodium fakiparum-infected normal and glucose-6-phosphate dehydrogenase (G6PD)-deficient human red blood cells in vitro.5'-Phosphoribosyl-l-pyrophosphate (PRPP) content of infected normal red blood cells was increased 50-60-fold at the parasite trophozoite growth stage over that of uninfected cells. The PRPP increment in infected G6PD-deficient cells at comparable stage and parasitemia was only 40% of the value in normal infected cells. Red blood cell PRPP synthetase activity did not change during the growth cycle of the parasite and was similar in both normal and G6PD-deficient cells. Reduced glutathione (GSH) content of G6PD-deficient cells under conditions of culture fell to low or undetectable levels. These low levels of GSH were shown to inhibit the function of red blood cell PRPP synthetase, which requires GSH for full activity. Measurements of the incorporation of 1-14C or 6-04C selectively labeled glucose into parasite nucleic acids revealed that in normal infected red cells, -20% of the pentose was produced via the oxidation of glucose-6-phosphate, whereas in infected G6PD-deficient cells (Mediterranean type), none of the pentose was produced via the oxidative pathway. It is concluded that the low level of reduced GSH found in G6PD deficiency and the resultant partial inhibition of PRPP synthetase together with the missing oxidative pathway for ribose phosphate production can account fully for the reduced parasite growth rate in G6PD-deficient red blood cells described previously. Of these two mechanisms, the predominant one is the impaired PRPP synthetase activity due to low GSH levels in enzyme-deficient red blood cells. The contribution to the ribose-phosphate pool by the hexose monophosphate shunt is relatively minor. A co-existing oxidative stress (which is often hypothesized to mediate the destruction of parasitized red blood cells) is not required to explain growth inhibition in this scheme and does not represent the most straightforward explgnation of the data described in this report.

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“…Furthermore, malaria parasites grow poorly in vitamin E-deficient mice (28). ROS-generating systems kill murine malaria parasites in vitro (10,26,27) and in vivo (14,15,16) and kill Plasmodium falciparum in vitro (7,13,45,72).…”

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confidence: 99%

Phagocyte-Derived Reactive Oxygen Species Do Not Influence the Progression of Murine Blood-Stage Malaria Infections

et al. 2005

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Phagocyte-derived reactive oxygen species have been implicated in the clearance of malaria infections. We investigated the progression of five different strains of murine malaria in gp91 phox؊/؊ mice, which lack a functional NADPH oxidase and thus the ability to produce phagocyte-derived reactive oxygen species. We found that the absence of functional NADPH oxidase in the gene knockout mice had no effect on the parasitemia or total parasite burden in mice infected with either resolving (Plasmodium yoelii and Plasmodium chabaudi K562) or fatal (Plasmodium berghei ANKA, Plasmodium berghei K173 and Plasmodium vinckei vinckei) strains of malaria. This lack of effect was apparent in both primary and secondary infections with P. yoelii and P. chabaudi. There was also no difference in the presentation of clinical or pathological signs between the gp91 phox؊/؊ or wild-type strains of mice infected with malaria. Progression of P. berghei ANKA and P. berghei K173 infections was unchanged in glutathione peroxidase-1 gene knockout mice compared to their wild-type counterparts. The rates of parasitemia progression in gp91 phox؊/؊ mice and wild-type mice were not significantly different when they were treated with L-N G -methylarginine, an inhibitor of nitric oxide synthase. These results suggest that phagocyte-derived reactive oxygen species are not crucial for the clearance of malaria parasites, at least in murine models.

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Activity of divicine in Plasmodium vinckei‐infected mice has implications for treatment of favism and epidemiology of G‐6‐PD deficiency

Cited by 51 publications

References 18 publications

Oxidative stress and protective mechanisms in erythrocytes in relation to Plasmodium vinckei load.

Oxidative stress and protective mechanisms in erythrocytes in relation to Plasmodium vinckei load.

Ribose metabolism and nucleic acid synthesis in normal and glucose-6-phosphate dehydrogenase-deficient human erythrocytes infected with Plasmodium falciparum.

Phagocyte-Derived Reactive Oxygen Species Do Not Influence the Progression of Murine Blood-Stage Malaria Infections

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