Characterisation of the antimalarial activity of retinol and assessment of lipid peroxidation in malaria infection

    Research output: ThesisDoctoral Thesis

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    Abstract

    Malaria remains a major cause of morbidity and death, especially in developing countries. The effectiveness of conventional antimalarial drugs is waning and there is an urgent need for novel therapeutic approaches. An understanding of malaria parasite biology should facilitate the development of effective therapies that prevent and/or treat malaria. The present studies explore the potential of vitamin A (retinol) as an antimalarial agent. Retinol may act by changing the oxidant milieu within the malaria parasite. Therefore, the nature and consequences of oxidant injury during malaria infection, and its treatment with retinol, have also been explored. The antimalarial potential of retinol was characterised using an established in vitro culture system allowing assessment of efficacy through [3H]-hypoxanthine uptake at different erythrocytic stages of development of Plasmodium falciparum. Retinol losses during culture were significant (>50%). After adjusting for these losses, all parasite stages (early rings to mature trophozoites) showed similar retinol sensitivity, with values of the mean assayed concentration resulting in 50% growth inhibition (IC50) ranging from 10.1 to 21.4 μM. This range was above that in normal human serum (<3 μM) but below that associated with haemolysis in culture (>43 μM). Retinol pre-treatment of uninfected erythrocytes did not inhibit merozoite invasion. Retinol-treated parasites exhibited vacuolisation of the food vacuole and membrane rupture. A P. berghei murine model was used to determine the in vivo preventive and therapeutic efficacy of retinol. Multiple-dose retinol given to healthy Swiss mice before parasite inoculation reduced parasitaemia by 30%, a result comparable to the previously reported reduction in morbidity after vitamin A supplementation in children. A lesser reduction in parasitaemia of 10% was observed when retinol was given after the parasitaemia reached 10-15%. Retinol was ineffective in reducing parasitaemia when given either as single-dose supplementation post-inoculation or at regular intervals before and after infection. Retinol supplementation did not change plasma retinol concentrations during malaria infection whether or not retinol was given, but malaria attenuated the increase in liver retinol content. These data suggest that retinol has most value as prophylaxis. In contrast to published data from humans, previously healthy mice did not develop low plasma retinol concentrations during acute infection
    Original languageEnglish
    QualificationDoctor of Philosophy
    Publication statusUnpublished - 2005

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