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Uric acid: emerging as key factor in malaria

February 6, 2014 - 17:09 -- Pierre Lutgen

Plasmodium falciparum-infected erythrocytes contain large quantities of uric acid precipitates. These precipitates are present in the parasitophorous vacuole, in the cytoplasm, not in the food vacuole of the parasite. Uric acid precipitates are highly inflammatory molecules that are considered a danger signal for innate immunity and are the causative agent of gout. Hypoxanthine is a metabolic precursor of uric acid and is essential for Plasmodium growth. It is transformed by the xanthine oxidase into xanthine the true precursor of uric acid. Hypoxanthine is commonly a required reagent in parasite cultures. Its concentration in infected erythrocytes is much higher than in uninfected ones (J Gallego-Delgado et al., Current Rheumatology Reports, Jan 2014, 16:401). At rupture of the schizonts these uric acid precipitates are released into the blood stream and into micro-vessels and stimulate immune cells to produce inflammatory cytokines IL-6, Il-8 and TNF-alpha (T Lopera et al., PlosOne, Oct 2012, 7:10). Since the inflammatory reaction induced by Plasmodium falciparum is considered a major cause of malaria pathogenesis, identifying the mechanisms used by the parasite is essential for the development of new drugs. It has for example been demonstrated that the incubation with immune erythrocytes reduced parasite maturation and decreased parasite multiplication in a dose dependant manner (P Monatrakul et al., Malaria Journal 2010).

The control of uric acid may offer the possibility for the development of new antimalarial drugs.

Allopurinol, the common drug used against gout, inhibits the xanthine oxidase which transforms hypoxanthine into xanthine. This same drug also reduces the inflammatory interleukines, TNF, IL-6, IL-8 released by Plasmodium falciparum (JM Orengo et al., PloSOne 2009, 4, e5194). Several flavonoids like rutin, kaempferol, naringenin, quercetin reduce serum uric acid levels (J Huang et al., Food Chem Toxicol 2011, 49, 1943-7). Quercetin protects against renal uric acid disorder ( J Wang et al., Evid Based Complement Alternat Med, 2012 548430). Another study compared the inhibition of bovine xanthine oxidase of several natural compounds and found that luteolin had the strongest action. Contrary to previous reports curcumin had none (JM Pauff et al., J Nat Prod 2009, 72, 725-731). A Vietnamese study even found that luteolin was more potent than allopurinol i.e. had a 2 times lower IC50 (MTT Nguyen et al., Biol Pharm Bull 27, 2004, 1414-21). Several studies have shown that Artemisia plants have a strong inhibitory action on xanthine oxidase which is also a ROS producer. This is probably due to luteolin which binds strongly to xanthine oxidase (J Yan et al, Food Chemistry, 2013, 141, 3766-73) and eventually explains the strong antimalarial properties of Artemisia afra rich in luteolin.

Furosemide (Lasix) another diuretic agent like is able to inhibit hypoxanthine uptake. But most antimalarials also show this effect. The incorporation of radiolabled hypoxanthine is one of the most reliable test for malaria drug research. A PhD thesis from South Africa (Meryl A Abrahams, 1996, UCT) is based on a similar assay . They found that hydroxydavanone, a molecule present in Artemisia afra at concentration 0.1-1.0 ng had an inhibitory effect stronger than artemisinine, and much stronger than chloroquine or mefloquine. In South Africa it was found that the essential oil nerolidol had a stronger inhibition of hypoxanthine incorporation than quinine ( ST Seatlholo, Thesis Witwaterstrand, 2007).

Saponins cause notable delays in uric acid crystallization. They accelerate the excretion. (G L Chen, Am J Chin Med 34,01, 2006). Whitaferin, a saponin, which is called Indian ginseng, also alleviates gout (EP Sabines et al, J Phaarm Pharmaceut Sci 11:4, 45-56.2008. Noni is a fruit extensively used against gout. It is very rich in scopoletin. This coumarin inhibits the xanthine oxidase ( A Palu et al., Phytother Res., 2009) and the monosodium urate crystal induced inflammation ( X Xiao et al., Int Immunopharmacol, 2012, 14, 454-62). Stems of Artemisia annua are relatively richer in scopoletin than leaves (US patent 6 337 0959). Esculetin, another coumarin, was found to be even more potent as inhibitor (HC Lin et al., Biochemical Pharmcacology, 75-6, 2008, 1416-25).

Chlorogenic acid is also a strong inhibitor of xanthine oxidase (SH Wang et al., Planta Medica, 2009, 75-11, 1237-40). Its role in Artemisia annua has probably been ignored because this hydrophilic molecule hardly dissolves in the organic solvents used in most of the studies. The University of Louvain has shown that it is present in Artemisia annua infusions, often at concentrations much higher than artemisinin (PM de Magalhaes et al. Food Chemistry 2012). Recently the University of Leiden (J, Mouton, Fr Van der Kooy, European Journal of Medicinal plants, 4-1, 52-63, 20149) has confirmed that it is well present in Artemisia annua tea infusions. Its concentration is sometimes higher in stems than in leaves (O Tokusoglu et al., J of Food Technol. 3, 2005, 444-448). Its concentration in many plants increases with storage time (SO Amoo et al., BMC Complement and Altern Med. 2012, 12: 87). Chlorogenic acid has strong antioxidant properties which might counteract the ROS generated by xanthine oxidase or by artemisinin and its derivatives.