Oxidative Stress in Malaria

Based on scientific research, the combination of antimalarials and antioxidant supplements appears to work well, as antioxidants can reverse or minimize oxidative damage caused by parasites and the use of antimalarials.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546694/ Oxidative Stress in Malaria - PMC (nih.gov)

In this paper we review oxidative stress mechanisms involved in the disease and discuss the potential benefits of antioxidant supplementation as an adjuvant antimalarial strategy.

Recent studies suggest that oxidative stress can take part in the pathogenesis of thrombocytopenia associated to malaria.

Among the antioxidant molecules, the GSH molecule stands out as being the most powerful protector of eukaryotic cells in the host defense against oxidative stress, acting upon several different mechanisms [40].

A study conducted with 273 children between the ages of 1–10 with acute uncomplicated P. falciparum malaria in Kampala, Uganda, verified the antioxidant status in the pathogenesis of the disease. Children with acute malaria had low antioxidant plasma concentrations. On the other hand, in children with higher plasma lycopene levels, there was fast parasitemia clearance [45].

In fact, several substances used as antimalarials are pro-oxidants, which is why they have pharmacological power. This is the case for

chloroquine, primaquine, and artemisinin

among others. This effect may be due to the drug’s ability to promote direct production of free radicals [135] or by inhibiting molecules with antioxidant activity [136].

Despite the common belief that the ability to induce oxidative stress is a typical active mechanism of antimalarial drugs, in recent years several plant extracts and other natural products have been tested for their antioxidant properties, thus interfering with the mechanisms of the disease by modulating the cellular signaling pathway and not by directly inducing the parasites to death. This approach has shown very promising results, with high rates of schizonticide and antiparasitic activity, but with minor changes in the host redox balance. Some of the plants tested for this purpose include

Piper betle L. leaves [148], Anogeissus leiocarpus[149], Nigella sativa seeds [150] and flavonoids from Artemisia annua L. [151].

The ability of cocoa fruit to kill malaria parasites is also suggested [152].

Likewise, Agaricus sylvaticus mushroom, which exhibits high antioxidant capacity [153], has been tested in mice infected with P. berghei. It promotes an increase in the total antioxidant capacity of animals and a decrease in lipid peroxidation and nitric oxide markers in lung and brain samples of these animals. These biochemical changes were correlated with a significant reduction in the parasitemia of animals [17,18].

Furthermore, the use of antioxidant supplements can reverse or minimize the oxidative damage to hosts caused by the use of antimalarial drugs.

The administration of curcumin, an herbal antioxidant obtained from Curcuma longa, prevented hepatotoxicity in rats treated with chloroquine [154].

Likewise, the administration of glutathione promoted reduced parasitemia and increased survival of mice infected with P. berghei[155].

7. Conclusions

The role of oxidative stress in the pathophysiology of malaria is a multifactorial phenomenon and represents an important aspect of the intricate and complex host-parasite relationship. The sources of oxygen-nitrogen reactive species generation implicated in the disease are: (1) The host’s inflammatory response; (2) catalysis of Haber-Weiss and Fenton reactions due to high availability of free iron; (3) the occurrence of ischemia and reperfusion syndrome, the fluctuating result in the ability of red blood cells being able to transport oxygen during malarial paroxysm and of cytoadherence; (4) direct production by parasites; and (5) the action of certain pro-oxidants antimalarial drugs.

Therefore, the use of antioxidant supplements of synthetic or natural origin may constitute a far more effective adjuvant antimalarial strategy that causes less damage to the host.

https://link.springer.com/chapter/10.1007/978-981-13-8763-0_23 Oxidative Stress in Malarial Diseases: Plasmodium-Human Host Interactions and Therapeutic Interventions | SpringerLink

Oxidative stress is a major contributor of disease etiology, progression and outcomes.

Host systems and parasite infectivity play critical roles in the generation and manipulation of oxidative stress in malaria. Host systems involve the immunological and inflammatory responses that generate free radical species as host signalling processes as well as parasite combating and destructive entities. Parasites trigger molecules with inherent free radical generation in the host. Without the ability to synthesize amino acids, the parasite depends on the breakdown of haemoglobin to salvage the same within the food vacuole. This creates a highly oxidative stress environment from the Fenton reaction through the central ferrous moiety. Elimination of host oxidative stress process, from haemoglobin degradation product haeme, has critically evolved to protect parasites from the hostile intracellular compartment where it is an obligatory inhabitant. Parasites produce antioxidant species from both enzymatic and non-enzymatic molecules which cushions the parasites proteins from oxidation. The parasite also converts haeme, through biocrystallization, to haemozoin, a seemingly biologically inert molecule. In the presence of parasite DNA, haemozoin induces oxidative and inflammatory mediators (cytokines, chemokines, inducible nitric oxide synthase, nitric oxide, oxygen free radical, nitrogen free radicals, peroxynitrite etc.) with a high propensity toward oxidative stress able to override host antioxidant defence systems. Other parasite proponents, e.g. glycosylphosphotidylinositol, are instrumental in negatively modulating host oxidative stress.

Without intervention, the disease machineries of oxidative stress go into a vicious cycle of self-propagation mode that leads to host debilitation, cachexia and death.

Current drugs are mainly antiparasitic and relieve the “disease” aspect of malaria sparingly.

Phytotherapeutics and phytochemicals (asiatic acid, maslinic acid, oleanolic acid), which display anti-oxidant and pro-oxidant properties, have shown both “antiparasite” and “anti-disease” effects promising efficacy in combating malaria.

These pleiotropic properties are displayed in different environments with potential to buffer malarial disease syndrome.

https://academic.oup.com/jac/article/75/6/1363/5762648?login=false Oxidative and nitrosative stresses in cerebral malaria: can we target them to avoid a bad prognosis? | Journal of Antimicrobial Chemotherapy | Oxford Academic (oup.com)

Evidence suggests a role for oxidative and nitrosative stresses in this clinical syndrome, as a result of host–Plasmodium interactions. In this review, the evidence will be discussed with a particular emphasis on pharmacological interventions, including adjunct therapies as potential modulators of oxidative stress and nitrosative stress in CM.

Based on the existing therapies and the evidence gathered on the dual role of ROS and NO in CM, it has become clear that preventing the progression of malaria infection to severe disease depends on treatment timing and host response to infection, i.e. whilst ROS and free FP are important to kill the parasite, they may also harm the host, causing haemolysis and excessive ROS formation.^113,132

Overall, clinical and experimental data demonstrate that anti-ROS and FP therapies are potentially important for malaria treatment, both historically and in future treatment regimens, and are likely to prove useful in reducing disease-associated mortality and morbidity.

All of this evidence clearly indicates that controlling the prognosis of CM depends on fine tuning between treatment timing and targeting of host/parasite oxidative and nitrosative responses.

Thus, drugs targeting these pathways could be employed as adjuncts to antimalarial combination therapy in order to achieve greater reductions in mortality and morbidity in CM patients.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9180384/ Oxidative Stress in Malaria: Potential Benefits of Antioxidant Therapy - PMC (nih.gov)

The involvement of oxidative stress in malaria is complex and progresses with changes in the host’s pro-oxidant and antioxidant balance.

The main sources of antioxidant defenses involved in malaria are: (1) host enzyme antioxidants (SOD, CAT, GSH-Px, GST, GR, Prx, and Trx); (2) host non-enzymatic antioxidants (vitamins A, D, E, and C; carotenoids; uric acid; and GSH); (3) non-enzymatic antioxidants from the host’s metal chelation system (iron, copper, and metallothionein-chelating proteins); (4) exogenous antioxidants of dietary origin or drugs (flavonoids, phenolic compounds, minerals, NAC, and the mushroom A. sylvaticus).

The studies presented in this revision showed that supplementation, mainly with vitamins A and D, is advantageous.

This provides a potential and beneficial strategy for the prophylactic application of vitamins and the prevention of malaria.

Notwithstanding,

supplementation with antioxidants from different sources would act in the prevention and control of oxidative changes generated by the parasite during infection, with a consequent increase in the total antioxidant capacity and a reduction of cellular damage to the host, constituting a complementary therapy to antimalarial treatment.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013505/pdf/40265_2018_Article_911.pdf Drugs in Development for Malaria (nih.gov)