Modulation of the antioxidant defence in different developmental stages of Schistosoma mansoni by praziquantel and artemether

Abstract

Human schistosomiasis is a chronic and debilitating parasitic disease caused by parasitic trematode worms (schistosomes). Praziquantel (PZQ) is the drug of choice as it is active against all Schistosoma species, can be administered easily, has high cure and egg reduction rates, with no or only mild side effects. Rapid re-infection following treatment and the concerns about PZQ resistance has led to the search for new drugs to treat schistosomiasis. Significant progress has been made with artemisinin derivatives (e.g., artemether [ART]) that are used for chemoprophylaxis. This present study aims to look at the effects of ART and PZQ on the antioxidant defence of immature (three-week-old) and mature (six-week-old) stages of S. mansoni. The possible development of time- or concentration-dependent changes in oxidative stress is assessed by incubation with different sublethal drug concentrations (50, 75, 100 ng/mL for both ART and PZQ) and different time periods (one and three hours). The results indicated a time- and concentration-dependent depletion of glutathione (GSH), which was greater in the immature worms after incubation with ART. On addition of ART to the incubation medium of mature and immature worms, elevation in lipid peroxidation (TBARS) level was observed, which was time- and concentration-dependent, and more prominent in the immature schistosomes. Addition of PZQ to the incubation medium containing the immature schistosomes did not have a significant effect on TBARS level, except after three hours' incubation with the highest concentration used; however, a significant rise was seen in the mature worms. The PZQ had no effect on the activities of superoxide dismutase (SOD), glutathione peroxidase (tGPx, sGPx and nGPx) and glutathione transferase (GST) in mature or immature worms. While ART induced SOD activity in mature worms, it induced tGPx, nGPx and GST activities in a time- and concentration-dependent manner in both mature and immature worms. Activation was more prominent in the immature schistosomes. The results of the present study indicate that the immature schistosomes are more prone to oxidative killing, which probably participates in the mechanism of antischistosomal action of ART against the immature stage of S. mansoni. The results suggest that the mechanism of schistosomicidal action of PZQ is probably not substantially dependent on oxidative stress or oxidative killing.

Towards an understanding of the mechanism of action of praziquantel

“…These results suggest that treatment with PZQ may result in a molecular response similar to that observed when schistosomes undergo oxidative stress [20]. It should be noted, however, that this conclusion is in contrast to that of El-Bassiouni et al [35] who observed that treatment of 3 or 6-week p.i. S. mansoni with up to 100 ng/mL PZQ in vitro for 1 or 3 h had no effect on the activities of superoxide dismutase, glutathione peroxidase or glutathione transferase though this may be due to the relatively low levels of PZQ employed.…”

Accumulation of artemisinin trioxane derivatives within neutral lipids of Plasmodium falciparum malaria parasites is endoperoxide-dependent

“…The quantitative contribution of oxidative stress to the potency of the endoperoxides remains to be established. However, the generation of ROS by ART derivatives in a variety of eukaryotic cell types [27, 28, 67], in juvenile schistosomes [68], and in P. falciparum , is clearly associated with cytotoxicity. Overall, this study provides evidence that the interaction of endoperoxides with neutral lipids may be an important component in their mechanism of action against malaria parasites.…”

Enzymatic antioxidant systems in helminth parasites

“…Differently from CT-SOD, SP-SOD and GPx, the GST are not present either in the digestive tract or on the tegumentum of adult worms (Holy et al 1989). Studies aimed to evaluate the possible toxicity of the drug artemether on S. mansoni have shown that in the immature stage of the parasite (inside the intermediate host represented by the gasteropode), a depletion of parasitic GST can be observed, occurring in a time-and dose-dependent way, suggesting a possible use of this drug as schistosomicide (El-Bassiouni et al 2007). …”