Oxidative Stress: A Potential Therapeutic Target in Placental Malaria

Abstract

Placental malaria, characterized by sequestration of Plasmodium falciparum in the maternal placental blood space and associated inflammatory damage, contributes to poor birth outcomes and ~200,000 infant deaths annually. Specific mechanisms that contribute to placental damage and dysfunction during malaria are not completely understood. To investigate a potential role for oxidative stress, antioxidant genes and markers for oxidative damage were assessed by quantitative PCR and immunohistochemistry in Plasmodium chabaudi AS-infected pregnant mice. Widespread evidence of lipid peroxidation was observed and was associated with higher antioxidant gene expression in conceptuses of infected mice. To assess the extent to which this oxidative damage might contribute to poor birth outcomes and be amenable to therapeutic intervention, infected pregnant mice were treated with N-acetylcysteine, a free radical scavenger, or tempol, an intracellular superoxide dismutase mimetic. The results show that mice treated with N-acetylcysteine experienced malaria induced–pregnancy loss at the same rate as control animals and failed to mitigate placental oxidative damage. In contrast, tempol-treated mice exhibited subtle improvement in embryo survival at gestation day 12. Although lipid peroxidation was not consistently reduced in the placentas of these mice, it was inversely related to embryo viability. Moreover, reduced IFN-γ and CCL2 plasma levels in treated mice were associated with midgestational embryo viability. Thus, although oxidative stress is remarkable in placental malaria and its mitigation by antioxidant therapy may improve pregnancy outcomes, the underlying mechanistic basis and potential therapeutic strategies require additional investigation.

Composition of the gut microbiota transcends genetic determinants of malaria infection severity and influences pregnancy outcome

“…Accumulation of haemozoin in the P. falciparum- infected human placenta is a key feature of the infection, and, embedded in fibrin or present in infiltrating maternal phagocytes, is linked with pathogenesis [96]. Haemozoin accumulation in the infected Swiss Webster placenta is associated with enhanced anti-oxidant gene expression [ Morffy Smith, in review ] and may be a key driver of embryotoxic oxidative stress [49]. Compared to mid-gestational conceptuses from infected ABX-FMT JAX mice, infected NCI-sourced placentae tended to accumulate more haemozoin, with significant accumulation in both foetal (trophoblast) [ Morffy Smith, in review ] and maternal inflammatory cells.…”

“…Infections were initiated as previously described [[28], [29], [30],49,50]. Briefly, mice were infected intravenously with 10 3 iRBCs diluted in 200 μl of 1× PBS per 20 g of body weight.…”

Testing an infection model to explain excess risk of preterm birth with long-term iron supplementation in a malaria endemic area

“…Placental intervillositis occurs [36], with induction of oxidative stress biomarkers [42]. Oxidative stress, is an imbalance between oxidants and antioxidants in favour of oxidants, and leads to disruption of redox signalling and physiological function [43]. Placental parasites result in haemozoin formation leading to stimulation of cytokine responses [44, 45], regulation of iNOS expression [46] and NLRP3 inflammasome priming [47].…”

The Preventive Effects of Xanthohumol on Vascular Calcification Induced by Vitamin D3 Plus Nicotine

“…Some studies have suggested that oxidative stress plays a critical role in the pathogenesis of VC, and it is associated with certain conditions such as hypercholesterolemia, hypertension, diabetes mellitus, and dialysis-dependent end stage renal disease [ 33 ]. A brief summary of the existing literature regarding antioxidants for VC is important, as no effective treatment is currently obtainable for this disease [ 34 , 35 , 36 , 37 ]. Therefore, it is important to increase antioxidative capacity and reduce oxidative to prevent VC.…”