Abstract
BackgroundThe role of intracellular radical oxygen species (ROS) in pathogenesis of cerebral malaria (CM) remains incompletely understood.Methods and FindingsWe undertook testing Tempol—a superoxide dismutase (SOD) mimetic and pleiotropic intracellular antioxidant—in cells relevant to malaria pathogenesis in the context of coagulation and inflammation. Tempol was also tested in a murine model of CM induced by Plasmodium berghei Anka infection. Tempol was found to prevent transcription and functional expression of procoagulant tissue factor in endothelial cells (ECs) stimulated by lipopolysaccharide (LPS). This effect was accompanied by inhibition of IL-6, IL-8, and monocyte chemoattractant protein (MCP-1) production. Tempol also attenuated platelet aggregation and human promyelocytic leukemia HL60 cells oxidative burst. In dendritic cells, Tempol inhibited LPS-induced production of TNF-α, IL-6, and IL-12p70, downregulated expression of co-stimulatory molecules, and prevented antigen-dependent lymphocyte proliferation. Notably, Tempol (20 mg/kg) partially increased the survival of mice with CM. Mechanistically, treated mice had lowered plasma levels of MCP-1, suggesting that Tempol downmodulates EC function and vascular inflammation. Tempol also diminished blood brain barrier permeability associated with CM when started at day 4 post infection but not at day 1, suggesting that ROS production is tightly regulated. Other antioxidants—such as α-phenyl N-tertiary-butyl nitrone (PBN; a spin trap), MnTe-2-PyP and MnTBAP (Mn-phorphyrin), Mitoquinone (MitoQ) and Mitotempo (mitochondrial antioxidants), M30 (an iron chelator), and epigallocatechin gallate (EGCG; polyphenol from green tea) did not improve survival. By contrast, these compounds (except PBN) inhibited Plasmodium falciparum growth in culture with different IC50s. Knockout mice for SOD1 or phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (gp91phox–/–) or mice treated with inhibitors of SOD (diethyldithiocarbamate) or NADPH oxidase (diphenyleneiodonium) did not show protection or exacerbation for CM.ConclusionResults with Tempol suggest that intracellular ROS contribute, in part, to CM pathogenesis. Therapeutic targeting of intracellular ROS in CM is discussed.
Highlights
Cerebral malaria (CM), caused by Plasmodium falciparum, is the deadliest form of malaria and is responsible for the deaths of approximately 500,000 humans each year, children in sub-Saharan countries
Results with Tempol suggest that intracellular radical oxygen species (ROS) contribute, in part, to cerebral malaria (CM) pathogenesis
Malondialdehyde plasma levels [46] or urinary F2-isoprostane [47] are increased in malaria patients, while antioxidant levels are suppressed [37,48,49,50]. These results indicate that unbalanced production of free radicals takes place in the disease and underscores the systemic component of P. falciparum infection, which is certainly not restricted to the brain
Summary
Cerebral malaria (CM), caused by Plasmodium falciparum, is the deadliest form of malaria and is responsible for the deaths of approximately 500,000 humans each year, children in sub-Saharan countries. Hemostatic dysregulation in malaria has been associated with lower nitric oxide (NO) bioavailability, complement activation, platelet GPIb shedding, microparticle formation, release of prohemostatic parasite molecules, and formation of ultralarge von Willebrand factor aggregates [10,11,12,13,17,18,19,20,21,22,23,24,25] These results highlight participation of several components of vascular biology in malaria pathogenesis [6] and as targets for adjuvant therapy [26,27,28,29]. The role of intracellular radical oxygen species (ROS) in pathogenesis of cerebral malaria (CM) remains incompletely understood
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