We 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 (gp91(
phox-/-)) or mice treated with inhibitors of SOD (
diethyldithiocarbamate) or
NADPH oxidase (
diphenyleneiodonium) did not show protection or exacerbation for CM.
CONCLUSION: