Tempol, an Intracellular Antioxidant, Inhibits Tissue Factor Expression, Attenuates Dendritic Cell Function, and Is Partially Protective in a Murine Model of Cerebral Malaria
نویسندگان
چکیده
BACKGROUND The role of intracellular radical oxygen species (ROS) in pathogenesis of cerebral malaria (CM) remains incompletely understood. METHODS AND FINDINGS 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 Results with Tempol suggest that intracellular ROS contribute, in part, to CM pathogenesis. Therapeutic targeting of intracellular ROS in CM is discussed.
منابع مشابه
Defibrotide interferes with several steps of the coagulation-inflammation cycle and exhibits therapeutic potential to treat severe malaria.
OBJECTIVE The coagulation-inflammation cycle has been implicated as a critical component in malaria pathogenesis. Defibrotide (DF), a mixture of DNA aptamers, displays anticoagulant, anti-inflammatory, and endothelial cell (EC)-protective activities and has been successfully used to treat comatose children with veno-occlusive disease. DF was investigated here as a drug to treat cerebral malaria...
متن کاملTanshinone IIA attenuates ovalbumin-induced airway inflammation and hyperresponsiveness in a murine model of asthma
Objective(s): Tanshinone IIA (T. IIA), one of the most pharmacologically active components extracted from Salviae miltiorrhiza, has anti-inflammatory and antioxidant features. The aim of the present study is to investigate the benefit of T. IIA on asthma using a murine model of asthma induced by ovalbumin (OVA). Materials and Methods: Male BALB/c mice were used in the present study. The mice we...
متن کاملObestatin inhibits apoptosis and astrogliosis of hippocampal neurons following global cerebral ischemia reperfusion via antioxidant and anti-inflammatory mechanisms
Objective(s): Obestatin is a newly discovered peptide with antioxidant activities in different animal models. Recent studies have shown that Obestatin inhibits apoptosis following cardiac ischemia/reperfusion injury. Brain ischemia/reperfusion induces irreversible damage especially in the hippocampus area. This study aimed at examining the protective impact of Obestati...
متن کاملEffect of Cytomegalovirus Recombinant Phosphoprotein 150 (pp150) on Function and Maturation of Murine Dendritic Cells: an In-Vitro Study
Background: Tegument protein pp150 of cytomegaloviruses (CMVs) plays a vital role in all stages of viral life cycle, representing the most important tegument protein candidate for HCMV treatment. However, the exact role of pp150 in immune regulation is yet to be elucidated. Objective: To examine the effects of pp150 on the maturity and function of muri...
متن کاملRadioprotection by tempol: Studies on tissue antioxidant levels, hematopoietic and gastrointestinal systems, in mice whole body exposed to sub- lethal doses of gamma radiation
Background: Ionizing radiation induces the production of reactive oxygen species (ROS), which play an important causative role in cell death. Wholebody exposure of mice to gamma radiation leads to diminution of tissue antioxidant defense systems increases the peroxidative damage to membrane lipids and damages the haematopoietic and gastrointestinal systems. Tempol (TPL), a cell membranep...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره 9 شماره
صفحات -
تاریخ انتشار 2014