Abstract
Edaravone, a potent free radical scavenger, is clinically used for the treatment of cerebral infarction in Japan. Here, we examined the effects of edaravone on the dynamics of high-mobility group box-1 (HMGB1), which is a key mediator of ischemic-induced brain damage, during a 48-h postischemia/reperfusion period in rats and in oxygen-glucose-deprived (OGD) PC12 cells. HMGB1 immunoreactivity was observed in both the cytoplasm and the periphery of cells in the cerebral infarction area 2 h after reperfusion. Intravenous administration of 3 and 6 mg/kg edaravone significantly inhibited nuclear translocation and HMGB1 release in the penumbra area and caused a 26.5 +/- 10.4 and 43.8 +/- 0.5% reduction, respectively, of the total infarct area at 24 h after reperfusion. Moreover, edaravone also decreased plasma HMGB1 levels. In vitro, edaravone dose-dependently (1-10 microM) suppressed OGD- and H(2)O(2)-induced HMGB1 release in PC12 cells. Furthermore, edaravone (3-30 microM) blocked HMGB1-triggered apoptosis in PC12 cells. Our findings suggest a novel neuroprotective mechanism for edaravone that abrogates the release of HMGB1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Animals
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Antipyrine / analogs & derivatives*
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Antipyrine / pharmacology
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Antipyrine / therapeutic use
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Apoptosis / drug effects
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Butadienes / pharmacology
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Cell Hypoxia / drug effects
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Cell Hypoxia / physiology
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Cell Nucleus / metabolism
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Cerebral Infarction / drug therapy*
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Cerebral Infarction / metabolism
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Cerebral Infarction / pathology
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Cerebrum / metabolism
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Cerebrum / pathology
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Cytochromes c / metabolism
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Cytoplasm / drug effects
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Cytoplasm / metabolism
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Edaravone
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Free Radical Scavengers / pharmacology*
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Free Radical Scavengers / therapeutic use
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Glucose / deficiency
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HMGB1 Protein / blood
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HMGB1 Protein / metabolism*
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Hydrogen Peroxide / pharmacology
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Male
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Neurons / drug effects*
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Neurons / metabolism*
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Neuroprotective Agents / pharmacology
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Neuroprotective Agents / therapeutic use
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Nitriles / pharmacology
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Oxidative Stress / drug effects
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Oxidative Stress / physiology
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PC12 Cells
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Rats
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Rats, Wistar
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S100 Proteins / metabolism
Substances
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Butadienes
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Enzyme Inhibitors
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Free Radical Scavengers
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HMGB1 Protein
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Neuroprotective Agents
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Nitriles
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S100 Proteins
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U 0126
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Cytochromes c
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Hydrogen Peroxide
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Extracellular Signal-Regulated MAP Kinases
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Glucose
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Edaravone
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Antipyrine