Abstract
Production of reactive oxygen species (ROS) results in up-regulation of the extracellular signal-regulated kinase (ERK) cascade in response to numerous stimuli. Cerebral ischemia induces calcium-dependent kinase activation followed by ROS production. Here, we examined how ROS mediates the activation of ERK following cerebral ischemia in the rat hippocampus. We found that alpha-tocopherol, a free radical scavenger, attenuated the initial, robust activation of ERK by inhibiting Raf-1 dephosphorylation at Ser259. Alpha-tocopherol also down-regulated the second and mild activation of ERK through inhibition of Src-dependent phosphorylation of Raf-1 at Tyr340/341. Our results suggest that ROS production mediates the biphasic activation of ERK through different signaling cascades following post-ischemic reperfusion. Mediation of these signaling pathways involves changes in Raf-1 phosphorylation at different sites.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain / enzymology
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Brain / physiopathology
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Brain Ischemia / enzymology*
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Brain Ischemia / physiopathology
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Catalytic Domain / drug effects
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Catalytic Domain / physiology
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Free Radical Scavengers / pharmacology
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Male
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Oxidative Stress / drug effects
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Oxidative Stress / physiology*
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Phosphorylation / drug effects
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Proto-Oncogene Proteins c-raf / metabolism*
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Rats
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Rats, Sprague-Dawley
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Reactive Oxygen Species / metabolism*
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Reperfusion Injury / enzymology
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Reperfusion Injury / physiopathology
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Up-Regulation / drug effects
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Up-Regulation / physiology
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alpha-Tocopherol / pharmacology
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src-Family Kinases / metabolism
Substances
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Free Radical Scavengers
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Reactive Oxygen Species
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src-Family Kinases
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Proto-Oncogene Proteins c-raf
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Extracellular Signal-Regulated MAP Kinases
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alpha-Tocopherol