Abstract
The widely prescribed drug desferrioxamine is a known activator of the hypoxia-inducible transcription factor 1 (HIF-1) and the subsequent transcription of erythropoietin. In the brain, HIF-1 is a master switch of the transcriptional response to hypoxia, whereas erythropoietin is a potent neuroprotectant. The authors show that desferrioxamine dose-dependently and time-dependently induces tolerance against focal cerebral ischemia in rats and mice, and against oxygen-glucose deprivation in purified cortical neurons. Desferrioxamine induced HIF-1 DNA binding and transcription of erythropoietin in vivo, the temporal kinetics of which were congruent with tolerance induction. Desferrioxamine is a promising drug for the induction of tolerance in humans when ischemia can be anticipated.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Survival / drug effects
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Cells, Cultured
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Cerebral Cortex / drug effects
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Cerebral Cortex / metabolism
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Constriction
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Cycloheximide / pharmacology
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DNA-Binding Proteins / metabolism
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Deferoxamine / administration & dosage
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Deferoxamine / therapeutic use*
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Dose-Response Relationship, Drug
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Embryo, Mammalian
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Erythropoietin / genetics
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Gene Expression / drug effects
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Glucose / administration & dosage
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Iron Chelating Agents / administration & dosage
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Iron Chelating Agents / therapeutic use*
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Ischemic Attack, Transient / prevention & control*
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Male
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Middle Cerebral Artery
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Neurons / drug effects
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Neurons / metabolism
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Nuclear Proteins / metabolism
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Oxygen / administration & dosage
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Protein Synthesis Inhibitors / pharmacology
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Rats
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Rats, Wistar
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Reperfusion
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Thiazoles / metabolism
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Thiazolidinediones*
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Time Factors
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Transcription Factors*
Substances
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DNA-Binding Proteins
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Hif1a protein, rat
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Iron Chelating Agents
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Nuclear Proteins
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Protein Synthesis Inhibitors
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Thiazoles
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Thiazolidinediones
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Transcription Factors
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Erythropoietin
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DN 108
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Cycloheximide
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Glucose
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Deferoxamine
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Oxygen