Desferrioxamine induces delayed tolerance against cerebral ischemia in vivo and in vitro.
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.
Prass
Konstantin
K
Department of Neurology, Medical Faculty Charité, Humboldt-University, Berlin, Germany.
Ruscher
Karsten
K
Karsch
Maria
M
Isaev
Nikolay
N
Megow
Dirk
D
Priller
Josef
J
Scharff
Anna
A
Dirnagl
Ulrich
U
Meisel
Andreas
A
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003250:Constriction; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D003676:Deferoxamine / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004921:Erythropoietin / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000008:administration & dosage; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002546:Ischemic Attack, Transient / Q000517:prevention & control*; D008297:Male; D020768:Middle Cerebral Artery; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010100:Oxygen / Q000008:administration & dosage; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015424:Reperfusion; D013844:Thiazoles / Q000378:metabolism; D045162:Thiazolidinediones; D013997:Time Factors; D014157:Transcription Factors
D004268:DNA-Binding Proteins; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents; D009687:Nuclear Proteins; D011500:Protein Synthesis Inhibitors; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D004921:Erythropoietin; C114240:DN 108; D003513:Cycloheximide; D005947:Glucose; D003676:Deferoxamine; D010100:Oxygen