A role for hypoxia-inducible factor-1alpha in desferoxamine neuroprotection.
The newborn brain has increased vulnerability to hypoxia-ischemia from maturational differences in the oxidative stress response. We hypothesized that desferoxamine (DFO), an iron chelator, would provide protection in an in vitro model of ischemia in part through activation of the hypoxia-inducible gene hypoxia-inducible factor-1alpha (HIF-1alpha). Hippocampal neurons from E16 CD1 mice were exposed to 3 h of oxygen and glucose deprivation with and without pretreatment with 10 mmol/L DFO in the presence and absence of 2 micromol/L antisense oligonucleotides specific for HIF-1alpha (antiHIF-1alpha). DFO pretreatment resulted in 45% reduction in cell death (p = 0.006). This protection was diminished with transfection of antiHIF-1alpha (p = 0.049). Blocking HIF-1alpha reduces DFO protection suggesting that DFO protects through iron chelation and HIF-1alpha induction.
Hamrick
Shannon Elise Goldsmith
SE
Department of Pediatrics, University of California San Francisco, 521 Parnassus Avenue, C 215, San Francisco, CA 94143-0663, USA.
McQuillen
Patrick Sean
PS
Jiang
Xiangning
X
Mu
Dezhi
D
Madan
Ashima
A
Ferriero
Donna Marie
DM
D000704:Analysis of Variance; D000818:Animals; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D003676:Deferoxamine / Q000627:therapeutic use*; D004622:Embryo, Mammalian; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000166:cytology; D000860:Hypoxia / Q000517:prevention & control*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology*; D014162:Transfection / Q000379:methods; D016875:tau Proteins / Q000378:metabolism
D005904:Glial Fibrillary Acidic Protein; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D020320:Oligoribonucleotides, Antisense; D014157:Transcription Factors; D016875:tau Proteins; D005947:Glucose; D003676:Deferoxamine