Abstract
Hypoxia-inducible factor-1alpha (HIF-1alpha) has been considered as a regulator of both prosurvival and prodeath pathways in the nervous system. The present study was designed to elucidate the role of HIF-1alpha in neonatal hypoxic-ischemic (HI) brain injury. Rice-Vannucci model of neonatal hypoxic-ischemic brain injury was used in seven-day-old rats, by subjecting unilateral carotid artery ligation followed by 2 h of hypoxia (8% O2 at 37 degrees C). HIF-1alpha activity was inhibited by 2-methoxyestradiol (2ME2) and enhanced by dimethyloxalylglycine (DMOG). Results showed that 2ME2 exhibited dose-dependent neuroprotection by decreasing infarct volume and reducing brain edema at 48 h post HI. The neuroprotection was lost when 2ME2 was administered 3 h post HI. HIF-1alpha upregulation by DMOG increased the permeability of the BBB and brain edema compared with HI group. 2ME2 attenuated the increase in HIF-1alpha and VEGF 24 h after HI. 2ME2 also had a long-term effect of protecting against the loss of brain tissue. The study showed that the early inhibition of HIF-1alpha acutely after injury provided neuroprotection after neonatal hypoxia-ischemia which was associated with preservation of BBB integrity, attenuation of brain edema, and neuronal death.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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2-Methoxyestradiol
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Amino Acids, Dicarboxylic / pharmacology
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Amino Acids, Dicarboxylic / therapeutic use
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Animals
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Animals, Newborn
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Blood-Brain Barrier / drug effects
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Blood-Brain Barrier / metabolism
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Brain / drug effects*
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Brain / metabolism*
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Brain / physiopathology
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Brain Edema / drug therapy
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Brain Edema / metabolism
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Brain Edema / physiopathology
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Brain Infarction / drug therapy
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Brain Infarction / metabolism
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Brain Infarction / physiopathology
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Cytoprotection / drug effects
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Cytoprotection / physiology
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Estradiol / analogs & derivatives
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Estradiol / pharmacology
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Estradiol / therapeutic use
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Female
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Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Hypoxia-Ischemia, Brain / drug therapy*
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Hypoxia-Ischemia, Brain / metabolism*
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Hypoxia-Ischemia, Brain / physiopathology
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Neuroprotective Agents / pharmacology
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Neuroprotective Agents / therapeutic use
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Rats
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Tubulin Modulators / pharmacology
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Vascular Endothelial Growth Factor A / drug effects
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Amino Acids, Dicarboxylic
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Enzyme Inhibitors
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Hif1a protein, rat
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Hypoxia-Inducible Factor 1, alpha Subunit
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Neuroprotective Agents
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Tubulin Modulators
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, rat
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Estradiol
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2-Methoxyestradiol
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oxalylglycine