HIF-1 alpha inhibition ameliorates neonatal brain damage after hypoxic-ischemic injury.
BACKGROUND
Hypoxia-inducible-factor-1alpha (HIF-1alpha) has been considered as a regulator of both prosurvival and prodeath pathways in the nervous system. This study was designed to elucidate the role of HIF-1alpha in neonatal hypoxia-ischemia (HI) brain injury.


METHODS
2-methoxyestradiol (2ME2), a HIF-1alpha inhibitor, was tested at different dosages (1.5, 15 and 150 mg/kg) and a therapeutic window was tested by administrating 2-methoxyestradiol (15 mg/kg) immediately or 3 hours after the induction of a hypoxic ischemic injury. Infarct size using TTC staining and brain edema were measured at 48 hours post hypoxia-ischemia. Blood-brain barrier (BBB) permeability was examined by IgG staining. Vascular endothelial growth factor (VEGF) and HIF-1alpha expression and distribution were studied by immunohistochemistry and western blotting analysis.


RESULTS
2ME2 exhibited dose-dependent neuroprotection by decreasing infarct volume and attenuating brain edema. 2ME2 also attenuated BBB disruption, and decreased HIF-1alpha and vascular endothelial growth factor (VEGF) expression. The neuroprotection, however, was lost when 2ME2 was administered 3 hours after neonatal HI.


CONCLUSIONS
The study shows that the acute inhibition of HIF-1alpha is neuroprotective in neonatal hypoxic-ischemic injury by preserving BBB integrity and reducing brain edema.
Chen
Wanqiu
W
Department of Physiology and Pharmacology, Loma Linda University Medical Center, Risley Hall, Room 214, Loma Linda, CA 92354, USA.
Jadhav
Vikram
V
Tang
Jiping
J
Zhang
John H
JH
D000077584:2-Methoxyestradiol; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology; D001930:Brain Injuries / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives / Q000627:therapeutic use; D007839:Functional Laterality / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D020925:Hypoxia-Ischemia, Brain / Q000150:complications*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013778:Tetrazolium Salts; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013778:Tetrazolium Salts; D042461:Vascular Endothelial Growth Factor A; D004958:Estradiol; D000077584:2-Methoxyestradiol; C009591:triphenyltetrazolium