HIF-1alpha inhibition ameliorates neonatal brain injury in a rat pup hypoxic-ischemic model.
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.
Chen
Wanqiu
W
Department of Physiology and Pharmacology, Loma Linda University, School of Medicine, Loma Linda, CA, USA.
Jadhav
Vikram
V
Tang
Jiping
J
Zhang
John H
JH
D000077584:2-Methoxyestradiol; D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000831:Animals, Newborn; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D020520:Brain Infarction / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D050257:Tubulin Modulators / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism
D000600:Amino Acids, Dicarboxylic; D004791:Enzyme Inhibitors; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D050257:Tubulin Modulators; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D004958:Estradiol; D000077584:2-Methoxyestradiol; C040947:oxalylglycine