Brain-targeted hypoxia-inducible factor stabilization. Reduces neonatal hypoxic-ischemic brain injury

Chia Yi Kuan*, Hong Ru Chen, Ning Gao, Yi Min Kuo, Ching Wen Chen, Dianer Yang, Melissa M. Kinkaid, Erding Hu, Yu Yo Sun

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Hypoxia-inducible factor-1α (HIF1α) is a major regulator of cellular adaptation to hypoxia and oxidative stress, and recent advances of prolyl-4-hydroxylase (P4H) inhibitors have produced powerful tools to stabilize HIF1α for clinical applications. However, whether HIF1α provokes or resists neonatal hypoxic-ischemic (HI) brain injury has not been established in previous studies. We hypothesize that systemic and brain-targeted HIF1α stabilization may have divergent effects. To test this notion, herein we compared the effects of GSK360A, a potent P4H inhibitor, in in-vitro oxygen-glucose deprivation (OGD) and in in-vivo neonatal HI via intracerebroventricular (ICV), intraperitoneal (IP), and intranasal (IN) drug-application routes. We found that GSK360A increased the erythropoietin (EPO), heme oxygenase-1 (HO1) and glucose transporter 1 (Glut1) transcripts, all HIF1α target-genes, and promoted the survival of neurons and oligodendrocytes after OGD. Neonatal HI insult stabilized HIF1α in the ipsilateral hemisphere for up to 24 h, and either ICV or IN delivery of GSK360A after HI increased the HIF1α target-gene transcripts and decreased brain damage. In contrast, IP-injection of GSK360A failed to reduce HI brain damage, but elevated the risk of mortality at high doses, which may relate to an increase of the kidney and plasma EPO, leukocytosis, and abundant vascular endothelial growth factor (VEGF) mRNAs in the brain. These results suggest that brain-targeted HIF1α-stabilization is a potential treatment of neonatal HI brain injury, while systemic P4H-inhibition may provoke unwanted adverse effects.

Original languageEnglish
Article number105200
JournalNeurobiology of Disease
StatePublished - Jan 2021


  • Birth asphyxia
  • Erythropoietin
  • Hypoxic-ischemic encephalopathy
  • Intranasal
  • Prolyl-hydroxylase


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