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

• Type of Material: Article
• Authors: Hong-Ru Chen, University of Virginia; Chia-Yi Kuan, Emory University; Ning Gao, Emory University; Yi-Min Kuo, Taipei Veterans General Hospital; Ching-Wen Chen, University of Virginia; Dianer Yang, Emory University; Melissa M Kinkaid, University of Virginia; Erding Hu, GlaxoSmithKline; Yu-Yo Sun, Emory University
• Language: English
• Date: 2021-01-01
• Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 The Authors. Published by Elsevier Inc.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.nbd.2020.105200
• Title of Journal or Parent Work: NEUROBIOLOGY OF DISEASE
• Volume: 148
• Start Page: 105200
• End Page: 105200
• Grant/Funding Information: This work was supported by the National Institute of Health grants (NS095064, NS100419, and NS108763 to C.K. and NS106592 to Y.Y.S.).
• Keywords: SUSCEPTIBILITY; HIF-ALPHA; INHIBITION; COMPLEX; Intranasal; PLASMINOGEN-ACTIVATOR; Erythropoietin; Life Sciences & Biomedicine; Prolyl-hydroxylase; Hypoxic-ischemic encephalopathy; Science & Technology; INTRANASAL DELIVERY; Neurosciences & Neurology; MODEL; HIF-1-ALPHA; Neurosciences; ERYTHROPOIETIN; Birth asphyxia

Abstract

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.