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Author Notes:

Correspondence: Dr. Ling Wei, 101 Woodruff Circle, WMB 617, Atlanta, GA, USA 30322; Ph: 404-712-8221; Fax: 404-727-6300; Email: lwei7@emory.edu

Acknowledgments: We gratefully acknowledge the technical support from Xiang Jun Zeng in the cloning and production of the shRNA virus and Dongdong Chen for assistance in cell culture.

Disclosures: No conflict of interest

Subject:

Research Funding:

This work was supported by National Institutes of Health Grants NS045810, NS062097, NS058710; and American Heart Association Grant 0840110N.

Keywords:

  • Focal cerebral ischemia
  • hypoxia inducible factor
  • prolyl hydroxylase
  • preconditioning
  • postconditioning
  • dimethyloxaloylglycine

Inhibition of prolyl hydroxylases by dimethyloxaloylglycine after stroke reduces ischemic brain injury and requires hypoxia inducible factor-1

Tools:

Journal Title:

Neurobiology of Disease

Volume:

Volume 45, Number 2

Publisher:

, Pages 733-742

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Pathological oxygen deprivation inhibits prolyl hydroxylase (PHD) activity and stimulates a protective cellular oxygen-sensing response in part through the stabilization and activation of the Hypoxia Inducible Factor (HIF) 1α transcription factor. The present investigation tested the therapeutic potential of enhanced activation of oxygen-sensing pathways by competitive pharmacologic PHD inhibition after stroke, hypothesizing that post-ischemic PHD inhibition would reduce neuronal cell death and require the activation of HIF-1α. The PHD inhibitor dimethyloxaloylglycine (DMOG, 100μM) reduced cell death by oxygen glucose deprivation (OGD), an in vitro model of ischemia, and the protection required HIF-1α. In vivo, DMOG (50mg/kg, i.p.) administered 30 or 60 min after distal occlusion of the middle cerebral artery (MCA) in mice enhanced the activation of HIF-1α protein, enhanced transcription of the HIF-regulated genes vascular endothelial growth factor, erythropoietin, endothelial nitric oxide synthase, and pyruvate dehydrogenase kinase-1, reduced ischemic infarct volume and activation of the pro-apoptotic caspase-3 protein, reduced behavioral deficits after stroke, and reduced the loss of local blood flow in the MCA territory after stroke. Inhibition of HIF-1α in vivo by Digoxin or Acriflavine abrogated the infarct sparing properties of DMOG. These data suggest that supplemental activation of oxygen-sensing pathways after stroke may provide a clinically applicable intervention for the promotion of neurovascular cell survival after ischemia.

Copyright information:

© 2011 Elsevier Inc. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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