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

Only 5.5 years old and I bet not one thing has been done to get this into a stroke protocol. No one cares about helping stroke survivors, certainly not the ASA, NSA or the WSO. You are completely on your own, start saving your money to hire your own researchers. Your children and grandchildren will need it. 

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

Department of Anesthesiology, Emory University, Atlanta, GA 30322, USA

https://doi.org/10.1016/j.nbd.2011.10.020Get rights and content

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, 100 μM) reduced cell death by oxygen glucose deprivation (OGD), an in vitro model of ischemia, and the protection required HIF-1α. In vivo, DMOG (50 mg/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.

Highlights

► PHD inhibition by DMOG after stroke reduces ischemic damage. ► Post-ischemic DMOG enhances peri-infarct HIF-1α expression. ► Neuroprotection by DMOG in vivo requires HIF-1α activity.

Keywords

Focal cerebral ischemia

Hypoxia inducible factor

Prolyl hydroxylase

preconditioning

Postconditioning

Dimethyloxaloylglycine

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Copyright © 2011 Elsevier Inc. All rights reserved.