title: Inhibition of prolyl hydroxylases by dimethyloxaloylglycine after stroke reduces ischemic brain injury and requires hypoxia inducible factor-1α.
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.
authors: Department of Anesthesiology, Emory University, Atlanta, GA 30322, USA. meogle@gmail.com
authors: Molly E
authors: ME
authors: Ogle
authors: Xiaohuan
authors: X
authors: Gu
authors: Alyssa R
authors: AR
authors: Espinera
authors: Ling
authors: L
authors: Wei
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D007150:Immunohistochemistry; D017078:Laser-Doppler Flowmetry; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000600:Amino Acids, Dicarboxylic; D004791:Enzyme Inhibitors; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011393:Procollagen-Proline Dioxygenase; C040947:oxalylglycine