PMID- 22061780
OWN - NLM
STAT- MEDLINE
DCOM- 20120518
LR  - 20211021
IS  - 1095-953X (Electronic)
IS  - 0969-9961 (Print)
IS  - 0969-9961 (Linking)
VI  - 45
IP  - 2
DP  - 2012 Feb
TI  - Inhibition of prolyl hydroxylases by dimethyloxaloylglycine after stroke reduces 
      ischemic brain injury and requires hypoxia inducible factor-1alpha.
PG  - 733-42
LID - 10.1016/j.nbd.2011.10.020 [doi]
AB  - 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) 1alpha 
      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-1alpha. The PHD 
      inhibitor dimethyloxaloylglycine (DMOG, 100 muM) reduced cell death by oxygen 
      glucose deprivation (OGD), an in vitro model of ischemia, and the protection 
      required HIF-1alpha. 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-1alpha 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-1alpha 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.
CI  - Copyright (c) 2011 Elsevier Inc. All rights reserved.
FAU - Ogle, Molly E
AU  - Ogle ME
AD  - Department of Anesthesiology, Emory University, Atlanta, GA 30322, USA. 
      meogle@gmail.com
FAU - Gu, Xiaohuan
AU  - Gu X
FAU - Espinera, Alyssa R
AU  - Espinera AR
FAU - Wei, Ling
AU  - Wei L
LA  - eng
GR  - NS062097/NS/NINDS NIH HHS/United States
GR  - R01 NS058710/NS/NINDS NIH HHS/United States
GR  - R01 NS058710-04/NS/NINDS NIH HHS/United States
GR  - NS058710/NS/NINDS NIH HHS/United States
GR  - NS045810/NS/NINDS NIH HHS/United States
GR  - R01 NS062097/NS/NINDS NIH HHS/United States
GR  - R01 NS045810-06/NS/NINDS NIH HHS/United States
GR  - R01 NS045810/NS/NINDS NIH HHS/United States
GR  - R01 NS062097-03/NS/NINDS NIH HHS/United States
GR  - R01 NS045155/NS/NINDS NIH HHS/United States
GR  - R01 NS045155-04/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20111029
PL  - United States
TA  - Neurobiol Dis
JT  - Neurobiology of disease
JID - 9500169
RN  - 0 (Amino Acids, Dicarboxylic)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - EC 1.14.11.2 (Procollagen-Proline Dioxygenase)
RN  - VVW38EB8YS (oxalylglycine)
SB  - IM
MH  - Amino Acids, Dicarboxylic/*pharmacology
MH  - Animals
MH  - Blotting, Western
MH  - Brain/drug effects/metabolism/physiopathology
MH  - Brain Ischemia/*metabolism/physiopathology
MH  - Cells, Cultured
MH  - Cerebrovascular Circulation/drug effects
MH  - Enzyme Inhibitors/*pharmacology
MH  - Gene Expression/drug effects
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*biosynthesis
MH  - Immunohistochemistry
MH  - Laser-Doppler Flowmetry
MH  - Mice
MH  - Neurons/drug effects/metabolism
MH  - Procollagen-Proline Dioxygenase/*antagonists & inhibitors
MH  - Real-Time Polymerase Chain Reaction
MH  - Reverse Transcriptase Polymerase Chain Reaction
PMC - PMC3286647
MID - NIHMS342026
COIS- Conflict of interest: N/A
EDAT- 2011/11/09 06:00
MHDA- 2012/05/19 06:00
PMCR- 2013/02/01
CRDT- 2011/11/09 06:00
PHST- 2011/06/27 00:00 [received]
PHST- 2011/10/02 00:00 [revised]
PHST- 2011/10/22 00:00 [accepted]
PHST- 2011/11/09 06:00 [entrez]
PHST- 2011/11/09 06:00 [pubmed]
PHST- 2012/05/19 06:00 [medline]
PHST- 2013/02/01 00:00 [pmc-release]
AID - S0969-9961(11)00352-4 [pii]
AID - 10.1016/j.nbd.2011.10.020 [doi]
PST - ppublish
SO  - Neurobiol Dis. 2012 Feb;45(2):733-42. doi: 10.1016/j.nbd.2011.10.020. Epub 2011 
      Oct 29.