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.

Neuronal HIF-1α and HIF-2α deficiency improves neuronal survival and sensorimotor function in the early acute phase after ischemic stroke

Once again this will not be followed up with human clinical trials. But since we have NO stroke strategy or stroke leadership in any part of stroke this will fall thru the cracks. Our fucking failures of stroke associations once again will lead the way to failure but not doing anything about this.
http://jcb.sagepub.com/content/early/2016/01/08/0271678X15624933.abstract?

1. Philipp Barteczek
2. Lexiao Li
3. Anne-Sophie Ernst
4. Laura-Inés Böhler
5. Hugo H Marti
6. Reiner Kunze⇑

1. Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany

1. Reiner Kunze, Institute of Physiology and Pathophysiology, University of Heidelberg, Im Neuenheimer Feld 326, Heidelberg 69120, Germany. Email: reiner.kunze@physiologie.uni-heidelberg.de

Abstract

Hypoxia-inducible factors mediate adaptive responses to ischemia, among others, by induction of anti- and pro-survival genes. Thus, the impact of HIF on neuronal survival upon stroke is controversial. Therefore, neuron-specific knockout mice deficient for Hif1a and Hif2a were exposed to inspiratory hypoxia or ischemia–reperfusion injury. Both Hif1a- and Hif2a-deficient mice showed no altered infarct and edema size, suggesting that both HIF-α subunits might compensate for each other. Accordingly, hypoxic HIF-target gene regulation was marginally affected with exception of anti-survival Bnip3 and pro-survival erythropoietin. In the early acute stage upon stroke, Hif1a/Hif2a double knockout mice exhibited significantly reduced expression of the anti-survival Bnip3, Bnip3L, and Pmaip1. Accordingly, global cell death and edema were significantly reduced upon 24 h but not 72 h reperfusion. Behavioral assessment indicated that Hif1a/Hif2a-deficient mice initially performed better, but became significantly more impaired after 72 h accompanied by increased apoptosis and reduced angiogenesis. Our findings suggest that in neurons HIF-1 and HIF-2 have redundant functions for cellular survival under ischemic conditions. By contrast, lack of anti-survival factors in Hif1a/Hif2a-deficient mice might protect from early acute neuronal cell death and neurological impairment, indicating a benefit of HIF-pathway inhibition in neurons in the very acute phase after ischemic stroke.