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

详细信息    查看全文

• 作者：Molly E. Ogle ^{meogle@gmail.com} ; Xiaohuan Gu ^{xgu22@emory.edu} ; Alyssa R. Espinera ^{aespine@emory.edu} ; Ling Wei ; ^{lwei7@emory.edu}
• 关键词：Focal cerebral ischemia ; Hypoxia inducible factor ; Prolyl hydroxylase ; preconditioning ; Postconditioning ; Dimethyloxaloylglycine
• 刊名：Neurobiology of Disease
• 出版年：2012
• 出版时间：February 2012
• 年：2012
• 卷：45
• 期：2
• 页码：733-742
• 全文大小：1314 K

文摘

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) 1¦Á 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-1¦Á. The PHD inhibitor dimethyloxaloylglycine (DMOG, 100 ¦ÌM) reduced cell death by oxygen glucose deprivation (OGD), an in vitro model of ischemia, and the protection required HIF-1¦Á. 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-1¦Á 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-1¦Á 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.