Protective Effect of Vitamin E Against Focal Brain Ischemia and Neuronal Death Through Induction of Target Genes of Hypoxia-Inducible factor-1

Neuroscience. 2004;126(2):433-40. doi: 10.1016/j.neuroscience.2004.03.057.

Abstract

Vitamin E has been shown to have protective effects against cerebral ischemia, possibly due to its anti-oxidant effects. However, its non-anti-oxidant, intracellular molecular mechanism remains elusive. For in vivo experiments in rats, orally administered vitamin E significantly reduced not only the brain infarct volume but also space navigation disability after permanent middle cerebral artery (MCA) occlusion. The level of anti-oxidant after MCA occlusion was significantly increased specifically in the ipsilateral brain tissues of vitamin E-treated rats. For in vitro experiments, posttreatment with vitamin E protected primary cultured neurons from nitric oxide-induced insult. Vitamin E induced the expression of the alpha subunit of hypoxia-inducible factor-1 (HIF-1) and its target genes, including vascular endothelial growth factor (VEGF) and heme oxygenase-1. The hypoxia response element on the VEGF promoter was responsible for this vitamin E-induced transcriptional activation of VEGF gene. Taken together, these results suggest that cerebral infarction increased the permeability of vitamin E across the blood-brain barrier, and this increased vitamin E in brain tissue elicited neuroprotective effects not only through scavenging oxidants, as are previously well reported, but also by transactivating HIF-1-dependent genes, which results in protection of brains from ischemic insults.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Brain Ischemia / genetics
  • Brain Ischemia / metabolism
  • Brain Ischemia / prevention & control*
  • Cell Death / drug effects
  • Cell Death / physiology
  • DNA-Binding Proteins / biosynthesis*
  • DNA-Binding Proteins / genetics
  • Dose-Response Relationship, Drug
  • Escape Reaction / drug effects
  • Escape Reaction / physiology
  • Heat-Shock Proteins / biosynthesis*
  • Heat-Shock Proteins / genetics
  • Heme Oxygenase (Decyclizing)
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Male
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use
  • Nuclear Proteins / biosynthesis*
  • Nuclear Proteins / genetics
  • Oxygenases*
  • Rats
  • Rats, Inbred SHR
  • Transcription Factors*
  • Vascular Endothelial Growth Factor A / biosynthesis*
  • Vascular Endothelial Growth Factor A / genetics
  • Vitamin E / pharmacology
  • Vitamin E / therapeutic use*

Substances

  • Antioxidants
  • DNA-Binding Proteins
  • Heat-Shock Proteins
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Neuroprotective Agents
  • Nuclear Proteins
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, rat
  • Vitamin E
  • Oxygenases
  • Heme Oxygenase (Decyclizing)
  • Hmox1 protein, rat