title: Protective effect of vitamin E against focal brain ischemia and neuronal death through induction of target genes of hypoxia-inducible factor-1.
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.
authors.affiliation: Department of Physiology, School of Medicine, Ehime University, Shitsukawa, Shigenobu-cho, Onsen-gun, Ehime 791-0295, Japan.
authors.forename: B
authors.initials: B
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Tanaka
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.forename: M
authors.initials: M
authors.lastname: Sakanaka
authors.forename: R
authors.initials: R
authors.lastname: Hata
authors.forename: N
authors.initials: N
authors.lastname: Maeda
authors.forename: N
authors.initials: N
authors.lastname: Mitsuda
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004924:Escape Reaction / Q000187:drug effects / Q000502:physiology; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006419:Heme Oxygenase (Decyclizing); D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D010105:Oxygenases; D051381:Rats; D011918:Rats, Inbred SHR; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics; D014810:Vitamin E / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D014810:Vitamin E; D010105:Oxygenases; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat