title: Natural vitamin E α-tocotrienol protects against ischemic stroke by induction of multidrug resistance-associated protein 1.
abstract: OBJECTIVE
  α-Tocotrienol (TCT) represents the most potent neuroprotective form of natural vitamin E that is Generally Recognized As Safe certified by the U.S. Food and Drug Administration. This work addresses a novel molecular mechanism by which α-TCT may be protective against stroke in vivo. Elevation of intracellular oxidized glutathione (GSSG) triggers neural cell death. Multidrug resistance-associated protein 1 (MRP1), a key mediator of intracellular oxidized glutathione efflux from neural cells, may therefore possess neuroprotective functions.
  
  
  METHODS
  Stroke-dependent brain tissue damage was studied in MRP1-deficient mice and α-TCT-supplemented mice.
  
  
  RESULTS
  Elevated MRP1 expression was observed in glutamate-challenged primary cortical neuronal cells and in stroke-affected brain tissue. MRP1-deficient mice displayed larger stroke-induced lesions, recognizing a protective role of MRP1. In vitro, protection against glutamate-induced neurotoxicity by α-TCT was attenuated under conditions of MRP1 knockdown; this suggests the role of MRP1 in α-TCT-dependent neuroprotection. In vivo studies demonstrated that oral supplementation of α-TCT protected against murine stroke. MRP1 expression was elevated in the stroke-affected cortical tissue of α-TCT-supplemented mice. Efforts to elucidate the underlying mechanism identified MRP1 as a target of microRNA (miR)-199a-5p. In α-TCT-supplemented mice, miR-199a-5p was downregulated in stroke-affected brain tissue.
  
  
  CONCLUSIONS
  This work recognizes MRP1 as a protective factor against stroke. Furthermore, findings of this study add a new dimension to the current understanding of the molecular bases of α-TCT neuroprotection in 2 ways: by identifying MRP1 as a α-TCT-sensitive target and by unveiling the general prospect that oral α-TCT may regulate miR expression in stroke-affected brain tissue.
authors: Department of Surgery, Davis Heart and Lung Research Institute, Ohio State University Medical Center, Columbus, Ohio, USA.
authors: Han-A
authors: HA
authors: Park
authors: Natalia
authors: N
authors: Kubicki
authors: Surya
authors: S
authors: Gnyawali
authors: Yuk Cheung
authors: YC
authors: Chan
authors: Sashwati
authors: S
authors: Roy
authors: Savita
authors: S
authors: Khanna
authors: Chandan K
authors: CK
authors: Sen
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002545:Brain Ischemia / Q000378:metabolism / Q000517:prevention & control*; D016923:Cell Death / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D020521:Stroke / Q000378:metabolism / Q000517:prevention & control*; D024508:Tocotrienols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D018696:Neuroprotective Agents; D024508:Tocotrienols; D014810:Vitamin E; C082032:tocotrienol, alpha; C421109:multidrug resistance-associated protein 1