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Article: Natural vitamin E alpha-tocotrienol protects against ischemic stroke by induction of multidrug resistance-associated protein 1

TitleNatural vitamin E alpha-tocotrienol protects against ischemic stroke by induction of multidrug resistance-associated protein 1
Authors
Issue Date2011
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://stroke.ahajournals.org
Citation
Stroke, 2011, v. 42 n. 8, p. 2308-2314 How to Cite?
AbstractBACKGROUND AND PURPOSE: alpha-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 alpha-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 alpha-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 alpha-TCT was attenuated under conditions of MRP1 knockdown; this suggests the role of MRP1 in alpha-TCT-dependent neuroprotection. In vivo studies demonstrated that oral supplementation of alpha-TCT protected against murine stroke. MRP1 expression was elevated in the stroke-affected cortical tissue of alpha-TCT-supplemented mice. Efforts to elucidate the underlying mechanism identified MRP1 as a target of microRNA (miR)-199a-5p. In alpha-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 alpha-TCT neuroprotection in 2 ways: by identifying MRP1 as a alpha-TCT-sensitive target and by unveiling the general prospect that oral alpha-TCT may regulate miR expression in stroke-affected brain tissue.
Persistent Identifierhttp://hdl.handle.net/10722/197231
ISSN
2015 Impact Factor: 5.787
2015 SCImago Journal Rankings: 3.671
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorPark, HAen_US
dc.contributor.authorKubicki, Nen_US
dc.contributor.authorGnyawali, Sen_US
dc.contributor.authorChan, YCen_US
dc.contributor.authorRoy, Sen_US
dc.contributor.authorKhanna, Sen_US
dc.contributor.authorSen, CKen_US
dc.date.accessioned2014-05-23T02:27:36Z-
dc.date.available2014-05-23T02:27:36Z-
dc.date.issued2011en_US
dc.identifier.citationStroke, 2011, v. 42 n. 8, p. 2308-2314en_US
dc.identifier.issn0039-2499en_US
dc.identifier.urihttp://hdl.handle.net/10722/197231-
dc.description.abstractBACKGROUND AND PURPOSE: alpha-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 alpha-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 alpha-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 alpha-TCT was attenuated under conditions of MRP1 knockdown; this suggests the role of MRP1 in alpha-TCT-dependent neuroprotection. In vivo studies demonstrated that oral supplementation of alpha-TCT protected against murine stroke. MRP1 expression was elevated in the stroke-affected cortical tissue of alpha-TCT-supplemented mice. Efforts to elucidate the underlying mechanism identified MRP1 as a target of microRNA (miR)-199a-5p. In alpha-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 alpha-TCT neuroprotection in 2 ways: by identifying MRP1 as a alpha-TCT-sensitive target and by unveiling the general prospect that oral alpha-TCT may regulate miR expression in stroke-affected brain tissue.en_US
dc.languageengen_US
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://stroke.ahajournals.orgen_US
dc.relation.ispartofStrokeen_US
dc.subject.meshAntioxidants - pharmacologyen_US
dc.subject.meshBrain Ischemia - metabolism - prevention and controlen_US
dc.subject.meshMultidrug Resistance-Associated Proteins - metabolismen_US
dc.subject.meshStroke - metabolism - prevention and controlen_US
dc.subject.meshVitamin E - analogs and derivatives - pharmacologyen_US
dc.titleNatural vitamin E alpha-tocotrienol protects against ischemic stroke by induction of multidrug resistance-associated protein 1en_US
dc.typeArticleen_US
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1161/STROKEAHA.110.608547en_US
dc.identifier.pmid21719775-
dc.identifier.pmcidPMC3362046en_US
dc.identifier.scopuseid_2-s2.0-79961209314-
dc.identifier.hkuros221317en_US
dc.identifier.volume42en_US
dc.identifier.issue8en_US
dc.identifier.spage2308en_US
dc.identifier.epage2314en_US
dc.identifier.isiWOS:000293077400042-
dc.publisher.placeUnited Statesen_US

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