BACKGROUND AND PURPOSE: 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.
BACKGROUND AND PURPOSE: 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-deficientmice 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-deficientmice 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 murinestroke. 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: Savita Khanna; Sashwati Roy; Andrew Slivka; Tara K S Craft; Soma Chaki; Cameron Rink; Margaret A Notestine; A Courtney DeVries; Narasimham L Parinandi; Chandan K Sen Journal: Stroke Date: 2005-09-15 Impact factor: 7.914
Authors: Edgar R Miller; Roberto Pastor-Barriuso; Darshan Dalal; Rudolph A Riemersma; Lawrence J Appel; Eliseo Guallar Journal: Ann Intern Med Date: 2004-11-10 Impact factor: 25.391
Authors: S W Leslie; L M Brown; R D Trent; Y H Lee; J L Morris; T W Jones; P K Randall; S S Lau; T J Monks Journal: Mol Pharmacol Date: 1992-02 Impact factor: 4.436
Authors: Jan Lewerenz; Sandra J Hewett; Ying Huang; Maria Lambros; Peter W Gout; Peter W Kalivas; Ann Massie; Ilse Smolders; Axel Methner; Mathias Pergande; Sylvia B Smith; Vadivel Ganapathy; Pamela Maher Journal: Antioxid Redox Signal Date: 2012-08-03 Impact factor: 8.401
Authors: Viren Patel; Cameron Rink; Gayle M Gordillo; Savita Khanna; Urmila Gnyawali; Sashwati Roy; Bassel Shneker; Kasturi Ganesh; Gary Phillips; J Layne More; Atom Sarkar; Robert Kirkpatrick; Elmahdi A Elkhammas; Emily Klatte; Michael Miller; Michael S Firstenberg; E Antonio Chiocca; Kalanithi Nesaretnam; Chandan K Sen Journal: J Nutr Date: 2012-02-01 Impact factor: 4.798