['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.', 'Stroke-dependent brain tissue damage was studied in MRP1-deficient mice and α-TCT-supplemented mice.', '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.'] Does natural vitamin E α-tocotrienol protect against ischemic stroke by induction of multidrug resistance-associated protein 1?