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

Abstract

BACKGROUND 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.