Natural Vitamin E α-Tocotrienol Protects Against Ischemic Stroke by Induction of Multidrug Resistance-Associated Protein 1

• Published in: Stroke (1970) Vol. 42; no. 8; pp. 2308 - 2314
• Main Authors: PARK, Han-A, KUBICKI, Natalia, GNYAWALI, Surya, YUK CHEUNG CHAN, ROY, Sashwati, KHANNA, Savita, SEN, Chandan K
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.08.2011
• Subjects: Animals; Antioxidants - pharmacology; Biological and medical sciences; Brain Ischemia - metabolism; Brain Ischemia - prevention & control; Cell Death - drug effects; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Male; Medical sciences; Mice; Multidrug Resistance-Associated Proteins - metabolism; Nervous system (semeiology, syndromes); Neurology; Neurons - drug effects; Neurons - metabolism; Neuroprotective Agents - pharmacology; Stroke - metabolism; Stroke - prevention & control; Tocotrienols; Vascular diseases and vascular malformations of the nervous system; Vitamin E - analogs & derivatives; Vitamin E - pharmacology; Cerebral infarction; Stroke; Nervous system diseases; glutathione; Vitamin; vitamin E; Cardiovascular disease; Antioxidant; Cerebral disorder; Vascular disease; Central nervous system disease; Brain ischemia; microRNA; Cerebrovascular disease
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/STROKEAHA.110.608547

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. 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.