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Natural Vitamin E, α-Tocotrienol, as a Neuroprotectant

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2010, Doctor of Philosophy, Ohio State University, Human Ecology: Human Nutrition.

Natural vitamin E exists as the well known tocopherols and poorly studied tocotrienols. α-Tocotrienol (TCT) represents the most potent neuroprotective form of vitamin E. This work addresses a novel molecular mechanism by which α-TCT may be protective against stroke. Reduced glutathione (GSH) is a low molecular weight intracellular thiol in all aerobic cells. Under conditions of oxidative stress such as during stroke, large amounts of GSH are rapidly oxidized to glutathione disulfide (GSSG). The current study demonstrates that elevation of intracellular GSSG concentration may trigger neural cell death via a 12-lipoxygenase (12-Lox) dependent mechanism. Furthermore, this work elucidates that α-TCT may improve GSSG clearance in cells subjected to oxidative stress via upregulaton of multidrug resistance-associated protein 1 (MRP1) in the stroke-affected brain.

Objective: This dissertation addresses three specific aims: (i) determine the role of intracellular GSSG in neural cell death; (ii) characterize the significance of MRP1 as a GSSG efflux pathway in experimental stroke; and (iii) determine the MRP1-dependent neuroprotective property of α-TCT against stroke

Experimental approach and results: To elucidate the specific significance of GSSG in neural cell death, intracellular GSSG was specifically elevated by single cell microinjection. Control HT4 neural cells were microinjected with either the corresponding reduced form GSH or the vehicle (PBS). GSSG, but not GSH, caused cell death at pathophysiologically relevant concentrations. GSSG-induced death of the neural cells was protected in the presence of 12-Lox inhibitor or α-TCT. GSSG-dependent glutathionylation of 12-Lox emerged a critical player in neural cell death. Next, to test whether impaired cellular clearance of GSSG aggravates stroke-induced brain injury in vivo, middle cerebral artery occlusion (MCAO) was performed in MRP1-/- mice. Larger stroke-induced lesion in MRP-/- mice recognized a protective role of MRP1. In vitro, protection against glutamate-induced neurotoxicity by α-TCT was attenuated under conditions of MRP1 knockdown suggesting a role of MRP1 in α-TCT-dependent neuroprotection. In vivo studies demonstrated that oral supplementation of α-TCT protected brain against stroke-induced injury. MRP1 expression was elevated in the stroke affected tissue of α-TCT-supplemented mice. Efforts to elucidate the underlying mechanism identified MRP1 as a target of miR-199a-5p. In α-TCT supplemented mice, miR-199a-5p was downregulated in the stroke-affected tissue. This work recognizes MRP1 as a protective factor against stroke.

Conclusions: Work in this dissertation adds a new dimension to the current understanding of the molecular bases of α-TCT neuroprotection by identifying MRP1 as a α-TCT-sensitive target and by unveiling the general prospect that oral α-TCT may regulate microRNA expression in stroke-affected brain tissue.

Chandan Sen, Ph.D. (Advisor)
Savita Khanna, Ph.D. (Committee Member)
Sashwati Roy, Ph.D. (Committee Member)
Narasimham Parinandi, Ph.D. (Committee Member)
202 p.

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Citations

  • Park, H.-A. (2010). Natural Vitamin E, α-Tocotrienol, as a Neuroprotectant [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1291061955

    APA Style (7th edition)

  • Park, Han-A. Natural Vitamin E, α-Tocotrienol, as a Neuroprotectant. 2010. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1291061955.

    MLA Style (8th edition)

  • Park, Han-A. "Natural Vitamin E, α-Tocotrienol, as a Neuroprotectant." Doctoral dissertation, Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1291061955

    Chicago Manual of Style (17th edition)