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Title page for ETD etd-03252014-112738


Type of Document Dissertation
Author Meredith, Martha Elizabeth
Author's Email Address elizabeth.meredith@vanderbilt.edu
URN etd-03252014-112738
Title Multiple roles for Ascorbic Acid in the Brain: Transporter Regulation, Neurotransmitter Synthesis, and Brain Endothelial Cell Stability
Degree PhD
Department Molecular Physiology and Biophysics
Advisory Committee
Advisor Name Title
Roger Colbran Committee Chair
Eric Delpire Committee Member
Kate Ellacott Committee Member
Michael Aschner Committee Member
Owen McGuinness Committee Member
Keywords
  • permeability
  • neurotransmitter
  • oxidative stress
  • SVCT2
  • ascorbic acid
  • diabetes
  • blood brain barrier
Date of Defense 2014-03-10
Availability unrestricted
Abstract
The roles for ascorbic acid (ASC) in regulation of its transporter, in neurotransmitter synthesis, and in brain endothelial cell barrier permeability were investigated in the brain. First, during mouse development, levels of the main transporter for ASC, the sodium-dependent vitamin C transporter 2 (SVCT2), were low throughout gestation and increased substantially postnatally. This was inversely associated with ASC levels in brain, in which ASC content increased just before birth and decreased postnatally. In adults, low cortex ASC did not affect the SVCT2 level. Second, neurotransmitter levels were increased or decreased in conjunction with altered ASC concentrations in embryos. Dopamine and norepinephrine were decreased in embryos with low levels of cortex ASC, while protein levels of the primary enzyme responsible for synthesis, tyrosine hydroxylase, were decreased. Dopamine and serotonin were increased in embryos with excess ASC. Third, intracellular ASC significantly decreased brain endothelial cell permeability. Culture of endothelial cells in high glucose (25 mM) and activation of the receptor for advanced glycation end-products increased endothelial permeability, an effect that was prevented by intracellular ASC. ASC decreased endothelial permeability under basal glucose conditions by acting, at least in part, through Epac1 and cytoskeleton rearrangement. In all, the data presented here shows the importance of ASC in the brain, especially in the context of development, neurotransmitter synthesis, and brain endothelial cell stability.
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