Review ArticleVitamin C function in the brain: vital role of the ascorbate transporter SVCT2
Section snippets
Vitamin C chemistry, cellular uptake, and recycling
Vitamin C, or ascorbic acid, has many different functions in humans and other mammals. In addition to its well-known role as an antioxidant, the vitamin serves as a cofactor in several important enzyme reactions, including those involved in the synthesis of catecholamines, carnitine, cholesterol, amino acids, and certain peptide hormones [1]. Of course, its best-known function is to facilitate the hydroxylation of proline and lysine residues in collagen, allowing proper intracellular folding of
Vitamin C accumulation and maintenance in the central nervous system (CNS): role of SVCT2
Vitamin C may be more than simply a “micronutrient” in the CNS, because it is present in millimolar concentrations in neuron-rich areas. There are two novel aspects of how ascorbate enters the CNS that distinguish its uptake from that seen in other organ systems (Fig. 2). First, although ascorbate transport across the blood–brain barrier occurs [37], [38], it is very slow [37], and second, the ability to maintain a steep ascorbate concentration gradient from blood to neuronal cells is generated
Functions of vitamin C in the brain
The functions of ascorbate in the CNS and brain are numerous. Although all actions of ascorbate involve the donation of a single electron, they can be divided into those considered antioxidant and non-antioxidant in nature. Many of the latter functions involve monovalent reduction of Fe3+ or Cu2+ at the active sites of dioxygenase enzymes in hydroxylation reactions. Regarding the antioxidant functions, ascorbate directly acts to scavenge oxygen- or nitrogen-based radical species generated
Brain ascorbate deficiency
Scurvy causes severe lassitude and asthenia in humans. Although the disease has been associated with paraparesis in humans, death seems to be due more to complications of systemic collagen dysfunction rather than to a distinct neurologic syndrome [135]. This likely relates to the fact that ascorbate is avidly retained by the CNS during ascorbate deficiency [136]. Indeed, as described by James Lind in his Treatise on Scurvy in 1772 [137], even in sailors whose organs were ravaged by hemorrhage
Potential therapeutic functions of vitamin C in neurodegenerative disorders
Oxidative stress in the brain with a focus on neurodegenerative diseases has been extensively reviewed [150], so only aspects relevant to ascorbate will be considered here. Neurons seem to be especially sensitive to ascorbate deficiency, perhaps because they have 10-fold higher rates of oxidative metabolism than supporting glia [151], [152]. This neuronal sensitivity is most apparent when the ascorbate supply is low under conditions under which there is excess oxidant stress. The involvement of
Conclusions
That ascorbate is important for neuronal maturation and function, as well as for protection of the brain against oxidant stress, is well supported by the evidence presented in this review. The vitamin is maintained at high concentrations in brain and in neurons, in particular relative to other organs. In addition, strong homeostatic mechanisms maintain brain and neuronal ascorbate concentrations within very tight limits. Thus, not only is it difficult to deplete brain ascorbate, but it is also
Acknowledgment
This work was supported by NIH Grant DK 50435.
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