Review Article
Vitamin C function in the brain: vital role of the ascorbate transporter SVCT2

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Abstract

Ascorbate (vitamin C) is a vital antioxidant molecule in the brain. However, it also has a number of other important functions, participating as a cofactor in several enzyme reactions, including catecholamine synthesis, collagen production, and regulation of HIF-1α. Ascorbate is transported into the brain and neurons via the sodium-dependent vitamin C transporter 2 (SVCT2), which causes accumulation of ascorbate within cells against a concentration gradient. Dehydroascorbic acid, the oxidized form of ascorbate, is transported via glucose transporters of the GLUT family. Once in cells, it is rapidly reduced to ascorbate. The highest concentrations of ascorbate in the body are found in the brain and in neuroendocrine tissues such as adrenal, although the brain is the most difficult organ to deplete of ascorbate. Combined with regional asymmetry in ascorbate distribution within different brain areas, these facts suggest an important role for ascorbate in the brain. Ascorbate is proposed as a neuromodulator of glutamatergic, dopaminergic, cholinergic, and GABAergic transmission and related behaviors. Neurodegenerative diseases typically involve high levels of oxidative stress and thus ascorbate has been posited to have potential therapeutic roles against ischemic stroke, Alzheimer's disease, Parkinson's disease, and Huntington's disease.

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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