Vitamin C function in the brain: vital role of the ascorbate transporter SVCT2 (original) (raw)
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Vitamin C in Health and Disease: Its Role in the Metabolism of Cells and Redox State in the Brain
Ever since Linus Pauling published his studies, the effects of vitamin C have been surrounded by contradictory results. This may be because its effects depend on a number of factors such as the redox state of the body, the dose used, and also on the tissue metabolism. This review deals with vitamin C pharmacokinetics and its participation in neurophysiological processes, as well as its role in the maintenance of redox balance. The distribution and the concentration of vitamin C in the organs depend on the ascorbate requirements of each and on the tissue distribution of sodium-dependent vitamin C transporter 1 and 2 (SVCT1 and SVCT2). This determines the specific distribution pattern of vitamin C in the body. Vitamin C is involved in the physiology of the nervous system, including the support and the structure of the neurons, the processes of differentiation, maturation, and neuronal survival; the synthesis of catecholamine, and the modulation of neurotransmission. This antioxidant interacts with self-recycling mechanisms, including its participation in the endogenous antioxidant system. We conclude that the pharmacokinetic properties of ascorbate are related to the redox state and its functions and effects in tissues.
Neurobiology of vitamin C: Expanding the focus from antioxidant to endogenous neuromodulator
Pharmacological Research, 2019
Ascorbic acid (AA) is a water-soluble vitamin (C) found in all bodily organs. Most mammals synthesize it, humans are required to eat it, but all mammals need it for healthy functioning. AA reaches its highest concentration in the brain where both neurons and glia rely on tightly regulated uptake from blood via the glucose transport system and sodiumcoupled active transport to accumulate and maintain AA at millimolar levels. As a prototype antioxidant, AA is not only neuroprotective, but also functions as a cofactor in redox-coupled reactions essential for the synthesis of neurotransmitters (e.g., dopamine and norepinephrine) and paracrine lipid mediators (e.g., epoxiecoisatrienoic acids) as well as the epigenetic regulation of DNA. Although redox capacity led to the promotion of AA in high doses as potential treatment for various neuropathological and psychiatric conditions, ample evidence has not supported this therapeutic strategy. Here, we focus on some long-neglected aspects of AA neurobiology, including its modulatory role in synaptic transmission as demonstrated
Vitamin C crosses the blood-brain barrier in the oxidized form through the glucose transporters
Journal of Clinical Investigation, 1997
Vitamin C concentrations in the brain exceed those in blood by 10-fold. In both tissues, the vitamin is present primarily in the reduced form, ascorbic acid. We identified the chemical form of vitamin C that readily crosses the blood-brain barrier, and the mechanism of this process. Ascorbic acid was not able to cross the blood-brain barrier in our studies. In contrast, the oxidized form of vitamin C, dehydroascorbic acid (oxidized ascorbic acid), readily entered the brain and was retained in the brain tissue in the form of ascorbic acid. Transport of dehydroascorbic acid into the brain was inhibited by D -glucose, but not by L -glucose. The facilitative glucose transporter, GLUT1, is expressed on endothelial cells at the blood-brain barrier, and is responsible for glucose entry into the brain. This study provides evidence showing that GLUT1 also transports dehydroascorbic acid into the brain. The findings define the transport of dehydroascorbic acid by GLUT1 as a mechanism by which the brain acquires vitamin C, and point to the oxidation of ascorbic acid as a potentially important regulatory step in accumulation of the vitamin by the brain. These results have implications for increasing antioxidant potential in the central nervous system. (
Vitamin C Transporters, Recycling and the Bystander Effect in the Nervous System: SVCT2 versus Gluts
Journal of stem cell research & therapy, 2014
Vitamin C is an essential micronutrient in the human diet; its deficiency leads to a number of symptoms and ultimately death. After entry into cells within the central nervous system (CNS) through sodium vitamin C transporters (SVCTs) and facilitative glucose transporters (GLUTs), vitamin C functions as a neuromodulator, enzymatic cofactor, and reactive oxygen species (ROS) scavenger; it also stimulates differentiation. In this review, we will compare the molecular and structural aspects of vitamin C and glucose transporters and their expression in endothelial or choroid plexus cells, which form part of the blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier, respectively. Additionally, we will describe SVCT and GLUT expression in different cells of the brain as well as SVCT2 distribution in tanycytes and astrocytes of the hypothalamic region. Finally, we will describe vitamin C recycling in the brain, which is mediated by a metabolic interaction between astrocytes and n...
Ascorbic acid transport in brain microvascular pericytes
Biochemical and biophysical research communications, 2015
a b s t r a c t Intracellular vitamin C, or ascorbic acid, has been shown to prevent the apoptosis of cultured vascular pericytes under simulated diabetic conditions. We sought to determine the mechanism by which ascorbate is transported into pericytes prior to exerting this protective effect. Measuring intracellular ascorbate, we found that pericytes display a linear uptake over 30 min and an apparent transport K m of 21 mM, both of which are consistent with activity of the Sodium-dependent Vitamin C Transporter 2 (SVCT2). Uptake of both radiolabeled and unlabeled ascorbate was prevented by inhibiting SVCT2 activity, but not by inhibiting the activity of GLUT-type glucose transporters, which import dehydroascorbate to also generate intracellular ascorbate. Likewise, uptake of dehydroascorbate was prevented with the inhibition of GLUTs, but not by inhibiting the SVCT2, indicating substrate specificity of both transporters. Finally, presence of the SVCT2 in pericytes was confirmed by western blot analysis, and immunocytochemistry was used to localize it to the plasma membrane and intracellular sites. Together, these data clarify previous inconsistencies in the literature, implicate SVCT2 as the pericyte ascorbate transporter, and show that pericytes are capable of concentrating intracellular ascorbate against a gradient in an energy-and sodium-dependent fashion.
Brain Research, 2000
Expression of the Na -ascorbate cotransporter, SVCT2, was detected in rat brain and in primary cultures of cerebral astrocytes by Northern blot analysis. SVCT2 expression in cultured astrocytes increased in response to the cyclic AMP analog, dibutyryl cyclic AMP. A 1 mathematical model of ascorbic acid transport was developed to evaluate the hypothesis that Na -ascorbate cotransport across the plasma membrane regulates the steady state intracellular concentration of ascorbic acid in these cells. The outcomes predicted by this model were compared to experimental observations obtained with primary cultures of rat cerebral astrocytes exposed to normal and pathologic conditions. Both cotransport activity and intracellular ascorbic acid concentration increased in astrocytes activated by dibutyryl cyclic 1 AMP. Conversely transport activity and ascorbic acid concentration were decreased by hyposmotic cell swelling, low extracellular Na 1 concentration, and depolarizing levels of extracellular K . In cells incubated for up to 3 h in medium having an ascorbic acid concentration typical of brain extracellular fluid, the changes in intracellular ascorbic acid concentration actually measured were not 1 significantly different from those predicted by modeling changes in Na -ascorbate cotransport activity. Thus, it was not necessary to specify alterations in vitamin C metabolism or efflux pathways in order to predict the steady state intracellular ascorbic acid concentration. These results establish that SVCT2 regulates intracellular ascorbic acid concentration in primary astrocyte cultures. They further indicate 1 that the intracellular-to-extracellular ratio of ascorbic acid concentration at steady state depends on the electrochemical gradients of Na and ascorbate across the plasma membrane.
Ascorbic Acid and Its Role in Safeguarding Neurons: Updated Evidence
Ascorbic acid, commonly known as vitamin C, is a water-soluble vitamin synthesized in plants as well as many animal species, but not in humans. Humans obtain ascorbic acid from dietary sources and via vitamin supplementation. Ascorbic acid possesses important biological functions, including serving as a cofactor for many enzymes, acting as an antioxidant, and participating in regulating cell growth, apoptosis, and signaling, which collectively contribute to its essentialness in maintaining and safeguarding the physiological homeostasis and the health of human body. This article summarizes recent evidence for ascorbic acid acting as a booster in neuron physiology and a protector in neuron degeneration.
Sodium vitamin C cotransporter SVCT2 is expressed in hypothalamic glial cells
Glia, 2005
Kinetic analysis of vitamin C uptake demonstrated that different specialized cells take up ascorbic acid through sodium–vitamin C cotransporters. Recently, two different isoforms of sodium–vitamin C cotransporters (SVCT1/SLC23A1 and SVCT2/SLC23A2) have been cloned. SVCT2 was detected mainly in choroidal plexus cells and neurons; however, there is no evidence of SVCT2 expression in glial and endothelial cells of the brain. Certain brain locations, including the hippocampus and hypothalamus, consistently show higher ascorbic acid values compared with other structures within the central nervous system. However, molecular and kinetic analysis addressing the expression of SVCT transporters in cells isolated from these specific areas of the brain had not been done. The hypothalamic glial cells, or tanycytes, are specialized ependymal cells that bridge the cerebrospinal fluid with different neurons of the region. Our hypothesis postulates that SVCT2 is expressed selectively in tanycytes, where it is involved in the uptake of the reduced form of vitamin C (ascorbic acid), thereby concentrating this vitamin in the hypothalamic area. In situ hybridization and optic and ultrastructural immunocytochemistry showed that the transporter SVCT2 is highly expressed in the apical membranes of mouse hypothalamic tanycytes. A newly developed primary culture of mouse hypothalamic tanycytes was used to confirm the expression and function of the SVCT2 isoform in these cells. The results demonstrate that tanycytes express a high-affinity transporter for vitamin C. Thus, the vitamin C uptake mechanisms present in the hypothalamic glial cells may perform a neuroprotective role concentrating vitamin C in this specific area of the brain. © 2004 Wiley-Liss, Inc.
Subcellular compartmentation of ascorbate and its variation in disease states
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2014
Beyond its general role as antioxidant, specific functions of ascorbate are compartmentalized within the eukaryotic cell. The list of organelle-specific functions of ascorbate has been recently expanded with the epigenetic role exerted as a cofactor for DNA and histone demethylases in the nucleus. Compartmentation necessitates the transport through intracellular membranes; members of the GLUT family and sodium-vitamin C cotransporters mediate the permeation of dehydroascorbic acid and ascorbate, respectively. Recent observations show that increased consumption and/or hindered entrance of ascorbate in/to a compartment results in pathological alterations partially resembling to scurvy, thus diseases of ascorbate compartmentation can exist. The review focuses on the reactions and transporters that can modulate ascorbate concentration and redox state in three compartments: endoplasmic reticulum, mitochondria and nucleus. By introducing the relevant experimental and clinical findings we make an attempt to coin the term of ascorbate compartmentation disease.