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Vitamin C Transporters, Recycling and the Bystander Effect in the Nervous System: SVCT2 versus Gluts.

Nualart F, Mack L, García A, Cisternas P, Bongarzone ER, Heitzer M, Jara N, Martínez F, Ferrada L, Espinoza F, Baeza V, Salazar K - J Stem Cell Res Ther (2014)

Bottom Line: 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.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 neurons, and the role of the "bystander effect" in the recycling mechanism of vitamin C in both normal and pathological conditions.

View Article: PubMed Central - PubMed

Affiliation: Center for Advanced Microscopy CMA BIO-BIO, Neurobiology and Stem cell Laboratory, Concepcion University, Chile.

ABSTRACT
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 neurons, and the role of the "bystander effect" in the recycling mechanism of vitamin C in both normal and pathological conditions.

No MeSH data available.


Related in: MedlinePlus

Schematic model of the uptake and compartmentalization of vitamin C in the CNS. Functional activity of astrocytes and tanycytes (hypothalamic stem cells)Vitamin C enters the CNS by SVCT2 present in choroid plexus cells and also probably through GLUT1. The concentration of ascorbate is balanced between cerebrospinal fluid (CSF) and the extracellular fluid (ECF) by diffusion through ependymal cells. Once inside the brain, AA is incorporated by neurons by using SVCT2. SVCT2 is not expressed in astrocytes; thus, it is postulated that astrocytes incorporate DHA through GLUT1. Additionally, it has been postulated that ascorbate also may enter the brain through the blood-brain barrier; however, the mechanism has not been elucidated. (Modified from Rice [62]).
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Figure 2: Schematic model of the uptake and compartmentalization of vitamin C in the CNS. Functional activity of astrocytes and tanycytes (hypothalamic stem cells)Vitamin C enters the CNS by SVCT2 present in choroid plexus cells and also probably through GLUT1. The concentration of ascorbate is balanced between cerebrospinal fluid (CSF) and the extracellular fluid (ECF) by diffusion through ependymal cells. Once inside the brain, AA is incorporated by neurons by using SVCT2. SVCT2 is not expressed in astrocytes; thus, it is postulated that astrocytes incorporate DHA through GLUT1. Additionally, it has been postulated that ascorbate also may enter the brain through the blood-brain barrier; however, the mechanism has not been elucidated. (Modified from Rice [62]).

Mentions: Although it is known that the CNS can maintain ascorbate levels during periods of low and high plasma ascorbate levels [41], the exact mechanism by which AA enters the CNS remains to be elucidated. There are two primary barriers that limit the entry of hydrophilic molecules into the CNS from the: 1) the blood-brain-barrier and 2) the blood-CSF barrier formed by epithelial cells of the choroid plexus [42] (Figure 2). AA entry into the CNS requires passage through one of these barriers aided by either facilitated diffusion or active transport. AA is present in higher concentrations in CSF (200–400 μM) and brain parenchyma than in plasma (30–60 μM) [7,43–45] (Figure 2). This gradient is further increased in neural tissue depending on the cell type and region studied [46,47]. Whole-body radiography at various times after injection with 14C-labeled AA demonstrated that it first concentrates in choroid plexus cells and then passes through the CSF into the brain [48]. The requirement of SVCT2 for vitamin C accumulation in the CNS was evident in SVCT2 knock-out mice that have undetectable levels of vitamin C in the brain [49]. Primary cultures of choroid plexus cells also accumulate AA against a concentration gradient [7], which is most likely due to the functional expression of SVCT2 in these cells [31] as observed in choroid plexus epithelium in vivo using in situ hybridization [31]. Primary choroid plexus cells can also be maintained on permeable membranes thus forming two fluid compartments separated by a cell monolayer simulating the blood-choroid plexus barrier and have been used to study transcellular transport of vitamin C as well as other molecules [50–53]. Angelow et al. [50] reported that AA is transported to the apical side in a concentration-dependent manner in this model with a Km of 67 μM [50,54], which is in agreement with the data derived from uptake measurements with choroid plexus tissue [7,55], SVCT2-cDNA transfected HPRE-cells [34], as well as embryonic mouse neurons [56]. Using this system, the mechanism by which AA is transported was assessed by inhibition studies using phloretin, a facilitative glucose transporter inhibitor that inhibits SVCT, and ouabain, which inhibits the Na-K-ATPase. Both phloretin and ouabain inhibited AA transport and uptake by choroid plexus epithelium in a concentration-dependent manner, demonstrating the importance of the Na-dependent transport of AA in choroid plexus cells [50]. This data also suggests that AA uptake occurs on the basolateral membrane and not the apical membrane, which faces the CSF, although further in vivo studies are necessary to confirm this.


Vitamin C Transporters, Recycling and the Bystander Effect in the Nervous System: SVCT2 versus Gluts.

Nualart F, Mack L, García A, Cisternas P, Bongarzone ER, Heitzer M, Jara N, Martínez F, Ferrada L, Espinoza F, Baeza V, Salazar K - J Stem Cell Res Ther (2014)

Schematic model of the uptake and compartmentalization of vitamin C in the CNS. Functional activity of astrocytes and tanycytes (hypothalamic stem cells)Vitamin C enters the CNS by SVCT2 present in choroid plexus cells and also probably through GLUT1. The concentration of ascorbate is balanced between cerebrospinal fluid (CSF) and the extracellular fluid (ECF) by diffusion through ependymal cells. Once inside the brain, AA is incorporated by neurons by using SVCT2. SVCT2 is not expressed in astrocytes; thus, it is postulated that astrocytes incorporate DHA through GLUT1. Additionally, it has been postulated that ascorbate also may enter the brain through the blood-brain barrier; however, the mechanism has not been elucidated. (Modified from Rice [62]).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126260&req=5

Figure 2: Schematic model of the uptake and compartmentalization of vitamin C in the CNS. Functional activity of astrocytes and tanycytes (hypothalamic stem cells)Vitamin C enters the CNS by SVCT2 present in choroid plexus cells and also probably through GLUT1. The concentration of ascorbate is balanced between cerebrospinal fluid (CSF) and the extracellular fluid (ECF) by diffusion through ependymal cells. Once inside the brain, AA is incorporated by neurons by using SVCT2. SVCT2 is not expressed in astrocytes; thus, it is postulated that astrocytes incorporate DHA through GLUT1. Additionally, it has been postulated that ascorbate also may enter the brain through the blood-brain barrier; however, the mechanism has not been elucidated. (Modified from Rice [62]).
Mentions: Although it is known that the CNS can maintain ascorbate levels during periods of low and high plasma ascorbate levels [41], the exact mechanism by which AA enters the CNS remains to be elucidated. There are two primary barriers that limit the entry of hydrophilic molecules into the CNS from the: 1) the blood-brain-barrier and 2) the blood-CSF barrier formed by epithelial cells of the choroid plexus [42] (Figure 2). AA entry into the CNS requires passage through one of these barriers aided by either facilitated diffusion or active transport. AA is present in higher concentrations in CSF (200–400 μM) and brain parenchyma than in plasma (30–60 μM) [7,43–45] (Figure 2). This gradient is further increased in neural tissue depending on the cell type and region studied [46,47]. Whole-body radiography at various times after injection with 14C-labeled AA demonstrated that it first concentrates in choroid plexus cells and then passes through the CSF into the brain [48]. The requirement of SVCT2 for vitamin C accumulation in the CNS was evident in SVCT2 knock-out mice that have undetectable levels of vitamin C in the brain [49]. Primary cultures of choroid plexus cells also accumulate AA against a concentration gradient [7], which is most likely due to the functional expression of SVCT2 in these cells [31] as observed in choroid plexus epithelium in vivo using in situ hybridization [31]. Primary choroid plexus cells can also be maintained on permeable membranes thus forming two fluid compartments separated by a cell monolayer simulating the blood-choroid plexus barrier and have been used to study transcellular transport of vitamin C as well as other molecules [50–53]. Angelow et al. [50] reported that AA is transported to the apical side in a concentration-dependent manner in this model with a Km of 67 μM [50,54], which is in agreement with the data derived from uptake measurements with choroid plexus tissue [7,55], SVCT2-cDNA transfected HPRE-cells [34], as well as embryonic mouse neurons [56]. Using this system, the mechanism by which AA is transported was assessed by inhibition studies using phloretin, a facilitative glucose transporter inhibitor that inhibits SVCT, and ouabain, which inhibits the Na-K-ATPase. Both phloretin and ouabain inhibited AA transport and uptake by choroid plexus epithelium in a concentration-dependent manner, demonstrating the importance of the Na-dependent transport of AA in choroid plexus cells [50]. This data also suggests that AA uptake occurs on the basolateral membrane and not the apical membrane, which faces the CSF, although further in vivo studies are necessary to confirm this.

Bottom Line: 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.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 neurons, and the role of the "bystander effect" in the recycling mechanism of vitamin C in both normal and pathological conditions.

View Article: PubMed Central - PubMed

Affiliation: Center for Advanced Microscopy CMA BIO-BIO, Neurobiology and Stem cell Laboratory, Concepcion University, Chile.

ABSTRACT
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 neurons, and the role of the "bystander effect" in the recycling mechanism of vitamin C in both normal and pathological conditions.

No MeSH data available.


Related in: MedlinePlus