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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

Vitamin C recycling and proposed interaction between neurons and astrocytes in normal or oxidative stress conditions of the brain. AUnder physiological conditions, reactive oxygen species (ROS) are constantly generated in the CNS. In these conditions, ROS oxidizes AA to DHA (A1), which preferentially enters the astrocyte by GLUT1 (A2). Inside the astrocyte, DHA is again reduced to AA (A3), and is then released into the extracellular space by a yet unknown mechanism (A4). The extracellular AA then enters the neuron via SVCT2 (A5/6), exerting its antioxidant effect and thereby protecting neurons against cell death. Moreover, under normal conditions, we postulate that GLUT3 expression by neurons is involved mainly in DHA efflux. Increased intracellular DHA concentration in the neuron inhibits glycolysis, increases PPP activity, consumes glutathione and increases the influx of lactate. This adaptive mechanism changes the normal metabolism of the neurons in response to the accumulation of DHA [19]. B. In pathophysiological conditions, ROS is massively generated (B1), resulting in increased extracellular DHA concentrations and subsequent DHA entry into astrocytes. However, given the large amount of oxidizing species, the astrocyte will not be able to efficiently reduce DHA to AA (B3), resulting in less AA efflux into the extracellular environment (B4). Subsequently, AA enters the neuron through SVCT2 (B5/6), bringing about a decrease in intracellular antioxidant protection due to its lower degree of uptake by the neuron. Simultaneously, the large extracellular generation of DHA promotes its entry into neurons via GLUT3 (red arrow). Finally, the massive incorporation of intracellular DHA may promote neuronal death by a yet unknown mechanism.
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Figure 5: Vitamin C recycling and proposed interaction between neurons and astrocytes in normal or oxidative stress conditions of the brain. AUnder physiological conditions, reactive oxygen species (ROS) are constantly generated in the CNS. In these conditions, ROS oxidizes AA to DHA (A1), which preferentially enters the astrocyte by GLUT1 (A2). Inside the astrocyte, DHA is again reduced to AA (A3), and is then released into the extracellular space by a yet unknown mechanism (A4). The extracellular AA then enters the neuron via SVCT2 (A5/6), exerting its antioxidant effect and thereby protecting neurons against cell death. Moreover, under normal conditions, we postulate that GLUT3 expression by neurons is involved mainly in DHA efflux. Increased intracellular DHA concentration in the neuron inhibits glycolysis, increases PPP activity, consumes glutathione and increases the influx of lactate. This adaptive mechanism changes the normal metabolism of the neurons in response to the accumulation of DHA [19]. B. In pathophysiological conditions, ROS is massively generated (B1), resulting in increased extracellular DHA concentrations and subsequent DHA entry into astrocytes. However, given the large amount of oxidizing species, the astrocyte will not be able to efficiently reduce DHA to AA (B3), resulting in less AA efflux into the extracellular environment (B4). Subsequently, AA enters the neuron through SVCT2 (B5/6), bringing about a decrease in intracellular antioxidant protection due to its lower degree of uptake by the neuron. Simultaneously, the large extracellular generation of DHA promotes its entry into neurons via GLUT3 (red arrow). Finally, the massive incorporation of intracellular DHA may promote neuronal death by a yet unknown mechanism.

Mentions: The bystander effect model can also describe vitamin C recycling between astrocytes and neurons in which neurons are the “activated cells” that induce oxidation of AA to DHA, which is subsequently taken up by the “bystander cell,” astrocytes. Dehydroascorbic reductase may play a pivotal role in regenerating AA from its oxidized product; however, this enzyme has only been localized in large neurons (i.e. pyramidal neurons and Purkinje neurons) [86]. Alternatively, neuronal intracellular AA may be oxidized to generate DHA, which may exit neurons through facilitated diffusion and enter astrocytes via GLUTs. Inside astrocytes DHA is reduced back to AA, which may be released through neurotransmitter stimulation, anion channels or glutamate heteroexchange [62] and taken up again by neurons via SVCT2 (Figure 5A).


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)

Vitamin C recycling and proposed interaction between neurons and astrocytes in normal or oxidative stress conditions of the brain. AUnder physiological conditions, reactive oxygen species (ROS) are constantly generated in the CNS. In these conditions, ROS oxidizes AA to DHA (A1), which preferentially enters the astrocyte by GLUT1 (A2). Inside the astrocyte, DHA is again reduced to AA (A3), and is then released into the extracellular space by a yet unknown mechanism (A4). The extracellular AA then enters the neuron via SVCT2 (A5/6), exerting its antioxidant effect and thereby protecting neurons against cell death. Moreover, under normal conditions, we postulate that GLUT3 expression by neurons is involved mainly in DHA efflux. Increased intracellular DHA concentration in the neuron inhibits glycolysis, increases PPP activity, consumes glutathione and increases the influx of lactate. This adaptive mechanism changes the normal metabolism of the neurons in response to the accumulation of DHA [19]. B. In pathophysiological conditions, ROS is massively generated (B1), resulting in increased extracellular DHA concentrations and subsequent DHA entry into astrocytes. However, given the large amount of oxidizing species, the astrocyte will not be able to efficiently reduce DHA to AA (B3), resulting in less AA efflux into the extracellular environment (B4). Subsequently, AA enters the neuron through SVCT2 (B5/6), bringing about a decrease in intracellular antioxidant protection due to its lower degree of uptake by the neuron. Simultaneously, the large extracellular generation of DHA promotes its entry into neurons via GLUT3 (red arrow). Finally, the massive incorporation of intracellular DHA may promote neuronal death by a yet unknown mechanism.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Vitamin C recycling and proposed interaction between neurons and astrocytes in normal or oxidative stress conditions of the brain. AUnder physiological conditions, reactive oxygen species (ROS) are constantly generated in the CNS. In these conditions, ROS oxidizes AA to DHA (A1), which preferentially enters the astrocyte by GLUT1 (A2). Inside the astrocyte, DHA is again reduced to AA (A3), and is then released into the extracellular space by a yet unknown mechanism (A4). The extracellular AA then enters the neuron via SVCT2 (A5/6), exerting its antioxidant effect and thereby protecting neurons against cell death. Moreover, under normal conditions, we postulate that GLUT3 expression by neurons is involved mainly in DHA efflux. Increased intracellular DHA concentration in the neuron inhibits glycolysis, increases PPP activity, consumes glutathione and increases the influx of lactate. This adaptive mechanism changes the normal metabolism of the neurons in response to the accumulation of DHA [19]. B. In pathophysiological conditions, ROS is massively generated (B1), resulting in increased extracellular DHA concentrations and subsequent DHA entry into astrocytes. However, given the large amount of oxidizing species, the astrocyte will not be able to efficiently reduce DHA to AA (B3), resulting in less AA efflux into the extracellular environment (B4). Subsequently, AA enters the neuron through SVCT2 (B5/6), bringing about a decrease in intracellular antioxidant protection due to its lower degree of uptake by the neuron. Simultaneously, the large extracellular generation of DHA promotes its entry into neurons via GLUT3 (red arrow). Finally, the massive incorporation of intracellular DHA may promote neuronal death by a yet unknown mechanism.
Mentions: The bystander effect model can also describe vitamin C recycling between astrocytes and neurons in which neurons are the “activated cells” that induce oxidation of AA to DHA, which is subsequently taken up by the “bystander cell,” astrocytes. Dehydroascorbic reductase may play a pivotal role in regenerating AA from its oxidized product; however, this enzyme has only been localized in large neurons (i.e. pyramidal neurons and Purkinje neurons) [86]. Alternatively, neuronal intracellular AA may be oxidized to generate DHA, which may exit neurons through facilitated diffusion and enter astrocytes via GLUTs. Inside astrocytes DHA is reduced back to AA, which may be released through neurotransmitter stimulation, anion channels or glutamate heteroexchange [62] and taken up again by neurons via SVCT2 (Figure 5A).

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