Vitamin C Deficiency in the Young Brain—Findings from Experimental Animal Models †
Abstract
:1. Introduction
2. Vitamin C Regulation In Vivo
2.1. Cellular Vitamin C Uptake
2.1.1. Ascorbic Acid Transport
2.1.2. Dehydroascorbic Acid Transport
2.2. Cellular Vitamin C Efflux
2.3. Vitamin C Pharmacokinetics
3. Vitamin C Transport to the Brain
3.1. Crossing the Blood–Brain Barrier
3.1.1. ASC Transport
3.1.2. DHA Transport
3.2. Inside the Brain
3.2.1. Vitamin C Transport to Neurons
3.2.2. Vitamin C Transport to Neuroglia
4. Vitamin C Functions in the Brain
4.1. Preventing Oxidation of Poly-Unsaturated Fatty Acids
4.2. Co-Factor for Fe2+-2-Oxogluterate-Dependent Dioxygenases
4.2.1. Collagen Synthesis
4.2.2. Hypoxia-Inducible Transcription Factors
4.2.3. Epigentic Regulation
4.2.4. Carnitine Availability
4.3. Signal Transduction
4.3.1. Monoaminergic Neurotransmitters
4.3.2. Glutamate Signaling
5. Effects of Vitamin C Deficiency on Brain Development
5.1. Prenatal Effects of Vitamin C Deficiency
5.1.1. Fetal Vitamin C Levels
5.1.2. Neuronal Consequences
5.1.3. Effect of Prenatal vitC Deficiency on Offspring Growth
5.1.4. Clinical Studies
5.2. Postnatal Effects of Vitamin C Deficiency
5.2.1. Perinatal Period and Early Life
5.2.2. Lipid Peroxidation
5.2.3. Changes in Brain Structure and Function
5.2.4. Infants Born Preterm
5.3. Vitamin C Deficiency in Young Life
5.3.1. Redox Homeostasis
5.3.2. Changes in Brain Structure and Function
5.3.3. Vitamin C Status in Children
6. Potential Challenges When Evaluating Clinical Studies of Vitamin C
7. Concluding Remarks
Funding
Institutional Review Board Statement
Conflicts of Interest
References
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VitC | Species/Strain | Time-Point | Principal Findings | Ref |
---|---|---|---|---|
Depletion (to the brain) | Mice/svct2−/− | E18.5–19.5 Term | Neonatal deaths. Petechial bleedings on brain surface an in parenchyma, reflecting weakened capillary walls. Increased lipid peroxidation (isoketals). Neuronal apoptosis in cerebral cortex and brain stem. Altered regulation of norepinephrine and dopamine and reduced dopaminergic neurons (decreased tyrosine kinase positive neurons). Aberrant DNA and histone methylation status. | [26,27,181] |
Depletion | Mice/gulo−/− | Term | Neonatal deaths. Petechial bleedings in brain parenchyma. Increased lipid peroxidation (MDA, 8-isoprostane), redox imbalance (increased GSH:GSSG and NO). Deviated structural development in cerebral cortex, hippocampus and cerebellum. Reduced BDNF and GDNF. | [226] |
Deficiency | Mice/gulo−/− | Term (E20) | Increased lipid peroxidation (MDA) in cerebellum but not cortex. | [137] |
Deficiency | Guinea pig/Dunkin Hartley | GD45 and GD 56 | Increased lipid peroxidation (MDA) at GD 56 not 45. Redox imbalance marker (SOD) was increased in both GD45 and 56. No effect on hippocampal volume or β-tubulin III in hippocampal stratum lucidum. Transitional growth reduction reported for GD45. | [74,227] |
VitC | Strain | Time-Point | Principal Findings | Ref |
---|---|---|---|---|
Deficiency | gulo−/− | PD1 | No reported change in lipid peroxidation. | [137] |
PD10 PD18 | Increased lipid peroxidation (MDA) in cerebellum, not cortex. | |||
Increased lipid peroxidation (F2-isoprostanes) in cortex not cerebellum. Increased redox imbalance (GSH) in cortex. Possible increase in GFAP stained cells (astrocytes) albeit not quantified. No functional effects on locomotion, agility or strength were detected. | ||||
Depleted | gulo−/− | PD21 | Increased redox imbalance (GSH). | [262] |
Deficient | PD60–100 | No redox imbalance. Reduced locomotion but no effect on spatial learning (MWM). Spatial memory was not assessed. Enhanced response to dopaminergic agonist indicating deviated regulation of dopaminergic signaling. | ||
Depletion | gulo−/− | Young adults (20 gr) | Increased lipid peroxidation (MDA) and increased protein carbonyls in cortex. Decreased dopamine and serotonin metabolites in cortex and striatum. Locomotor deficits and reduced social dominance. | [180] |
Depletion | gulo−/− | 4 wks–8 wks | Increased lipid peroxidation (MDA) in cortex, not cerebellum. | [97] |
Deficiency | 4 wks–8 wks | Increased lipid peroxidation (MDA) in cortex, not cerebellum. | ||
Deficient | gulo−/− | 6–18 wks old | Increased F4-neuroprostanes (also in vitC supplemented gulo−/− counterparts). Reduced sensimotory competence, most significant in deficient gulo−/−. Memory and cognition was not affected. | [263] |
Depletion (acute) | akr1−/− | Juvenile (5 wks old–1 wk deplet.) | No apparent redox imbalance. No recorded changes in hippocampal histology (n = 2). Reduced spatial memory competence. No effect on neurotransmitters (dopamine, norepinephrine, glutamic acid, GABA, acetylcholine and selected metabolites). | [264] |
Deficiency (long term) | Adult (12–13 wks) | No effect on spatial memory competence. | ||
Depletion | SMP30/ GNL−/− | PD30- 2,4,8 wks depletion | 4- and 8-wk depletion increased superoxide production ex vivo; reduced cells in cerebellar cortex after 8-wk depletion (though data not shown). No effect on SOD expression or activity. | [265] |
VitC | Strain | Time-Point | Principal Findings | Ref |
---|---|---|---|---|
Depletion | Dunkin Hartley | PD2–3 wks | Increased lipid peroxidation (MDA), increased protein carbonyls, induced DNA-based excision. | [24] |
Severe deficiency | Dunkin Hartley | PD7–11 wks | No effects on the investigated hippocampal structures or synaptic plasticity markers and BDNF in cortex, hippocampus or striatum. | [184] |
Deficiency | No additional apparent differences compared to severe deficiency. | |||
Pre- and postnatal deficiency | Dunkin Hartley | PD2–7 | No effect on lipid peroxidation (MDA, 8-F2-isoprostane); GSH not different. | [221] |
PD10 | Reduced hippocampal volume and reduced proliferation in hippocampal granular layer. | [74] | ||
PD27 | Reduced hippocampal volume and increased proliferation in granular layer and subgranluar zones. | |||
PD70 | Increased lipid peroxidation (MDA). Hippocampal volume reduction. Persistent decrease in hippocampal volume despite vitC repletion after birth. | [74,79] | ||
Deficiency | Dunkin Hartley | PD7–9 wks | No effect on lipid peroxidation (MDA) or redox markers (SOD, GSH). Reduced neuron numbers in hippocampus. Deviated serotonin metabolites and reduced synaptophysin. Reduced spatial memory competence. | [185,266] |
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Tveden-Nyborg, P. Vitamin C Deficiency in the Young Brain—Findings from Experimental Animal Models. Nutrients 2021, 13, 1685. https://doi.org/10.3390/nu13051685
Tveden-Nyborg P. Vitamin C Deficiency in the Young Brain—Findings from Experimental Animal Models. Nutrients. 2021; 13(5):1685. https://doi.org/10.3390/nu13051685
Chicago/Turabian StyleTveden-Nyborg, Pernille. 2021. "Vitamin C Deficiency in the Young Brain—Findings from Experimental Animal Models" Nutrients 13, no. 5: 1685. https://doi.org/10.3390/nu13051685
APA StyleTveden-Nyborg, P. (2021). Vitamin C Deficiency in the Young Brain—Findings from Experimental Animal Models. Nutrients, 13(5), 1685. https://doi.org/10.3390/nu13051685