Why is Vitamin C able to improve cognitive functions, quickly eliminating ‘brain fog’?
In the Special Edition: Primordial Octane Fuel [1], I talked about how ascorbic acid can stimulate and enhance the Pentose Phosphate Pathway (PPP) in astrocytes and neurons, creating a ‘Metabolic Switch’ that delivers energy in the form of lactate to neurons. Yet ascorbic acid has a truly decisive role in neuro-regeneration that is underappreciated.
What most people are not aware of, is that oligodendrocytes, which are glial cells that are responsible for the formation of myelin in the Central Nervous System (CNS), uses lactate as energy to support long-term axonal integrity. Oligodendrocytes form myelin sheaths by wrapping around neuronal axons in the central nervous system. Oligodendrocyte-formed myelin sheaths are paramount in the maintenance of neuronal functions in the central nervous system.
Myelination is not only important for a child’s developing brain, affecting neural processing speeds and cognition [2], it also affects neuroregeneration in the adult brain. In healthy adult brain, new myelin is continually being generated. [3] Damage to the myelin sheath will disrupt axonal conduction and cause severe neurological dysfunctions. Mental pathologies like narcissism [22. 23], schizophrenia [24], and even major depressive disorder are now associated with myelin abnormalities. [25]
Failed remyelination is the hallmark of Multiple Sclerosis (MS). However, the restoration of damaged myelin sheaths requires oligodendrocyte precursor cells to successfully differentiate into mature oligodendrocytes. In Multiple Sclerosis, the myelin sheaths are damaged and the remyelinating process is somehow hindered.
Vitamin C, Ascorbic Acid has been found to promote oligodendrocytes generation, differentiation and remyelination. [4]
Vitamin C Enhance Myelination
Ascorbic Acid has been known since the mid 1980s to play an important role in the Schwann cell based myelination of peripheral dorsal root ganglion neurons. In 2017, a group of scientists in their search for compounds that can increase the differentiation of oligodendrocyte progenitor cells (OPC), L-ascorbyl-2-phosphate, a stable form of ascorbic acid (vitamin C) was found to greatly promote oligodendrocytes generation and remyelination. [4].
Vitamin C was observed to enhance differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes. Vitamin C also facilitated the formation of myelin sheaths in oligodendrocyte precursor cells, significantly increasing the lengths of the myelinated axons. [4]
Vitamin C enhanced remyelination in mice that were given a diet containing cuprizone for five weeks to achieve complete demyelination. Three weeks after cessation of the cuprizone containing diet, the mice that were fed Vitamin C had more myelinated axons than the vehicle group that were fed an inactive ingredient. In addition to increased remyelination, the Vitamin C fed group also had better G-ratios. G-ratio is the ratio of the inner axonal diameter to the total outer diameter. A better G-ratio would indicate a more robust recovery. [4]
What is the mechanism that allows ascorbic acid to promote differentiation, maturation and remyelination in oligodendrocytes?
It is ALL about ENERGY!
Mitochondria is recognized as the powerhouse that supplies energy to all cells. However, oxidative phosphorylation comes with a price. That price is oxidative stress when reactive oxygen species is generated naturally during electron transport chain metabolism.
In mutant Schwann cells, mitochondria were visibly enlarged. So how important is mitochondria to oligodendrocytes?
When mice were bred where their oligodendrocytes and Schwann cells lack mitochondrial cytochrome C oxidase (or Complex IV), these mutants exhibited severe neuropathy with dysmyelination, muscle atrophy and paralysis. Intriguingly, perturbing mitochondrial respiration DID NOT cause glial cell death. In the adult central nervous of the mutant mice, there was no sign of demyelination, axonal degeneration nor even secondary inflammation after one year. [5]
In the absence of energy produced by mitochondria, oligodendrocytes were able to switch to glycolytic metabolism. Scientists found increased levels of brain lactate concentrations in mutant mice compared to controls. [5] This metabolic switch used by oligodendrocytes is remarkably similar to the astrocyte-neuron lactate shuttle, the ANLS used by neurons and astrocytes. [6]
In fact, scientists have found that differentiated oligodendrocyte cells prefer to use glucose in the cytosol and pyruvate derived from glucose in the mitochondria. What is even more surprising is that the pentose phosphate pathway is highly active in mature oligodendrocytes.
The pentose phosphate pathway runs parallel to glycolysis, and in the Primordial Octane Fuel article, I explained how it is actively employed by astrocytes and neurons to generate NADPH and lactate. [1] In 2015, scientists discovered that the pentose phosphate pathway (PPP) is also highly active in mature oligodendrocytes. Approximately 10% of glucose is metabolized via the PPP in oligodendrocytes. [7] Why do oligodendrocytes like to use the pentose phosphate pathway?
It is ALL about OXIDATIVE STRESS!
During the differentiation of oligodendrocytes from neural stem cells to mature oligodendrocytes, oligodendrocyte progenitor cells (OPC) have heightened susceptibility to oxidative stress and free-radical damage compared to mature oligodendrocytes due to lower levels of antioxidants and free radical scavengers available. In 2018, a study convincingly showed oxidative stress could disrupt oligodendrocyte differentiation by decreasing the expression of major genes that promote oligodendrocyte differentiation from neural stem cells, and at the same time, oxidative stress could also increase the expression of genes that INHIBIT differentiation.
Not only that, in an oxidative environment global histone acetylation could further contribute to the inhibition of oligodendrocyte differentiation. [8]
The pentose phosphate pathway (PPP) runs parallel to glycolysis and these two pathways are reversibly linked by enzymes. The pentose phosphate pathway consists of an oxidative phase that generates NADPH and a nonoxidative phase that interconverts phosphorylated sugars. [9] Glucose-6-phosphatedehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pathway. G6PD deficiency can lead to lower levels of NADPH. NADPH is the antioxidant reductant required to regenerate oxidized glutathione (GSSG) and thioredoxin.
The presence of adequate NADPH and reducing equivalents like glutathione (GSH) will greatly lower oxidative stress in oligodendrocytes. If oxidative stress can inhibit the differentiation of oligodendrocyte progenitor cells (OPC), is it reasonable to assume that OPCs also employ PPP actively?
Oligodendrocyte Progenitor Cells, Lactate & NADPH: The Pentose Phosphate Pathway Connection
Oligodendrocytes progenitor cells (OPCs) have been found to oxidize lactate at a higher rate than that observed for neurons and astrocytes. Their rate of lipid synthesis from lactate was more than SIX TIMES higher than those in astrocytes or neurons. Most interestingly, is that the flux of glucose through the pentose phosphate is double that of astrocytes and neurons. [10] Even though the PPP oxidizes less than 3% of the glucose consumed, this pathway could produce more carbon dioxide than the TCA cycle in oligodendrocytes as a result of the de novo synthesis of fatty acids. [11]
Why do oligodendrocyte progenitor cells engage actively in PPP, and oxidize lactate at rates four times that of type 1 astrocytes, type 2 astrocytes, and neurons [10]? Some scientists believe that lactate is oxidized by oligodendrocytes during lipogenesis,[12] where NADPH produced in the oxidative phase of the pentose phosphate pathway are utilized as a reducing agent that is essential for the synthesis of fatty acids. [13] The next question would be, why do oligodendrocyte progenitor cells make so much fatty acids?
Multiple Sclerosis, Lactate & Myelination: The Fatty Acid Connection
In May of 2019, a landmark study showed that both myelination and remyelination processes in the central nervous system is completely dependent upon fatty acid synthesis by oligodendrocytes. [14] When fatty acid synthase was depleted in transgenic mice, both accurate myelination and myelin growth were negatively impacted. Fatty acid synthesis was also found to be indispensable for remyelination. De novo fatty acid synthesis maintains the stability of myelinated axons and the correct lipid composition of myelin in the central nervous system. [14]
A paper released in May 2019 discussed the results of an analytical assessment on the relationship between body mass index (BMI) and Multiple Sclerosis documented in studies up until April 2018. The authors discovered a significant correlation between low body mass index and the severity of progression in Multiple Sclerosis. [15]
It is important to remember that the pentose phosphate pathway is connected to glycolysis. Glucose is the main source of energy for the brain. Access to glucose during development is vital for myelination as well as axonal survival. [16] Cell cultures under hypoglycemic conditions showed inhibition of oligodendrocyte precursor cell (OPC) differentiation and migration, reduction in oligodendrocyte lineage cell numbers and myelination, as well as axon degeneration. [16]
The source for NADPH generated during the oxidative phase of the pentose phosphate pathway is ultimately traced back to glucose. The distinct role played by glucose in lipid synthesis, especially during differentiation stages is now accepted to be essential, and glucose is believed to be irreplaceable by other carbon sources. [17]
When glucose availability is restricted, lactate is able to support oligodendrocyte development and myelination, as well as differentiation of OPCs. [18] It is entirely possible that oligodendrocytes prefer lactate over glucose as substrate for myelin production because brain slices treated with lactate produced greater amounts of myelination than those treated with glucose. [16]
Myelination, Fatty Acids & Lactate: The Vitamin C Connection
Now we come back full circle to ascorbic acid, Vitamin C, to see why it is able to enhance differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes; in addition to facilitating the formation of myelin sheaths in oligodendrocyte progenitor cells. [4]
Similar to its function as a “metabolic switch” in neurons and astrocytes [1], Vitamin C, ascorbic acid and its metabolite dehydroascorbic acid (DHA), is critical for lactate metabolism via the pentose phosphate pathway [1] in oliogodendrocyte progenitor cells (OPC). The increased lactate and NADPH generated by the pentose phosphate pathway as a result of stimulation by DHA, results in the increased antioxidant defense against oxidative stress. Most importantly, the generation of fatty acids supported by NADPH is what truly defines optimal OPC differentiation, myelination and remyelination in the central nervous system.
NADPH is the reductant required in all fatty acid synthesis in the human body. NADPH is part of the fatty acid synthase enzyme system responsible for the production of saturated long-chain fatty acids in our body. [19] Not only that, the antioxidant defense conferred by adequate NADPH concentration is now accepted to be crucial for survival of oligodendrocyte progenitor cells. Inhibition of the pentose phosphate pathway is regarded to be detrimental for the myelination and remyelination processes in white matter. Thus the maintenance of glutathione homeostasis against NADPH depletion should be the foremost consideration in the protection of oliogodendrocyte progenitor cells (OPC). [20]
The role of Vitamin C in glutathione homeostasis cannot be underestimated. Dehydroascorbic acid can stimulate the activity of G6PD, the rate-limiting enzyme for NADPH production in the pentose phosphate pathway. This stimulation of G6PD resulted in an impressive 3.3-fold increase in glutathione, due to increased production of NADPH. The observed doubling in G6PD enzyme activities were accompanied by an impressive 5.9-fold increase in G6PD protein levels. [21]
It is now crystal clear why many people experience significantly improved cognitive functioning after supplementing with ascorbic acid, Vitamin C.
Have you had your AA today?
References:
[1] Vitamin C – SPECIAL EDITION – Primordial Octane Fuel – EvolutaMente.it https://www.evolutamente.it/vitamin-c-special-edition-primordial-octane-fuel/
[2] Myelination Is Associated with Processing Speed in Early Childhood: Preliminary Insights https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4595421/
[3] Dynamics of oligodendrocyte generation and myelination in the human brain. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/25417154
[4] Vitamin C promotes oligodendrocytes generation and remyelination https://onlinelibrary.wiley.com/doi/pdf/10.1002/glia.23306
[5] Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity | Nature https://www.nature.com/articles/nature11007
[6] Vivo Evidence for a Lactate Gradient from Astrocytes to Neurons https://www.cell.com/cell-metabolism/pdf/S1550-4131(15)00526-4.pdf
[7] Characterization of Glucose-Related Metabolic Pathways in Differentiated Rat Oligodendrocyte Lineage Cellshttps://www.researchgate.net/publication/281034504_Characterization_of_Glucose-Related_Metabolic_Pathways_in_Differentiated_Rat_Oligodendrocyte_Lineage_Cells
[8] Oxidative Stress Disrupts Oligodendrocyte Maturation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138415/
[9] The Pentose Phosphate Pathway Generates NADPH and Synthesizes Five-Carbon Sugars – Biochemistry – NCBI Bookshelf https://www.ncbi.nlm.nih.gov/books/NBK22416/
[10] Oligodendrocytes use lactate as a source of energy and as a precursor of lipids – Sánchez‐Abarca – 2001 – Glia – Wiley Online Library https://onlinelibrary.wiley.com/doi/abs/10.1002/glia.1119
[11] Relationship between the pentose-phosphate pathway and the de novo synthesis of fatty acids and cholesterol in oligodendrocyte-enriched glial cultures – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/20493032
[12] Characterization of glucose‐related metabolic pathways in differentiated rat oligodendrocyte lineage cells https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832329/
[13] Fatty Acid Synthesis https://en.wikipedia.org/wiki/Fatty_acid_synthesis
[14] CNS myelination and remyelination depend on fatty acid synthesis by oligodendrocytes | eLife https://elifesciences.org/articles/44702
[15] Body mass index in patients with Multiple Sclerosis: a meta-analysis. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/31146649
[16] Regulation of oligodendrocyte development and myelination by glucose and lactate. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/21228163
[17] Quantifying Carbon Sources For de novo Lipogenesis in WildType and IRS-1 Knockout Brown Adipocytes http://www.jlr.org/content/early/2004/04/21/jlr.M400031-JLR200.full.pdf
[18] Oligodendrocyte Progenitor Cells Directly Utilize Lactate for Promoting Cell Cycling and Differentiation. – PubMed – NCBI
https://www.ncbi.nlm.nih.gov/pubmed/27861886
[19] Fatty Acids Are Synthesized and Degraded by Different Pathways – Biochemistry – NCBI Bookshelf https://www.ncbi.nlm.nih.gov/books/NBK22554/
[20] Antioxidant Protection of NADPH-Depleted Oligodendrocyte Precursor Cells Is Dependent on Supply of Reduced Glutathione https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4962338/
[21] Stimulation of the pentose phosphate pathway and glutathione levels by dehydroascorbate, the oxidized form of vitamin C https://www.ncbi.nlm.nih.gov/pubmed/10877828
[22] Pathological narcissism associated with reduced frontal cortex thickness in the brain https://www.psypost.org/2016/09/pathological-narcissism-associated-reduced-frontal-cortex-thickness-brain-44918
[23] Myelination of Axons Corresponds with Faster Transmission Speed in the Prefrontal Cortex of Developing Male Rats. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/30225359
[24] MYELIN AND AXON ABNORMALITIES IN SCHIZOPHRENIA MEASURED USING MRI TECHNIQUES https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720707/
[25] Myelination of the brain in Major Depressive Disorder: An in vivo quantitative magnetic resonance imaging study | Scientific Reports https://www.nature.com/articles/s41598-017-02062-y
