English corner: Altered GABA levels in MS patients

Perturbed GABA signaling and B6 sensivity
Altered GABA levels in MS patients
Deficiency in vitamin B complex vary, although common symptoms include fatigue, increased oxidative stress, inflammation and demyelination. In particular, vitamin B12 (cobalamin) has triggered an increased attention for its role in the methylation process, involvement in myelination and re-myelination and reversal of multiple sclerosis (MS) symptoms.
Is there a link between vitamin B and multiple sclerosis?
Background: Damage to the myelin sheath (demyelination) is one of the main manifestations of multiple sclerosis. Interestingly, both MS and vitamin B deficiencies result in severe myelin degeneration, leading to loss in neuronal signal transmission. (1)
Vit B6 decreases pro‐inflammatory cytokines
Vitamin B6 supplementation decreased the expression of pro‐inflammatory cytokines by suppressing nuclear factor‐κB and mitogen‐activated protein kinases signaling pathways (5)
Note: The signal transduction pathways regulate processes such as cell proliferation, cell differentiation, and cell death in eukaryotes.
Vitamin B6 and brain glutamate decarboxylase
Glutamate decarboxylase (GAD) catalyzes the irreversible decarboxylation of L-glutamate to the valuable food supplement γ-aminobutyric acid (GABA). B6 supplementation improves the activity of recombinant glutamate decarboxylase and the enzymatic production of γ -aminobutyric acid. Vitamin B₆ deficiency resulted in a delayed clearance from plasma of intravenously administered glutamate. GAD requires PLP for its glutamate decarboxylase activity [[Vous devez être inscrit et connecté pour voir ce lien]].
Altered GABA and glutamate levels are associated with multiple sclerosis central fatigue
In MS patients, GABA levels in the brain and circulation are reduced compared to healthy individuals. Therefore, the functioning of the GAD enzyme should be less disturbed / upset, if we want to increase GABA levels.
Sources & References
See next post.

Sources and references
1. Is there a link between vitamin B and multiple sclerosis?
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2. The Role of B6 in Brain Health
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B₆ is attributed a neuroprotective role which appears to be mainly linked with its ability to regulate the glutamatergic system and thus gamma‐aminobutyric acid (GABA) levels, a key inhibitory neurotransmitter in the central nervous system. Vitamin B₆ is an indispensable in the synthesis of GABA (from glutamate), utilising the PLP-dependent enzyme glutamic acid decarboxylyase (Ramos et al., 2017). Increased levels of glutamate, an excitatory neurotransmitter, can be linked with seizures, and similarly the application of GABA or B₆ can end or reduce seizure activity (Calderón‐Ospina & Nava‐Mesa, 2020).
Homocysteine hypothesis, Cognition & Alzheimer’s Disease
As B₆ is an essential homocysteine re-methylation cofactor, deficiency can disrupt the remethylation cycle of homocysteine to methionine. This leads to elevated plasma homocysteine which can result in far-reaching health impairments from prenatal development to late adulthood (Miller, 2003). Homocysteine is a physiological amino acid produced from protein break-down, and can develop into a pathological condition called hyperhomocysteinemia if these exceed certain levels (Cordaro et al,. 2021).  Supplementation with B vitamins, including vitamin B6, has been shown to reduce blood homocysteine levels.
Neurotransmitter Metabolism: Depression & Anxiety 
PLP-dependent enzymes are involved in the metabolism of the neurotransmitters dopamine, noradrenaline, serotonin, glycine, D-serine, glutamate, γ-aminobutyrate (GABA) and histamine (Clayton, 2006). Since its role in metabolism makes it a rate-limiting cofactor in the neurotransmitter synthesis, B₆ deficiency is widely considered to lead to brain function impairment and underpins the proposed link between B₆ and mental health outcomes.
Protective role against Mitochondria Damage
Research confirms that a lack of vitamin B₆ can cause damage and toxicity to mitochondria and that appropriate supplementation of it can improve mitochondria’s energy metabolism to a certain extent (Depeint et al., 2006). This is due to the mechanistic role which PLP plays in mitochondrial functions, acting as a cofactor and participating in catalytic reactions. 
3. Vitamin B-6-Induced Neuropathy: Exploring the Mechanisms of Pyridoxine Toxicity
[url=https://doi.org/10.1093/advances/nmab033 07/2021][Vous devez être inscrit et connecté pour voir ce lien] 07/2021[/url]. Felix Hadtstein, Misha Vrolijk.
=> Perturbed GABA signaling within sensory neurons may lead to excitotoxity.
4. Inflammation, vitamin B6 and related pathways
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Magne Ueland et al. 2016 – Elsevier Ltd. Molecular Aspects of Medicine.
Vitamin B6 intake and supplementation improve some immune functions in vitamin B6-deficient humans and experimental animals. A possible mechanism involved is mobilization of vitamin B6 to the sites of inflammation where it may serve as a co-factor in pathways producing metabolites with immunomodulating effects. Relevant vitamin B6-dependent inflammatory pathways include vitamin B6 catabolism, the kynurenine pathway, sphingosine 1-phosphate metabolism, the transsulfuration pathway, and serine and glycine metabolism.
5. Vitamin B₆ in Carpal Tunnel Syndrome
4-8mg B6 per day for adults instead of 1.3 mg DRA, after reload.  
Mind overdosing B6 because it would be counterproductive.
Consider Zinc deficiency would inhibit conversion of B6 into its active form. B6 is useless until the zinc deficiency is corrected.
Note 1:  We will be warned against a high dosage of vitamin B6. Indeed, it is necessary to avoid an overload of the organism because the saturation will lead to worse effects that if you had not taken anything. The brain protects itself against an excess of toxic metabolites. It is as if there were a deficit. A lack of GABA will take place and lead to painful sensations. Right.
Note 2: Don’t take into account case-studies with high dose B6 (200 – 300 mg). Too much of a good thing is bad.
- Do not take high dose pyridoxine. Toxic. No pyridoxine HCl, then.
- After reloading with PLP or PMP, a pause is required.
I’ve taken 100 mg of B6 PLP, 5 days a week for 3 weeks. So not the weekend. Then I took a one-month break (half-life). Everything should be made to avoid overload with PLP, otherwise the brain will block access. Metabolites will become toxic.
- When considering the studies, have a look first at the dosage (200 - 300 mg is wrong) and the type (HCL or PLP).  The ideal duration of the study is 12 weeks, with a dosage of 50 - 100 mg. Be careful with a high dosage over a period of one year (saturation).
-  If you suffer from a sensitive pathology, take a more moderate dosage. For example 20-25 mg of PLP. I would start with 50 mg for a week. Then 20-25 mg. With breaks on weekends. Zinc will be required to optimize B6 assimilation. 30 mg of zinc bisglycinate (or picolinate) in attack, for 5 days, then 15 mg. Avoid eating cheese when taking zinc (too much Ca).
*) The carpal tunnel syndrome as a probable primary deficiency of vitamin B₆ rather than a deficiency of a dependency state
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*) Treatment of carpal tunnel syndrome with vitamin B6
DOI: [Vous devez être inscrit et connecté pour voir ce lien]  J M Ellis 1987.
100 to 200 mg daily for 12 weeks.
5. Vitamin B6 prevents excessive inflammation by reducing accumulation of sphingosine‐1‐phosphate in a sphingosine‐1‐phosphate lyase–dependent manner
doi: [Vous devez être inscrit et connecté pour voir ce lien]  Xialin Du et al. 2020 Sep 23. 
Abstract:
Vitamin B6 is necessary to maintain normal metabolism and immune response, especially the anti‐inflammatory immune response. However, the exact mechanism by which vitamin B6 plays the anti‐inflammatory role is still unclear. Here, we report a novel mechanism of preventing excessive inflammation by vitamin B6 via reduction in the accumulation of sphingosine‐1‐phosphate (S1P) in a S1P lyase (SPL)‐dependent manner in macrophages. Vitamin B6 supplementation decreased the expression of pro‐inflammatory cytokines by suppressing nuclear factor‐κB and mitogen‐activated protein kinases signaling pathways. Furthermore, vitamin B6–reduced accumulation of S1P by promoting SPL activity. The anti‐inflammatory effects of vitamin B6 were inhibited by S1P supplementation or SPL deficiency. Importantly, vitamin B6 supplementation protected mice from lethal endotoxic shock and attenuated experimental autoimmune encephalomyelitis progression. Collectively, these findings revealed a novel anti‐inflammatory mechanism of vitamin B6 and provided guidance on its clinical use.
6. Pyridoxine Supplementation Improves the Activity of Recombinant Glutamate Decarboxylase and the Enzymatic Production of GABA
 2016 Jul 20. doi: [Vous devez être inscrit et connecté pour voir ce lien]
Glutamate decarboxylase (GAD) catalyzes the irreversible decarboxylation of L-glutamate to the valuable food supplement γ-aminobutyric acid (GABA). 
These results establish the utility of pyridoxine supplementation for the production of GABA.
7. High‐dose Vitamin B6 supplementation reduces anxiety and strengthens visual surround suppression
Doi: [Vous devez être inscrit et connecté pour voir ce lien]  David T. Field et al. 2022 Jul 19. 
Vitamins B6 and B12 are involved in metabolic processes that decrease neural excitation and increase inhibition. (…)
High‐dose Vitamin B6 supplementation can influence behavioural outcomes related to neural inhibition and the overall level of excitation. Such an influence can be predicted because in addition to its role as a coenzyme in converting excitatory glutamate into inhibitory GABA, Vitamin B6 is involved in a number of other pathways that are likely to reduce neural excitation; it is a co‐enzyme for the production of other neurotransmitters such as serotonin, dopamine, and noradrenaline; it acts as a cofactor in the kynurenine pathway in which it reduces the amount of quinolinic acid, which is an agonist to the excitatory NMDA receptor (Curto et al., ^{[Vous devez être inscrit et connecté pour voir ce lien]}; Zinger et al., ^{[Vous devez être inscrit et connecté pour voir ce lien]}) it is involved in the homocysteine‐cysteine cycle and through this reduces levels of homocysteine, which is an agonist of the NMDA receptor (Deep et al., ^{[Vous devez être inscrit et connecté pour voir ce lien]}; Zaric et al., ^{[Vous devez être inscrit et connecté pour voir ce lien]}) also via the homocysteine‐cysteine cycle it provides cysteine to the glutathione cycle, which reduces levels of the excitatory neurotransmitter glutamate by converting it to glutathione.
*) Homocysteine‐cysteine cycle and clearance of glutamate
Homocysteine is a sulfur-containing amino acid derived from the metabolism of methionine, an essential amino acid, and is metabolized by one of two pathways: remethylation or transsulfuration.
Vitamins B12, B6 and folate break down homocysteine to create other chemicals your body needs. 
Pyridoxine (vitamin B₆) is needed as a cofactor in this cycle, leading to cysteine, ammonia, and α-ketobutyrate. Alternatively, homocysteine can be remethylated to methionine with help from vitamin B12.
These studies support the potential for NAC to normalize excessive glutamate levels in brain. NAC treatment was associated with increased glutathione (statistically significant) and decreased glutamate. (*)
* [Vous devez être inscrit et connecté pour voir ce lien]
N-Acetylcysteine effects on glutathione and glutamate in schizophrenia: A preliminary MRS study
Yvonne S. Yang et al. 09/2022
*) Effects of vitamin B6 on age associated changes of rat brain glutamate decarboxylase activity
DOI:[Vous devez être inscrit et connecté pour voir ce lien] 2011
Glutamate and gamma-aminobutyric acid (GABA), act as excitatory and inhibitory neurotransmitters in CNS respectively. An increase in glutamate and a decrease in GABA concentration were observed in aged brain. The activity of the enzyme in aged rats was significantly lower as compared to that of young animals. Vitamin B6 induced activation of the brain enzyme in both ages, but the rate of the activation was markedly pronounced in aged animals.
It is suggested that vitamin B6 may restore the activity of the brain glutamate decarboxylase in aged rat.
*) Vitamin B-6-Induced Neuropathy: Exploring the Mechanisms of Pyridoxine Toxicity
[Vous devez être inscrit et connecté pour voir ce lien] Felix Hadtstein et al. Adv Nutr. 2021 Oct.
The present review is focused on investigating the mechanistic link between pyridoxine supplementation (PN) and sensory peripheral neuropathy. Excessive PN intake induces neuropathy through the preferential injury of sensory neurons. Recent reports on hereditary neuropathy due to pyridoxal kinase (PDXK) mutations may provide some insight into the mechanism, as genetic deficiencies in PDXK lead to the development of axonal sensory neuropathy. High circulating concentrations of PN may lead to a similar condition via the inhibition of PDXK. The mechanism behind PDXK-induced neuropathy is unknown; however, there is reason to believe that it may be related to γ-aminobutyric acid (GABA) neurotransmission. Compounds that inhibit PDXK lead to convulsions and reductions in GABA biosynthesis. The absence of central nervous system-related symptoms in PDXK deficiency could be due to differences in the regulation of PDXK, where PDXK activity is preserved in the brain but not in peripheral tissues. As PN is relatively impermeable to the blood–brain barrier, PDXK inhibition would similarly be confined to the peripheries and, as a result, GABA signaling may be perturbed within peripheral tissues, such as sensory neurons. Perturbed GABA signaling within sensory neurons may lead to excitotoxicity, neurodegeneration, and ultimately, the development of peripheral neuropathy. For several reasons, we conclude that PDXK inhibition and consequently disrupted GABA neurotransmission is the most plausible mechanism of toxicity.
*) Assessment of vitamin B6 intake in relation to tolerable upper intake levels
Norwegian dietary surveys for B6 intake
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VKM (2017). Assessment of vitamin B6 intake in relation to tolerable upper intake levels. Opinion of the Panel on Nutrition, Dietetic Products, Novel Food and Allergy of the Norwegian Scientific Committee for Food Safety. VKM Report 2017: 3, ISBN: 978-82-8259-260-4, Oslo, Norway.
Excerpt
A new metabolomics analysis indicated perturbation of the metabolism of several amino acids with a plasma level < 30 nmol/L and as a consequence EFSA has used this level as an indication of vitamin B6 deficiency (EFSA, 2016; Gregory et al., 2013). Eighty to ninety percent of vitamin B6 in the body is found in muscles and estimated body stores amount to about 170 mg with a half-life of 25-33 days. Vitamin B6 deficiency is mostly seen in combination with deficiency of other B vitamins. The most typical clinical symptoms of vitamin B6 deficiency are anaemia and neurological abnormalities (EFSA, 2016).
Note: Half-life between 15-20 days (parenteral) (Medscape) or 25-33 days (in the body).
=> 25 days half-life as middle data (Shane, 1978).
At an intake of 25 mg/day of vitamin B6, no adverse effects had been reported in a large number of published studies, also after long term use.
Norwegian dietary surveys for B6 intake
NOTE: There is no details on the type of B6. Presumably the most common form in the tests, that is to say HCL pyridoxine. But P5 (in the table) could refer to pyridoxal 5’ phosphate (PLP)
Table 2.2-2 Tolerable upper intake levels UL for vitamin B6 for different age groups proposed by the SCF (2000). The mean intake of vitamin B6 from the diet alone is 1.7 mg/day (between 0.8 mg and 3 mg). (p 28-29 of the PDF)
SCF = Scientific Committee for Food. Norway

Age (years)	UL mg/day	P5 from food included
1-3	5
4-6	7
7-10	10
11-14	20
Adults	25	25.8

Adults with a dietary intake from food at P95 will not exceed UL if supplemented with 20 mg vitamin B6 per day.
P95 = 95-percentile of vitamin B6 intake from diet alone. => 95 % of data taken into account.
UL = Upper Limit.
*) Quantification of the B6 vitamers in human plasma and urine in a study with pyridoxamine as an oral supplement; pyridoxamine as an alternative for pyridoxine
[Vous devez être inscrit et connecté pour voir ce lien]  Mathias D.G et al. 2021
The three daily dose (67 mg PMP x 3) resulted in a more constant plasma concentration during the day. We found steadily increasing levels of the biologically active PLP after PM supplementation, with minimal formation of PN. Thus, the B6 vitamer PM could be an interesting supplement with regards to the treatment of metabolic diseases and vitamin B6 deficiency.
=> Best absorption with medium dose (50 mg) than high dose (100 mg). Minimal PN transposition.
PM = Pyridoxamine
*) Altered in vivo brain GABA and glutamate levels are associated with multiple sclerosis central fatigue
[Vous devez être inscrit et connecté pour voir ce lien]  04.21
In MS patients, GABA levels in the brain and circulation are reduced compared to healthy individuals.
The associations between fatigue and GABA + and Glx suggest that there might be dysregulation of GABAergic/glutamatergic neurotransmission in the pathophysiological mechanism of central fatigue in MS.
Excerpt

In MS, GABA plays an important role in the pathophysiological mechanism of neurodegeneration, neuroprotection and functional reorganisation [13]. There is also a suggestion that a partial loss of compensatory downregulation of cortical inhibitory mechanisms involving reduced levels of GABAergic activity is associated with MS fatigue [14]. Glutamate, on the other hand, is abundant in the brain at approximately 5–15 mmol/kg brain tissue and plays a crucial role in the cerebral metabolism by being at the crossroads of many metabolic pathways [15]. Abnormal levels of glutamate have been reported in MS patients with different disease phenotypes; increased levels in active lesions and white matter lesions and low levels in gray matter regions [16].