English corner: B6, Brain inflammation and Quinolinate: The kynurenine pathway

B6, Brain inflammation and Quinolinate: the kynurenine pathway
Reducing Brain Inflammation with Vitamin B6
When metabolizing the amino acid tryptophan, B6 is required to neutralize the byproduct quinolinate (or quinolic acid). With the appropriate vitamin B6, quinolinic acid is not the final product of tryptophan catabolism. Otherwise, increased concentration of metabolites can be responsible for cytotoxicity, particularly in neurologic diseases.

For those individuals suffering from brain inflammation mediated by disease, medication or vaccine adverse reactions, vitamin B6 might just reduce the inflammation cascades and improve quality of life.  Chandler MARRS, PHD

B6 is needed to make melatonin and GABA, and to maximally suppress quinolinate. Molybdenum is needed to maximally suppress sulfite. [Vous devez être inscrit et connecté pour voir ce lien] stimulates excitatory glutamate receptors, and [Vous devez être inscrit et connecté pour voir ce lien] drives the generation of S-sulfocysteine, which does the same. Thus, B6 and molybdenum deficiency could both contribute to anxiety or insomnia.
NDLR: With adequate vitamin B-6 intake, a high percentage of the tryptophan administered was excreted as kynurenic acid and quinolinic acid through urine.
Quinolinic acid is one of the kynurenine metabolite downstream of PLP-dependent enzymes.
But when more vitamin B6 is used up / spent, for instance with arthrosis, this situation could lead to vitamin B6 deficiency. Deficiency of vitamin B6 blocks the metabolic pathway and leads to accumulation of kynurenine pathway intermediates such as hydroxy-L-kinurenine or quinolinic acid, which has been shown to play a role in neuropathic pain in an animal model. (1-2)
The kynurenine pathway
The kynurenine pathway is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD⁺). Metabolites involved in the kynurenine pathway include tryptophan, kynurenine, kynurenic acid, xanthurenic acid, quinolinic acid, and 3-hydroxykynurenine.
NAD+: NAD+ is necessary to create adenosine triphosphate (ATP), the compound that the body uses as fuel (for energy).
What is the function of the kynurenine pathway?
The kynurenine pathway is the primary route for tryptophan catabolism in the liver and the starting point for the synthesis of NAD⁺ in mammals. Dysregulation or over-activation of this pathway can lead to immune system activation and accumulation of potentially neurotoxic compounds.
In this way, if you lack B6, excess quinolinate happens and causes anxiety and neuropathic pain.
The following substances have been proven to lower levels of quinolinic acid (3):
[list=margin-top][*]Sulforaphane
[*]Selenium
[*]Melatonin
[*]Theanine
[*]Green Tea Polyphenols
[*]Curcumin + Piperine (improves Nrf2 and SOD / GPx).
[/list]
Note: These substances lower levels of quinolinic acid, but on an indirect way, by calming down the excitatory process. It could happen for a while, till the body finds another way to over-react.
Toxicity
When all is working well, tryptophan serves as a substrate for serotonin and melatonin. Excess tryptophan is degraded resulting in the by-products nictonic acid and nicotinamide adenine dinucleotide (NAD+) – or as most of us recognize, niacin, vitamin B3. Niacin is an essential nutrient in many physiological functions. Loss of niacin metabolism from this pathway can lead to significant disease, including, Pellagra, a disease characterized by scaly skin lesions, delusions and confusion. In addition to a loss of niacin synthesis, when vitamin B6 is deficient and the tryptophan pathway is disturbed, the incomplete degradation of tryptophan produces several metabolites that are neurotoxic, including one called [Vous devez être inscrit et connecté pour voir ce lien].
[Vous devez être inscrit et connecté pour voir ce lien] when unopposed in the brain. It generates ROS (reactive oxygen species indicative of mitochondrial oxidative stress and damage) and over-activates NMDA glutamate receptors (the brain’s primary excitatory neurotransmitter) to the point of apoptosis (cell death), all the while inhibiting brain astrocytes’ ability to clean up the excess glutamate. Once that cycle becomes initiated, quinolinic acid potentiates its own release and that of other neurotoxins, ensuring continued brain inflammation and damage.
With the appropriate vitamin B6, quinolinic acid is not the final product of tryptophan catabolism, NAD+ or niacin is, and any damage initiated by quinolinic acid as a natural by-product within this pathway is offset by two neuroprotective factors, kynurenine and picolinic acid. Vitamin B6 is critical for the kynurenine aminotransferase and kynurinase enzymes; enzymes that lead to neuroprotective compounds, kynurenine or picolinic acid. Kynurenine blocks the cytotoxic effects of quinolinic acid by blocking the NMDA receptor, making it unavailable to quinolinic acid, while picolinic acid is the primary metal chelator (remover) in the brain (likely critically important in post vaccine reactions). In other words, vitamin B6 controls the balance between inflammation and anti-inflammation within the brain and the [Vous devez être inscrit et connecté pour voir ce lien].
Final Thoughts
Tryptophan metabolism and the kynurenine pathway are implicated in disease processes where inflammation is prominent. Vitamin B6 may be critical to maintaining the appropriate balance between inflammatory and anti-inflammatory immune reactions. With modern nutritional deficits ([Vous devez être inscrit et connecté pour voir ce lien]), commercial agricultural practices ([Vous devez être inscrit et connecté pour voir ce lien]), estrogenic medications and environmental exposures (estrogens inhibit vitamin B6), it is entirely conceivable that many of us are vitamin B6 deficient and, as a result, functioning with a constant level of inflammation. Vitamin B6 supplementation, along with the other B vitamins might be warranted.
For those individuals suffering from brain inflammation mediated by disease, medication or vaccine adverse reactions, vitamin B6 might just reduce the inflammation cascades and improve quality of life. Given its direct impact on tryptophan metabolism, vitamin B6 ought to be considered critical for brain health.

Sources and References
See next post.
NB: La traduction en français va suivre . Un must-read 
[Vous devez être inscrit et connecté pour voir ce lien]

Sources and References
!!! Watch out for the right dosage: an excess of B6, in cure, will be counterproductive with vitamin B6 PLP. (Do not use PNP in cure, because of toxic metabolites).

0. This post is mainly inspired by this article:
Reducing Brain Inflammation with Vitamin B6
By Chandler MARRS, PHD
[Vous devez être inscrit et connecté pour voir ce lien]
1. Meningeal dendritic cells drive neuropathic pain through elevation of the kynurenine metabolic pathway in mice
doi: 10.1172/JCI153805.
In this study, we found that neuropathic pain is abrogated when the kynurenine metabolic pathway (KYNPATH) initiated by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is ablated pharmacologically or genetically. (…) These data revealed a role for dendritic cells (DCs) driving neuropathic pain development through elevation of the KYNPATH. This paradigm offers potential new targets for drug development against this type of chronic pain.
2. Vitamin B6 and chronic pain
[Vous devez être inscrit et connecté pour voir ce lien]
3. These substances have been proven to lower levels of quinolinic acid.
[Vous devez être inscrit et connecté pour voir ce lien]

Additional links on quinolinic acid
*) Quinolinic acid as byproduct of tryptophan assimilation when B6 lacks
The kynurenine pathway formed an intriguing link between the dietary availability of vitamin B6 and tryptophan metabolism.
With adequate vitamin B-6 intake, a high percentage of the tryptophan ingested was excreted as kynurenic acid and quinolinic acid in urine.[Vous devez être inscrit et connecté pour voir ce lien]
*) Over the past decade, a growing number of reports has described quinolinic acid accumulation during inflammation and has hypothesized that quinolinic acid may play a role in many disease processes. Inflammation triggers a complex cascade of cytokines which can activate the kynurenine pathway and cause quinolinic acid accumulation. In fact, IDO, the enzyme responsible for the first and rate-limiting step of this pathway, is induced by many inflammatory cytokines ([Vous devez être inscrit et connecté pour voir ce lien], [Vous devez être inscrit et connecté pour voir ce lien]). Interferon-γ (IFN-γ), specifically, is a powerful IDO-activating cytokine ([Vous devez être inscrit et connecté pour voir ce lien]). Quinolinic acid seems to have a controversial and unclear role during inflammation. In some instances, quinolinic acid appears to have an anti-inflammatory role by reducing Th1-like cells and increasing the Th2-like cells, which limits adaptive immunity overactivation ([Vous devez être inscrit et connecté pour voir ce lien]). However, quinolinic acid accumulation has also been considered a deleterious feature of inflammation, and its increased concentration can be responsible for cytotoxicity, particularly in neurologic diseases through numerous proposed mechanisms ([Vous devez être inscrit et connecté pour voir ce lien]).
Source: States of quinolinic acid excess in urine: A systematic review of human studies
doi: [Vous devez être inscrit et connecté pour voir ce lien]
IDO = indoleamine 2,3-dioxygenase
*) The Role of Tryptophan Dysmetabolism and Quinolinic Acid in Depressive and Neurodegenerative Diseases
[Vous devez être inscrit et connecté pour voir ce lien] by Knut Hestadetal. 2022
Abstract
Emerging evidence suggests that neuro-inflammation is involved in both depression and neurodegenerative diseases. The kynurenine pathway, generating metabolites which may play a role in pathogenesis, is one of several competing pathways of tryptophan metabolism. The present article is a narrative review of tryptophan metabolism, neuro-inflammation, depression, and neurodegeneration. A disturbed tryptophan metabolism with increased activity of the kynurenine pathway and production of quinolinic acid may result in deficiencies in tryptophan and derived neurotransmitters. Quinolinic acid is an N-methyl-D-aspartate receptor agonist, and raised levels in CSF, together with increased levels of inflammatory cytokines, have been reported in mood disorders. Increased quinolinic acid has also been observed in neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and HIV-related cognitive decline. Oxidative stress in connection with increased indole-dioxygenase (IDO) activity and kynurenine formation may contribute to inflammatory responses and the production of cytokines. Increased formation of quinolinic acid may occur at the expense of kynurenic acid and neuroprotective picolinic acid. While awaiting ongoing research on potential pharmacological interventions on tryptophan metabolism, adequate protein intake with appropriate amounts of tryptophan and antioxidants may offer protection against oxidative stress and provide a balanced set of physiological receptor ligands.
CSF = Cerebrospinal Fluid

Additional links on B6 metabolism on this forum:

[Vous devez être inscrit et connecté pour voir ce lien]

[Vous devez être inscrit et connecté pour voir ce lien]

- [Vous devez être inscrit et connecté pour voir ce lien]

- [Vous devez être inscrit et connecté pour voir ce lien]

- [Vous devez être inscrit et connecté pour voir ce lien] (neuro-sensitivité).

[Vous devez être inscrit et connecté pour voir ce lien]

[Vous devez être inscrit et connecté pour voir ce lien]

[Vous devez être inscrit et connecté pour voir ce lien]