Quoted from Nanna on the topic of kynurenic acid:
Here is some background information that might help you with the kynurenine pathway: Glutamate (excitation) and GABA (inhibition) act as on/off switches for neurons. When the neuron is on (glutamate-NMDA) there is increased energy consumption and NAD+/NADH cycling. When the neuron is turned off (GABA) energy is conserved and there is very little cellular activity.
The main purpose of the kynurenine pathway is to produce niacin and ultimately NADH and NADPH (
Ref). NADH and NADPH are a key energy redox antioxidants that allow the body to used calories as energy (ATP). NAD+ is also a required cofactor along with poly(ADP-ribose) polymerase-1 (PARP-1) for DNA repair.
But if there is too much DNA damage then PARP-1 will consume and deplete NAD+, which depletes the energy of the cell/neuron and kills it. For example:
Blockade of PARP activity attenuates poly(ADP-ribosyl)ation but offers only partial neuroprotection against NMDA-induced cell death in the rat retina. As long as everything is normal in a neuron/cell, then the kynurenine pathway is only producing niacin/NAD as the end-product. However, there are several ways that the neuron can detect DNA damage.
If a small amount of DNA damage occurs then NAD+ is consumed by
PARP-1 to repair DNA. But if a large amount of DNA damage is suddenly detected,
the cell goes into safe-mode by shutting down cellular activity (block NMDA, reduce PARP-1 activity, and increase GABA). This is partially accomplished by diverting kynurenine metabolism away from niacin production and into kynurenic acid. Kynurenic acid then blocks cellular activity by blocking glutamate receptors (NMDA, AMPA, etc...) (
Ref). The increase in kynurenic acid prevents further DNA damage and stress induced toxicity.
Kynurenic acid production is a safety-switch in the kynurenine pathway to prevent DNA damage and cell death. The side-effect of this is that it prevents DNA damage by shutting down the neuron (inhibiting glutamate receptors) so that it is no longer excited/firing (brain fog). Kynurenic acid prevents excitotoxicity at the expense of cognition. If you want to decrease kynurenic acid and brain fog, you should answer the question,
"Why is there an increase in DNA damage?" Different stressors (cancer, infection, poison, emotional stress) can cause DNA damage. So I do not consider kynurenic acid a cause of anything, but rather it is a safety-reaction to a cause.
The
true cause of brain fog is likely something that has nothing to do with the kynurenine pathway, but the body uses changes in the kynurenine pathway to prevent irreversible DNA damage. You can always recover from kynurenic acid induced brain fog, but you cannot recover from neuron loss (brain cell death) due to DNA damage.
In terms of autoimmune diseases,
"N-acetylcysteine (NAC) treatment significantly reduced kynurenine levels relative to placebo in vivo" -
Comprehensive metabolome analyses reveal N-acetylcysteine-responsive accumulation of kynurenine in systemic lupus erythematosus: implications for activation of the mechanistic target of rapamycinSure you can share that explanation. If you do, you may also want to share this quote:
"Kynurenic acid shows neuroprotective properties. (Ref12) Some researchers have posited that the increased levels found in cases of neurological degradation is due to a failed attempt to protect the cells. (Ref13)" -
Kynurenic acid: Role in disease
