Kynurenic acid (KYNA) is a product of the metabolism of L-tryptophan. It has anti-epileptic and anti-excitotoxic properties. From wikipedia:
KYNA has been proposed to act on four targets:
- As an antagonist at ionotropic AMPA, NMDA and Kainate glutamate receptors in the concentration range of 0.1-2.5 mM
- As a noncompetitive antagonist at the glycine site of the NMDA receptors.
- As an antagonist of the a7 nicotinic acetylcholine receptor. However, recently, direct recording of α7 nicotinic acetylcholine receptor currents in adult (noncultured) hippocampal interneurons by the cooper labaoratory validated a 2009 study that failed to find any blocking effect of kynurenic acid across a wide range of concentrations, thus suggesting that in noncultured, intact preparations from adult animals there is no effect of kynurenic acid on α7 nicotinic acetylcholine receptor currents
- As a ligand for the orphan G protein-coupled receptor GPR35. Another tryptophan metabolite, 5-hydroxyindoleacetic acid exerts its effects via the orphan G protein-couple receptor GPR35
KYNA is actually not that bad in moderate amounts., as it can buffer against excitotoxicity and helps mood. The problem is when your L-tryptophane metabolism is KYNA dominant or you have lots of inflammation, where microglia release KYNA in your brain. The symptoms of NMDA antagonism are very similar to schizophrenia, and scientists actually use PCP to induce schizophrenic states in rats. Not surprisingly, KYNA abundance has been implicated in schizophrenia. This makes sense. Now, for the real negative of KYNA: Quinolinic acid.
“Quinolinic acid is an excitotoxin in the CNS. It reaches pathological levels in response to inflammation in the brain, which activates resident microglia and macrophages. High levels of quinolinic acid can lead to hindered neuronal function or even apoptotic death. Quinolinic acid produces its toxic effect through several mechanisms, primarily as its function as an NMDA receptor agonist, which triggers a chain of deleterious effects, but also through lipid peroxidation, and cytoskeletal destabilization. The gliotoxic effects of quinolinic acid further amplify the inflammatory response. Quinolinic acid affects neurons located mainly in the hippocampus, striatum, and neocortex, due to the selectivity toward quinolinic acid by the specific NMDA receptors residing in those regions.
When inflammation occurs, quinolinic acid is produced in excessive levels through the kynurenine pathway. This leads to over excitation of the NMDA receptor, which results in an influx of Ca2+ into the neuron. High levels of Ca2+ in the neuron trigger an activation of destructive enzymatic pathways including protein kinase, phospholipase, NO synthase, and proteases. These enzymes will degenerate crucial proteins in the cell and increase NO levels, leading to an apoptotic response by the cell, which results in cell death.
In normal cell conditions, astrocytes in the neuron will provide a glutamate-glutamine cycle, which results in reuptake of glutamate from the synapse into the pre-synaptic cell to be recycled, keeping glutamate from accumulating to lethal levels inside the synapse. At high concentrations, quinolinic acid inhibits glutamine synthetase, a critical enzyme in the glutamate-glutamine cycle. In addition, It can also promote glutamate release and block its reuptake by astrocytes. All three of these actions result in increased levels of glutamate activity that could be neurotoxic.
This results in a loss of function of the cycle, and results in an accumulation of glutamate. This glutamate further stimulates the NMDA receptors, thus acting synergistically with quinolinic acid to increase its neurotoxic effect by increasing the levels of glutamate, as well as inhibiting its uptake. In this way, quinolinic acid self-potentiates its own toxicity. Furthermore, quinolinic acid results in changes of the biochemistry and structure of the astrocytes themselves, resulting in an apoptotic response. A loss of astrocytes results in a pro-inflammatory effect, further increasing the initial inflammatory response which initiates quinolinic acid production.
Quinolinic acid can also exert neurotoxicity through lipid peroxidation, as a result of its pro-oxidant properties. Quinolinic acid can interact with Fe(II) to form a complex that induces a reactive oxygen and nitrogen species (ROS/RNS), notably the hydroxyl radical •OH. This free radical causes oxidative stress by further increasing glutamate release and inhibiting its reuptake, and results in the breakdown of DNA in addition to lipid peroxidation. Quinolinic acid has also been noted to increase phosphorylation of proteins involved in cell structure, leading to destabilization of the cytoskeleton“
If you don’t want to read that, then I will give a summary. KYNA is released by microglia when there is inflammation. KYNA is neuroprotective. KYNA is metabolized to Quinolinic acid. Quinolinic acid is a NMDA agonist, and thus can act as an excitotoxin. It also kills neurons via lipid peroxidation and cytoskeleton destabilization. It induces ROS. It blocks glutamate from being metabolized, resulting in more neurotoxicity from excess glutamate. It also blocks glutamate reuptake. It kills astrocytes, resulting in more inflammation. It really fucks the brain. I hypothesize that schizophrenics have a build up of KYNA because they have low rates of the enzymes that metabolize KYNA too quinolinic acid. From wikipedia “Downregulation of kynurenine-3-monooxygenase (KMO) can be caused by genetic polymorphisms, cytokines, or both.” Many Schizophrenic people probably have a predisposition towards KMO down regulation, and inflammation probably synergizes with those genes, resulting in excess KYNA and thus dissociative symptoms. Autistic people probably have an overexpression of KMO, or a bottleneck situation like the schizophrenics, just higher up the pathway, resulting in excess quinolinic and not enough KYNA to buffer it. Both have a KYNA dominant L-Tryptophan metabolization. This can be caused by inflammation, which has been noted in autistic and schizo individuals.
Rosmarinic acid is great for autism and good for schizophrenia because it downregulates Indoleamine 2,3-dioxygenase (IDO) via COX inhibition. IDO catalyzes L-tryptophan into N-formylkynurenine. Rosmarinic acid is also a GABA-T inhibitor, which would be great for autism because it would quell the excitotoxic storms that autistic people suffer.
There’s also Syrian rue, which has a multitude of beneficial effects, including KYNA downregulation via norharmane/beta-Carboline, which directly inhibits IDO and nitric oxide synthase. Norharmane is also a benzo-site inverse agonist, so it has memory enhancing, anxiogenic, yet doesn’t seem excitotoxic. It might break even with quinolinic acid and thus causes less neurotoxicity than it takes away via quinolinic acid. Syrian rue has many other alkaloids, most beneficial in some way, but I suggest you read up on each one before buying it. It could be dangerous to take if you’re uninformed. https://en.wikipedia.org/wiki/Harmala_alkaloid#Chemical_forms