Kynurenine is the catabolite of the tryptophan that is one of the most important regulators of the immune response, the inflammation, and the neurological function — it is produced from the tryptophan by the tryptophan dioxygenase (TDO) enzyme in the liver and by the indoleamine 2,3-dioxygenase (IDO) enzymes in the immune cells and in the brain, and it is the central intermediate in the kynurenine pathway, which produces the neuroactive metabolites kynurenic acid (KYNA), quinolinic acid (QUIN), and the NAD+. The kynurenine pathway is the primary pathway of the tryptophan metabolism — approximately 95% of the dietary tryptophan is metabolised through the kynurenine pathway (rather than through the serotonin/melatonin pathway, which only accounts for approximately 1-2% of the tryptophan metabolism) — and the kynurenine pathway metabolites are some of the most important and most biologically active compounds in the brain and in the immune system. The kynurenic acid (KYNA) is a neuroprotective compound that blocks the NMDA receptors and reduces the excitotoxicity; the quinolinic acid (QUIN) is a neurotoxic compound that activates the NMDA receptors and promotes the oxidative stress and the neuroinflammation; and the balance between the KYNA and the QUIN (the KYNA/QUIN ratio) is one of the most important determinants of the neurological outcome in the neurodegenerative diseases, the stroke, and the traumatic brain injury. Without adequate kynurenine and kynurenine pathway regulation, the inflammation is uncontrolled, the neurodegeneration accelerates, and the mood is dysregulated — the hallmark of the kynurenine deficiency and of the elevated quinolinic acid states that are associated with the Alzheimer’s disease, the Parkinson’s disease, the depression, and the chronic inflammatory conditions.
Kynurenine and the Neuroinflammation
Kynurenine regulates the neuroinflammation primarily through its conversion to the kynurenic acid (KYNA) and to the quinolinic acid (QUIN) — the KYNA is a neuroprotective compound that blocks the glycine site of the NMDA receptors, reduces the glutamate excitotoxicity, and inhibits the release of the pro-inflammatory cytokines from the microglia. The QUIN is a neurotoxic compound that activates the NMDA receptors, promotes the calcium influx, stimulates the NADPH oxidase and the mitochondrial dysfunction, and triggers the apoptosis in the neurons. The balance between the KYNA and the QUIN is therefore a critical determinant of the neuroinflammation and of the neuronal survival — when the KYNA/QUIN ratio is high (as it normally is in the healthy brain), the neuroprotection prevails and the excitotoxicity is minimal; when the KYNA/QUIN ratio is low (as it is in the Alzheimer’s disease, the Parkinson’s disease, and the depression), the quinolinic acid toxicity dominates and the neurodegeneration accelerates. The kynurenine pathway is activated by the immune cytokines (IFN-gamma, TNF-alpha, IL-1 beta), by the stress hormones (cortisol, catecholamines), and by the bacterial toxins (LPS) — and this activation is the primary mechanism by which the peripheral immune system communicates with the brain and induces the sickness behaviour, the fatigue, the anhedonia, and the cognitive impairment that are associated with the chronic inflammation and the infection.
The clinical importance of the kynurenine for the neurological health is underscored by the observation that the elevated quinolinic acid levels in the brain and in the cerebrospinal fluid are one of the most consistent and most robust biomarkers of the Alzheimer’s disease, the Parkinson’s disease, and the depression. A study in 50 patients with the Alzheimer’s disease found that the QUIN levels in the cerebrospinal fluid were 2-3 times higher than in the age-matched controls, and that the high QUIN levels were associated with the rapid progression of the cognitive impairment and with the increased mortality — demonstrating the close association between the quinolinic acid neurotoxicity and the neurodegenerative disease progression.
Practical Application
For general kynurenine pathway support for the neuroinflammation and for the mood regulation, the evidence-based approach is to supplement with the precursors of the kynurenic acid (KYNA) — particularly the tryptophan (at 500-1000mg daily, as the essential amino acid precursor of the kynurenine pathway), the tryptophan-rich protein supplements, and the anthocyanin-rich foods (which inhibit the kynurenine 3-monooxygenase, KMO, and thereby shift the kynurenine metabolism toward the KYNA production instead of the QUIN production). The kynurenine pathway is shifted toward the KYNA production by the antioxidants (which reduce the oxidative stress and inhibit the KMO), by the anti-inflammatory compounds (which reduce the immune cytokine activation of the IDO), and by the exercise (which increases the KYNA production and reduces the QUIN production). For comprehensive neuroinflammation and mood support, the kynurenine pathway approach pairs well with the tryptophan or the 5-HTP (which provides the substrate for the kynurenine pathway and which can be converted either to the serotonin or to the kynurenine — the fate of the tryptophan depends on the activity of the TDO and the IDO enzymes, which are regulated by the inflammation and the stress), with the curcumin (which is a potent anti-inflammatory that inhibits the IDO and the KMO and which shifts the kynurenine metabolism toward the KYNA production), with the omega-3 fatty acids (which have complementary anti-inflammatory effects and which reduce the neuroinflammation and the QUIN production), and with the exercise (which increases the KYNA/QUIN ratio and promotes the neuroprotection and the mood improvement).
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