Kynurenic acid (KYNA) is a naturally occurring compound found throughout the human body, stemming from the breakdown of tryptophan, an amino acid obtained through diet. This substance acts as a neuromodulator, regulating various aspects of brain activity. Its presence in the brain influences how neurons communicate, impacting functions such as learning and overall brain health as we age. Understanding KYNA’s role helps explain how internal biochemistry affects neurological well-being.
How the Body Produces Kynurenic Acid
The body produces kynurenic acid primarily through the kynurenine pathway, which metabolizes most of the tryptophan not used for protein synthesis, approximately 95%. This pathway begins when tryptophan is converted into an intermediate compound called kynurenine. Specific enzymes, known as kynurenine aminotransferases (KATs), then transform kynurenine into kynurenic acid.
Among the various KAT enzymes, kynurenine aminotransferase II (KAT II) is largely responsible for kynurenic acid synthesis in the brain. While KATs preferentially utilize L-kynurenine as a substrate, they can also convert its D-enantiomer into kynurenic acid in various organs, including the brain. This conversion occurs in several locations throughout the body, with significant production happening in both the brain and the liver.
The Role of Kynurenic Acid in the Brain
Kynurenic acid functions in the brain as an antagonist of excitatory amino acid receptors, particularly the N-methyl-D-aspartate (NMDA) and alpha7-nicotinic acetylcholine (α7nACh) receptors. It acts like a natural brake, dampening excessive neuronal activity by binding to these receptors and preventing them from becoming overstimulated.
This neuroprotective effect helps shield neurons from excitotoxicity, a condition caused by prolonged over-activation of glutamate receptors that can lead to neuronal damage. By limiting this overstimulation, kynurenic acid supports the stability and survival of brain cells. Kynurenic acid also exhibits antioxidant properties, which help neutralize harmful reactive oxygen species within the brain.
Kynurenic Acid’s Connection to Neurological and Mental Health
Dysregulated levels of kynurenic acid have been associated with various neurological and mental health conditions. In schizophrenia, for instance, elevated concentrations of kynurenic acid are often observed in the brain tissue and cerebrospinal fluid of affected individuals. This increase is thought to contribute to the cognitive deficits and psychotic symptoms characteristic of the disorder, potentially by causing hypoglutamatergic activity through its antagonism of NMDA receptors.
Conversely, research into major depressive disorder has sometimes indicated lower levels of kynurenic acid. This suggests a complex role for kynurenic acid, where an imbalance in either direction may have implications for brain function and mood. Associations have also been noted between kynurenic acid and neurodegenerative disorders, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease. While the exact mechanisms are still being explored, imbalances in kynurenine pathway metabolites are implicated in these conditions.
For example, in Huntington’s disease, an absolute or relative deficiency of kynurenic acid compared to neurotoxic kynurenines is thought to impact neuronal function and survival. This highlights how the balance between neuroprotective and neurotoxic compounds within the kynurenine pathway can profoundly affect neurological health. These findings underscore kynurenic acid as a molecule with widespread influence on brain health, with its precise role in disease pathophysiology remaining a subject of active research.
Factors Influencing Kynurenic Acid Levels
Several internal and external factors can modulate the body’s production and levels of kynurenic acid. Immune system activation and inflammation can shift the kynurenine pathway towards increased kynurenic acid production. This alters how tryptophan is metabolized, impacting the balance of neuroactive metabolites.
The gut microbiome also plays a substantial role in influencing circulating kynurenic acid levels through its metabolism of tryptophan. The diverse population of microorganisms in the gut can affect the availability of tryptophan and, consequently, the downstream production of kynurenic acid. A Western-style diet, characterized by high saturated fat and added sugar, has been associated with lower levels of KYNA, suggesting a dietary influence.
Lifestyle factors like physical exercise can also affect kynurenic acid levels. Studies indicate that physical activity is negatively correlated with most kynurenine pathway metabolites, including kynurenic acid. Regular exercise can influence gut microbiota composition and function, which may impact tryptophan metabolism and KYNA synthesis.