Kynurenic acid (KYNA orKYN)[1] is a product of the normal metabolism of amino acidL-tryptophan. It has been shown that kynurenic acid possesses neuroactive activity. It acts as anantiexcitotoxic andanticonvulsant, most likely through acting as an antagonist at excitatory amino acid receptors. Because of this activity, it may influence important neurophysiological and neuropathological processes. As a result, kynurenic acid has been considered for use in therapy in certain neurobiological disorders. Conversely, increased levels of kynurenic acid have also been linked to certain pathological conditions.
Kynurenic acid was discovered in 1853 by the German chemistJustus von Liebig indog urine, which it was apparently named after.[2]
As a noncompetitive antagonist at the glycine site of theNMDA receptor.
As an antagonist of theα7 nicotinic acetylcholine receptor.[5] However, recently (2011) direct recording of α7 nicotinic acetylcholine receptor currents in adult (noncultured) hippocampal interneurons by theCooper laboratory[6] validated a 2009 study[7] 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.[6][7]
High levels of kynurenic acid have been identified in patients withtick-borne encephalitis,[10]schizophrenia andHIV-related illnesses. In all these situations, increased levels were associated with confusion and psychotic symptoms. Kynurenic acid acts in thebrain as aglycine-siteNMDAr antagonist, key in glutamatergic neurotransmission system, which is thought to be involved in thepathophysiology andpathogenesis of schizophrenia.
High levels of kynurenic acid have been identified in human urine in certain metabolic disorders, such as markedpyridoxine deficiency and deficiency/absence ofkynureninase.
When researchers decreased the levels of kynurenic acid in the brains of mice, their cognition was shown to improve markedly.[15] However, kynurenic acid also shows neuroprotective properties.[16] Some researchers have posited that the increased levels found in cases of neurological degradation is due to a failed attempt to protect the cells.[17]
Elevated levels of kynurenic acid compared to kynurenine appear to be associated with poorerT cell response and higher mortality in male subjects withCOVID-19, suggesting an explanation for the poorer clinical outcomes observed in males than in females.[18]
One controlled study kept mice on aketogenic diet and measured kynurenic acid concentrations in different parts of the brain.[19] It found that the mice on the ketogenic diet had greater kynurenic acid concentrations in thestriatum andhippocampus compared to mice on a normal diet, with no significant difference in the cortex.
In response to the studies showing detrimental behaviour following increases in kynurenic acid[15] the authors also note that the diet was generally well tolerated by the animals, with no "gross behavioural abnormalities". They posit that the increases in concentrations found were insufficient to produce behavioural changes seen in those studies.
^Elmslie KS, Yoshikami D (March 1985). "Effects of kynurenate on root potentials evoked by synaptic activity and amino acids in the frog spinal cord".Brain Research.330 (2):265–72.doi:10.1016/0006-8993(85)90685-7.PMID2985194.S2CID24345638.
^abMok MH, Fricker AC, Weil A, Kew JN (September 2009). "Electrophysiological characterisation of the actions of kynurenic acid at ligand-gated ion channels".Neuropharmacology.57 (3):242–9.doi:10.1016/j.neuropharm.2009.06.003.PMID19523966.S2CID29874580.
^Erhardt S, Schwieler L, Engberg G (2003). "Kynurenic Acid and Schizophrenia".Developments in Tryptophan and Serotonin Metabolism. Advances in Experimental Medicine and Biology. Vol. 527. pp. 155–65.doi:10.1007/978-1-4615-0135-0_18.ISBN978-1-4613-4939-6.PMID15206728.
^abMarx W, McGuinness AJ, Rocks T, Ruusunen A, Cleminson J, Walker AJ, et al. (November 2020). "The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a meta-analysis of 101 studies".Molecular Psychiatry.26 (8):4158–4178.doi:10.1038/s41380-020-00951-9.PMID33230205.S2CID227132820.
^Bartoli F, Misiak B, Callovini T, Cavaleri D, Cioni RM, Crocamo C, et al. (October 2020). "The kynurenine pathway in bipolar disorder: a meta-analysis on the peripheral blood levels of tryptophan and related metabolites".Molecular Psychiatry.26 (7):3419–3429.doi:10.1038/s41380-020-00913-1.PMID33077852.S2CID224314102.
^Urbańska EM, Chmiel-Perzyńska I, Perzyński A, Derkacz M, Owe-Larsson B (2014). "Endogenous Kynurenic Acid and Neurotoxicity".Handbook of Neurotoxicity. pp. 421–453.doi:10.1007/978-1-4614-5836-4_92.ISBN978-1-4614-5835-7.
