Kynurenic acid

Kynurenic acid
Ball-and-stick model of kynurenic acid
Names
IUPAC name
4-hydroxyquinoline-2-carboxylic acid
Other names
Kinurenic acid, kynuronic acid, quinurenic acid, transtorine
Identifiers
492-27-3 YesY
3D model (Jmol) Interactive image
ChEBI CHEBI:18344 YesY
ChEMBL ChEMBL299155 YesY
ChemSpider 3712 YesY
ECHA InfoCard 100.007.047
2918
KEGG C01717 YesY
PubChem 3845
Properties
C10H7NO3
Molar mass 189.168 g/mol
Melting point 282.5 °C (540.5 °F; 555.6 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
YesY verify (what is YesYN ?)
Infobox references

Kynurenic acid (KYNA or KYN) is a product of the normal metabolism of amino acid L-tryptophan. It has been shown that kynurenic acid possesses neuroactive activity. It acts as an antiexcitotoxic and anticonvulsant, 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 chemist Justus von Liebig in dog urine, which it was apparently named after.[1]

It is formed from L-kynurenine in a reaction catalyzed by the enzyme kynurenine—oxoglutarate transaminase.

Mechanism of action

KYNA has been proposed to act on four targets:

Role in disease

High levels of kynurenic acid have been identified in patients suffering from tick-borne encephalitis,[8] schizophrenia and HIV-related illnesses. In all these situations increased levels were associated with confusion and psychotic symptoms. Kynurenic acid acts in the brain as a glycine-site NMDAr antagonist, key in glutamatergic neurotransmission system, which is thought to be involved in the pathophysiology and pathogenesis of schizophrenia.

A kynurenic acid hypothesis of schizophrenia was proposed in 2007,[9][10] based on its action on midbrain dopamine activity and NMDArs, thus linking dopamine hypothesis of schizophrenia with the glutamate hypothesis of the disease.

High levels of kynurenic acid have been identified in human urine in certain metabolic disorders, such as marked pyridoxine deficiency and deficiency/absence of kynureninase.

When researchers decreased the levels of kynurenic acid in the brains of mice, the cognition was shown to improve markedly.[11]

Kynurenic acid shows neuroprotective properties.[12] Some researchers have posited that the increased levels found in cases of neurological degradation is due to a failed attempt to protect the cells.[13]

One controlled study kept mice on a ketogenic diet and measured kynurenic acid concentrations in different parts of the brain.[14] It found that the mice on the ketogenic diet had greater kynurenic acid concentrations in the striatum and hippocampus 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.

See also

References

  1. ↑ Liebig, J., Uber Kynurensäure, Justus Liebigs Ann. Chem., 86: 125-126, 1853.
  2. ↑ Elmslie KS, Yoshikami D. (1985) Effects of kynurenate on root potentials evoked by synaptic activity and amino acids in the frog spinal cord. Brain Res. Mar 25;330(2):265-72.
  3. ↑ Hilmas, C.; Pereira, EFR; Alkondon, M.; Rassoulpour, A.; Schwarcz, R.; Albuquerque, E.X. (2001). "The Brain Metabolite Kynurenic Acid Inhibits α7 Nicotinic Receptor Activity and Increases Non-α7 Nicotinic Receptor Expression: Physiopathological Implications". J. Neurosci. 21 (19): 7463–7473.
  4. 1 2 Dobelis P., Varnell A., and Donald C. Cooper. "Nicotinic α7 acetylcholine receptor-mediated currents are not modulated by the tryptophan metabolite kynurenic acid in adult hippocampal interneurons. (2011) Nature Precedings doi:10.1038/npre.2011.6277.1
  5. 1 2 Mok, MH; Fricker, AC; Weil, A; Kew, JN (2009). "Electrophysiological characterisation of the actions of kynurenic acid at ligand-gated ion channels". Neuropharmacology. 57: 242–249. doi:10.1016/j.neuropharm.2009.06.003.
  6. ↑ Wang J, Simonavicius N, Wu X, Swaminath G, Reagan J, Tian H, Ling L (2006). "Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35". J. Biol. Chem. 281 (31): 22021–8. doi:10.1074/jbc.M603503200. PMID 16754668.
  7. ↑ Grilli M, Raiteri L, Patti L, Parodi M, Robino F, Raiteri M, Marchi M (2006). "Modulation of the function of presynaptic α7 and non-α7 nicotinic receptors by the tryptophan metabolites, 5-hydroxyindole and kynurenate in mouse brain". Br. J. Pharmacol. 149 (6): 724–32. doi:10.1038/sj.bjp.0706914. PMC 2014664Freely accessible. PMID 17016503.
  8. ↑ Holtze M, Mickiené A, Atlas A, Lindquist L, Schwieler L (2012). "Elevated cerebrospinal fluid kynurenic acid levels in patients with tick-borne encephalitis". J. Intern. Med. 272 (4): 394–401. doi:10.1111/j.1365-2796.2012.02539.x. PMID 22443218.
  9. ↑ Erhardt S, Schwieler L, Nilsson L, Linderholm K, Engberg G (2007). "The kynurenic acid hypothesis of schizophrenia". Physiol Behav. 92 (1): 203–209. doi:10.1016/j.physbeh.2007.05.025. PMID 17573079.
  10. ↑ Erhardt S, Schwieler L, Engberg G (2003). "Kynurenic acid and schizophrenia". Adv. Exp. Med. Biol. 527: 155–65. doi:10.1007/978-1-4615-0135-0_18. PMID 15206728.
  11. ↑ Robert Schwarcz; Elmer, Greg I; Bergeron, Richard; Albuquerque, Edson X; Guidetti, Paolo; Wu, Hui-Qiu; Schwarcz, Robert (2010). "Reduction of Endogenous Kynurenic Acid Formation Enhances Extracellular Glutamate, Hippocampal Plasticity, and Cognitive Behavior". Neuropsychopharmacology. 35 (8): 1734–1742. doi:10.1038/npp.2010.39. PMC 3055476Freely accessible. PMID 20336058.
  12. ↑ Urbańska, Ewa M.; Chmiel-Perzyńska, Iwona; Perzyński, Adam; Derkacz, Marek; Owe-Larsson, Björn (2014). "Endogenous Kynurenic Acid and Neurotoxicity": 421–453. doi:10.1007/978-1-4614-5836-4_92.
  13. ↑ Zádori, D.; Klivényi, P.; Vámos, E.; Fülöp, F.; Toldi, J.; Vécsei, L. (2009). "Kynurenines in chronic neurodegenerative disorders: future therapeutic strategies". Journal of Neural Transmission. 116 (11): 1403–1409. doi:10.1007/s00702-009-0263-4. ISSN 0300-9564.
  14. ↑ Żarnowski, Tomasz; Chorągiewicz, Tomasz; Tulidowicz-Bielak, Maria; Thaler, Sebastian; Rejdak, Robert; Żarnowska, Iwona; Turski, Waldemar Andrzej; Gasior, Maciej (2011). "Ketogenic diet increases concentrations of kynurenic acid in discrete brain structures of young and adult rats". Journal of Neural Transmission. 119 (6): 679–684. doi:10.1007/s00702-011-0750-2. ISSN 0300-9564.
  15. ↑ Potter, Michelle C; Elmer, Greg I; Bergeron, Richard; Albuquerque, Edson X; Guidetti, Paolo; Wu, Hui-Qiu; Schwarcz, Robert (2010). "Reduction of Endogenous Kynurenic Acid Formation Enhances Extracellular Glutamate, Hippocampal Plasticity, and Cognitive Behavior". Neuropsychopharmacology. 35 (8). doi:10.1038/npp.2010.39. ISSN 0893-133X. PMC 3055476Freely accessible. PMID 20336058.
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