Kynurenic acid

Last updated
Kynurenic acid
Kynurenic acid.svg
Kynurenic acid molecule ball.png
Names
Preferred IUPAC name
4-Hydroxyquinoline-2-carboxylic acid
Other names
Kinurenic acid, kynuronic acid, quinurenic acid, transtorine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.007.047 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C10H7NO3/c12-9-5-8(10(13)14)11-7-4-2-1-3-6(7)9/h1-5H,(H,11,12)(H,13,14) Yes check.svgY
    Key: HCZHHEIFKROPDY-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C10H7NO3/c12-9-5-8(10(13)14)11-7-4-2-1-3-6(7)9/h1-5H,(H,11,12)(H,13,14)
    Key: HCZHHEIFKROPDY-UHFFFAOYAN
  • O=C\2c1c(cccc1)NC(=C/2)/C(=O)O
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).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

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.

Contents

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. [2]

Mechanism of action

KYNA has been proposed to act on five targets:

Role in disease

High levels of kynurenic acid have been identified in patients with tick-borne encephalitis, [9] 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.

The kynurenic acid hypothesis of schizophrenia was proposed in 2007, [10] [11] based on its action on midbrain dopamine activity and NMDArs, thus linking dopamine hypothesis of schizophrenia with the glutamate hypothesis of the disease.

Kynurenic acid is reduced in individuals with mood disorders, such as major depressive disorder [12] and bipolar disorder, [12] especially during depressive episodes. [13]

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, their cognition was shown to improve markedly. [14] However, kynurenic acid also shows neuroprotective properties. [15] Some researchers have posited that the increased levels found in cases of neurological degradation is due to a failed attempt to protect the cells. [16]

Elevated levels of kynurenic acid compared to kynurenine appear to be associated with poorer T cell response and higher mortality in male subjects with COVID-19, suggesting an explanation for the poorer clinical outcomes observed in males than in females. [17]

One controlled study kept mice on a ketogenic diet and measured kynurenic acid concentrations in different parts of the brain. [18] 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 [14] 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

Related Research Articles

<span class="mw-page-title-main">Nicotinic acetylcholine receptor</span> Acetylcholine receptors named for their selective binding of nicotine

Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral nervous system, muscle, and many other tissues of many organisms. At the neuromuscular junction they are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In the peripheral nervous system: (1) they transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system, and (2) they are the receptors found on skeletal muscle that receive acetylcholine released to signal for muscular contraction. In the immune system, nAChRs regulate inflammatory processes and signal through distinct intracellular pathways. In insects, the cholinergic system is limited to the central nervous system.

<span class="mw-page-title-main">Epibatidine</span> Toxic chemical from some poison dart frogs

Epibatidine is a chlorinated alkaloid that is secreted by the Ecuadoran frog Epipedobates anthonyi and poison dart frogs from the Ameerega genus. It was discovered by John W. Daly in 1974, but its structure was not fully elucidated until 1992. Whether epibatidine is the first observed example of a chlorinated alkaloid remains controversial, due to challenges in conclusively identifying the compound from the limited samples collected by Daly. By the time that high-resolution spectrometry was used in 1991, there remained less than one milligram of extract from Daly's samples, raising concerns about possible contamination. Samples from other batches of the same species of frog failed to yield epibatidine.

<span class="mw-page-title-main">Kynurenine</span> Chemical compound

l-Kynurenine is a metabolite of the amino acid l-tryptophan used in the production of niacin.

<span class="mw-page-title-main">Succinic semialdehyde dehydrogenase deficiency</span> Rare disorder involving deficiency in GABA degradation

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive disorder of the degradation pathway of the inhibitory neurotransmitter γ-aminobutyric acid, or GABA. The disorder has been identified in approximately 350 families, with a significant proportion being consanguineous families. The first case was identified in 1981 and published in a Dutch clinical chemistry journal that highlighted a number of neurological conditions such as delayed intellectual, motor, speech, and language as the most common manifestations. Later cases reported in the early 1990s began to show that hypotonia, hyporeflexia, seizures, and a nonprogressive ataxia were frequent clinical features as well.

<span class="mw-page-title-main">NMDA receptor antagonist</span> Class of anesthetics

NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for human and non-human animals; the state of anesthesia they induce is referred to as dissociative anesthesia.

A nicotinic agonist is a drug that mimics the action of acetylcholine (ACh) at nicotinic acetylcholine receptors (nAChRs). The nAChR is named for its affinity for nicotine.

<span class="mw-page-title-main">Kynurenine 3-monooxygenase</span> Enzyme

In enzymology, a kynurenine 3-monooxygenase (EC 1.14.13.9) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Cobratoxin</span> Chemical compound

α-Cobratoxin is a substance of the venom of certain Naja cobras. It is a nicotinic acetylcholine receptor (nAChR) antagonist which causes paralysis by preventing the binding of acetylcholine to the nAChR.

<span class="mw-page-title-main">Alpha-7 nicotinic receptor</span>

The alpha-7 nicotinic receptor, also known as the α7 receptor, is a type of nicotinic acetylcholine receptor implicated in long-term memory, consisting entirely of α7 subunits. As with other nicotinic acetylcholine receptors, functional α7 receptors are pentameric [i.e., (α7)5 stoichiometry].

<span class="mw-page-title-main">Xanthurenic acid</span> Chemical compound

Xanthurenic acid, or xanthurenate, is a metabolic intermediate that accumulates and is excreted by pyridoxine (vitamin B6) deficient animals after the ingestion of tryptophan.

<span class="mw-page-title-main">Quinolinic acid</span> Dicarboxylic acid with pyridine backbone

Quinolinic acid, also known as pyridine-2,3-dicarboxylic acid, is a dicarboxylic acid with a pyridine backbone. It is a colorless solid. It is the biosynthetic precursor to niacin.

The glutamate hypothesis of schizophrenia models the subset of pathologic mechanisms of schizophrenia linked to glutamatergic signaling. The hypothesis was initially based on a set of clinical, neuropathological, and, later, genetic findings pointing at a hypofunction of glutamatergic signaling via NMDA receptors. While thought to be more proximal to the root causes of schizophrenia, it does not negate the dopamine hypothesis, and the two may be ultimately brought together by circuit-based models. The development of the hypothesis allowed for the integration of the GABAergic and oscillatory abnormalities into the converging disease model and made it possible to discover the causes of some disruptions.

<span class="mw-page-title-main">GTS-21</span> Chemical compound

GTS-21 is a drug that has been shown to enhance memory and cognitive function. It has been studied for its potential therapeutic uses, particularly in the treatment of neurodegenerative diseases and psychiatric disorders.

<span class="mw-page-title-main">Hypertryptophanemia</span> Medical condition

Hypertryptophanemia is a rare autosomal recessive metabolic disorder that results in a massive buildup of the amino acid tryptophan in the blood, with associated symptoms and tryptophanuria.

<span class="mw-page-title-main">Kynurenine pathway</span> Metabolic pathway that produces the NAD coenzyme

The kynurenine pathway is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD+). Metabolites involved in the kynurenine pathway include tryptophan, kynurenine, kynurenic acid, xanthurenic acid, quinolinic acid, and 3-hydroxykynurenine. The kynurenine pathway is responsible for total catabolization of tryptophan about 95%. Disruption in the pathway is associated with certain genetic and psychiatric disorders.

<span class="mw-page-title-main">PHA-543,613</span> Chemical compound

PHA-543,613 is a drug that acts as a potent and selective agonist for the α7 subtype of neural nicotinic acetylcholine receptors, with a high level of brain penetration and good oral bioavailability. It is under development as a possible treatment for cognitive deficits in schizophrenia. It reduces excitotoxicity and protects striatal dopaminergic neurons in rat models. It also potentiates cognitive enhancement from memantine, decreases dynorphin release and inhibits GSK-B3.

The alpha-3 beta-4 nicotinic receptor, also known as the α3β4 receptor and the ganglion-type nicotinic receptor, is a type of nicotinic acetylcholine receptor, consisting of α3 and β4 subunits. It is located in the autonomic ganglia and adrenal medulla, where activation yields post- and/or presynaptic excitation, mainly by increased Na+ and K+ permeability.

<span class="mw-page-title-main">BNC-210</span> Chemical compound

BNC210 is an anxiolytic drug that acts via negative allosteric modulation of the α7-nicotinic acetylcholine receptor, by Bionomics Limited. It is currently being investigated for the treatment of post traumatic stress disorder. The drug has demonstrated clinically significant anxiety reduction in both animal models and in Phase I trials.

The alpha-3 beta-2 nicotinic receptor, also known as the α3β2 receptor, is a type of nicotinic acetylcholine receptor, consisting of α3 and β2 subunits.

<span class="mw-page-title-main">Hydroxynorketamine</span> Chemical compound

Hydroxynorketamine (HNK), or 6-hydroxynorketamine, is a minor metabolite of the anesthetic, dissociative, and antidepressant drug ketamine. It is formed by hydroxylation of the intermediate norketamine, another metabolite of ketamine. As of late 2019, (2R,6R)-HNK is in clinical trials for the treatment of depression.

References

  1. ↑ Liebig, J., Uber Kynurensäure, Justus Liebigs Ann. Chem., 86: 125-126, 1853.
  2. ↑ Han, Qian; Cai, Tao; Tagle, Danilo A.; Robinson, Howard; Li, Jianyong (August 2008). "Substrate specificity and structure of human aminoadipate aminotransferase/kynurenine aminotransferase II". Bioscience Reports. 28 (4): 205–215. doi:10.1042/BSR20080085. ISSN   0144-8463. PMC   2559858 . PMID   18620547.
  3. ↑ 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. PMID   2985194. S2CID   24345638.
  4. ↑ Hilmas C, Pereira EF, Alkondon M, Rassoulpour A, Schwarcz R, Albuquerque EX (October 2001). "The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications". The Journal of Neuroscience. 21 (19): 7463–73. doi: 10.1523/JNEUROSCI.21-19-07463.2001 . PMC   6762893 . PMID   11567036.
  5. 1 2 Dobelis P, Varnell A, Staley K, Cooper D (2011). "Nicotinic α7 acetylcholine receptor-mediated currents are not modulated by the tryptophan metabolite kynurenic acid in adult hippocampal interneurons". Nature Precedings. arXiv: 1204.1558 . doi: 10.1038/npre.2011.6277.1 .
  6. 1 2 Mok 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. PMID   19523966. S2CID   29874580.
  7. ↑ Wang J, Simonavicius N, Wu X, Swaminath G, Reagan J, Tian H, Ling L (August 2006). "Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35". The Journal of Biological Chemistry. 281 (31): 22021–22028. doi: 10.1074/jbc.M603503200 . PMID   16754668.
  8. ↑ Kapolka NJ, Taghon GJ, Rowe JB, Morgan WM, Enten JF, Lambert NA, Isom DG (June 2020). "DCyFIR: a high-throughput CRISPR platform for multiplexed G protein-coupled receptor profiling and ligand discovery". Proceedings of the National Academy of Sciences of the United States of America. 117 (23): 13117–13126. Bibcode:2020PNAS..11713117K. doi: 10.1073/pnas.2000430117 . PMC   7293659 . PMID   32434907.
  9. ↑ Holtze M, Mickiené A, Atlas A, Lindquist L, Schwieler L (October 2012). "Elevated cerebrospinal fluid kynurenic acid levels in patients with tick-borne encephalitis". Journal of Internal Medicine. 272 (4): 394–401. doi:10.1111/j.1365-2796.2012.02539.x. hdl: 10616/44938 . PMID   22443218. S2CID   2255818.
  10. ↑ Erhardt S, Schwieler L, Nilsson L, Linderholm K, Engberg G (September 2007). "The kynurenic acid hypothesis of schizophrenia". Physiology & Behavior. 92 (1–2): 203–9. doi:10.1016/j.physbeh.2007.05.025. PMID   17573079. S2CID   46156877.
  11. ↑ 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. ISBN   978-1-4613-4939-6. PMID   15206728.
  12. 1 2 Marx 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. PMID   33230205. S2CID   227132820.
  13. ↑ 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. PMID   33077852. S2CID   224314102.
  14. 1 2 Potter MC, Elmer GI, Bergeron R, Albuquerque EX, Guidetti P, Wu HQ, Schwarcz R (July 2010). "Reduction of endogenous kynurenic acid formation enhances extracellular glutamate, hippocampal plasticity, and cognitive behavior". Neuropsychopharmacology. 35 (8): 1734–42. doi:10.1038/npp.2010.39. PMC   3055476 . PMID   20336058.
  15. ↑ 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. ISBN   978-1-4614-5835-7.
  16. ↑ Zádori D, Klivényi P, Vámos E, Fülöp F, Toldi J, Vécsei L (November 2009). "Kynurenines in chronic neurodegenerative disorders: future therapeutic strategies" (PDF). Journal of Neural Transmission. 116 (11): 1403–9. doi:10.1007/s00702-009-0263-4. PMID   19618107. S2CID   11378729.
  17. ↑ Cai Y, Kim DJ, Takahashi T, Broadhurst DI, Yan H, Ma S, et al. (July 2021). "Kynurenic acid may underlie sex-specific immune responses to COVID-19". Science Signaling. 14 (690): eabf8483. doi: 10.1126/scisignal.abf8483 . ISSN   1945-0877. PMC   8432948 . PMID   34230210.
  18. ↑ Żarnowski T, Chorągiewicz T, Tulidowicz-Bielak M, Thaler S, Rejdak R, Żarnowski I, et al. (June 2012). "Ketogenic diet increases concentrations of kynurenic acid in discrete brain structures of young and adult rats". Journal of Neural Transmission. 119 (6): 679–84. doi:10.1007/s00702-011-0750-2. PMC   3359463 . PMID   22200857.