キヌレン酸

関: kynurenic acid

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/06/15 22:15:33」(JST)

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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:

As an antagonist at ionotropic AMPA, NMDA and Kainate glutamate receptors in the concentration range of 0.1-2.5 mM^[2]
As a noncompetitive antagonist at the glycine site of the NMDA receptor.
As an antagonist of the α7 nicotinic acetylcholine receptor.^[3] However, recently (2011) direct recording of α7 nicotinic acetylcholine receptor currents in adult (noncultured) hippocampal interneurons by the Cooper laboratory ^[4] validated a 2009 study ^[5] 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 ^[4]^[5]
As a ligand for the orphan G protein-coupled receptor GPR35.^[6] Another tryptophan metabolite, 5-hydroxyindoleacetic acid exerts its effects via the orphan G protein-coupled receptor GPR35 ^[7]

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 has been 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]

Link to ketogenic diet

One controlled study kept mice on a ketogenic diet and measured kyurenic 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.

References

^ Liebig, J., Uber Kynurensäure, Justus Liebigs Ann. Chem., 86: 125-126, 1853.
^ 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.
^ 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.
^ ^a ^b 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
^ ^a ^b 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.
^ 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.
^ 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 2014664. PMID 17016503.
^ 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.
^ 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.
^ 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.
^ 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 3055476. PMID 20336058.
^ Urbańska, Ewa M.; Chmiel-Perzyńska, Iwona; Perzyński, Adam; Derkacz, Marek; Owe-Larsson, Björn (2014). "Endogenous Kynurenic Acid and Neurotoxicity". pp. 421–453. doi:10.1007/978-1-4614-5836-4_92.
^ 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.
^ 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.
^ 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 3055476. PMID 20336058.

External links

Link found between TBE and schizophrenia - TheLocal.se, Sweden's news in English, 6 November 2007.

English Journal

The kynurenine pathway in neurodegenerative diseases: Mechanistic and therapeutic considerations.

Tan L, Yu JT, Tan L.SourceDepartment of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, China.
Journal of the neurological sciences.J Neurol Sci.2012 Dec 15;323(1-2):1-8. doi: 10.1016/j.jns.2012.08.005. Epub 2012 Aug 29.
The kynurenine pathway (KP), the primary route of tryptophan degradation in mammalian cells, consists of many metabolites including kynurenic acid (KYNA), quinolinic acid (QUIN), 3-hydroxykynurenine (3-HK) and picolinic acid (PIC). The former two are neuroactive, while the latter two are molecules w
PMID 22939820

Riboflavin and lumichrome in Dalmatian sage honey and other unifloral honeys determined by LC-DAD technique.

Tuberoso CI, Jerković I, Bifulco E, Marijanovic Z, Congiu F, Bubalo D.SourceDipartimento Farmaco Chimico Tecnologico, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy.
Food chemistry.Food Chem.2012 Dec 1;135(3):1985-90. Epub 2012 Jul 4.
Riboflavin (vitamin B(2)) and its metabolite lumichrome were quantified in 117 samples from 11 unifloral honeys types (Arbutus unedo L., Asphodelus microcarpus Salzm. et Viv., Citrus spp., Eucalyptus spp., Hedysarum coronarium L., Castanea sativa L. honeydew, Mentha spp., Paliurus spina-christi., Sa
PMID 22953948

Japanese Journal

Kynurenate and 7-Chlorokynurenate Formation in Chronically Epileptic Rats

WU Hui-Qiu,RASSOULPOUR Arash,GOODMAN Jeffrey H.,SCHARFMAN Helen E.,BERTRAM Edward H.,SCHWARCZ Robert
Epilepsia : journal of the International League against Epilepsy 46(7), 1010-1016, 2005-07-01
NAID 10019362259

Kynurenate and 7-chlorokynurenate formation in chronically epileptic rats

WU HQ
Epilepsia 46, 1010-1016, 2005
NAID 30014394158

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リンク元	「キヌレン酸」「kynurenic acid」

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Kynurenic acid
Names
	IUPAC name 4-hydroxyquinoline-2-carboxylic acid
	Other names Kinurenic acid, kynuronic acid, quinurenic acid, transtorine
Identifiers
CAS Registry Number	492-27-3
ChEBI	CHEBI:18344
ChEMBL	ChEMBL299155
ChemSpider	3712
	InChI 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) ; Key: HCZHHEIFKROPDY-UHFFFAOYSA-N ; 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 ;
Jmol-3D images	Image
KEGG	C01717
PubChem	3845
	SMILES O=C\2c1c(cccc1)NC(=C/2)/C(=O)O ;
Properties
Chemical formula	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).
	verify (what is: /?)
	Infobox references

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英: kynurenic acid、kynurenate
同: 4-ヒドロキシキナルジン酸 4-hydroxyquinaldic acid

「kynurenic acid」

　　[★]

キヌレン酸

関: kynurenate

[discovery-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.

[Dobelis_P..2C_Varnell_A..2C_and_Donald_C._Cooper._Nicotinic_.CE.B17_acetylcholine_receptor-mediated_currents_are_not_modulated_by_the_tryptophan_metabolite_kynurenic_acid_in_adult_hippocampal_interneurons.-4] 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

[Mok_MH.2C_Fricker_AC.2C_Weil_A.2C_Kew_JN_.282009.29_Electrophysiological_characterisation_of_the_actions_of_kynurenic_acid_at_ligand-gated_ion_channels.-5] 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.

[pmid16754668-6] 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.

[pmid17016503-7] 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 2014664. PMID 17016503.

[pmid22443218-8] 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.

[pmid17573079-9] 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.

[pmid15206728-10] 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.

[pmid20336058-11] 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 3055476. PMID 20336058.

[Urba.C5.84skaChmiel-Perzy.C5.84ska2014-12] Urbańska, Ewa M.; Chmiel-Perzyńska, Iwona; Perzyński, Adam; Derkacz, Marek; Owe-Larsson, Björn (2014). "Endogenous Kynurenic Acid and Neurotoxicity". pp. 421–453. doi:10.1007/978-1-4614-5836-4_92.

[Z.C3.A1doriKliv.C3.A9nyi2009-13] 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.

[.C5.BBarnowskiChor.C4.85giewicz2011-14] 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.

[PotterElmer2010-15] 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 3055476. PMID 20336058.

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kynurenate