KYNURENINES IN PATHOGENESIS OF ENDOGENOUS PSYCHIATRIC DISORDERS

Cover Page


Cite item

Full Text

Abstract

The essential amino acid tryptophan is metabolized on the methoxyindole pathway to serotonin, melatonin and 5-hydroxyindoleacetic acid and on the kynurenine pathway to kynurenine and related neuroactive metabolites, including 3-hydroxykynurenine, kynurenic acid, quinolinic acid and xanthurenic acid. Kynurenine and related metabolites play a significant role in the pathogenesis of major depressive disorder and schizophrenia. This paper is the review of literature data on the most modern state of this problem.

 

About the authors

Yu. E. Shilov

Mental health research center of RAMS, Moscow, Russian Federation

Author for correspondence.
Email: shilov.biochem@gmail.ru

Postgraduate Laboratory of Molecular Biochemistry «the Mental Health Research Center of the Russian Academy of Medical Science» Address: 115522, Moscow, Kashirskoye Highway 34; tel.: (495) 952-91-41

Russian Federation

M. V. Bezrukov

Mental health research center of RAMS, Moscow, Russian Federation

Email: bezrmv1chem@mail.ru

PhD, Senior Research Worker of Laboratory of Clinical Biochemistry «the Mental Health Research Center of the Russian Academy of Medical Science» Address: 115522, Moscow, Kashirskoye Highway 34; tel.: (495) 952-91-41

Russian Federation

References

  1. Eynard N., Flachaire E., Lestra C. et al. Platelet serotonin content and free and total plasma tryptophan in healthy volunteers during 24 hours. Clin. Chem. 1993; 39 (11): 2337–2340.
  2. Yuwiler A., Oldendorf W.H., Geller E. et al. Effect of albumin binding and amino acid competition on tryptophan uptake into brain. J. Neurochem. 1977; 28 (5): 1015–1023.
  3. Mangoni A. The «kynurenine shunt» and depression. Adv. Biochem. Psychopharmacol. 1974; 11 (0): 293–298.
  4. Fernstrom J.D. Effects of the diet on brain neurotransmitters. Metabolism. 1977; 26 (2): 207–223.
  5. Watanabe Y., Fujiwara, Yoshida R. et al. Stereospecificity of hepatic L-tryptophan 2,3-dioxygenase. Biochem. J. 1980; 189 (3): 393–405.
  6. Breton J., Avanzi N., Magagnin S. et al. Functional characterization and mechanism of action of recombinant human kynurenine 3-hydroxylase. Eur. J. Biochem. 2000; 267 (4): 1092–1099.
  7. Leklem J.E. Quantitative aspects of tryptophan metabolism in humans and other species: a review. Am. J. Clin. Nutr. 1971; 24 (6): 659–672.
  8. Han Q., Cai T., Tagle D.A. et al. Structure, expression, and function of kynurenine aminotransferases in human and rodent brains. Cell Mol. Life Sci. 2010; 67 (3): 353–368.
  9. Gal E.M., Sherman A.D. L-kynurenine: its synthesis and possible regulatory function in brain. Neurochem. Res. 1980; 5 (3): 223–239.
  10. Miller C.L., Llenos I.C., Dulay J.R. et al. Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia. Neurobiol. Dis. 2004; 15 (3): 618–629.
  11. Grant R.S., Naif H., Espinosa M. et al. IDO induction in IFN-gamma activated astroglia: a role in improving cell viability during oxidative stress. Redox. Rep. 2000; 5 (2-3): 101–104.
  12. Guillemin G.J., Smythe G.A., Takikawa O. et al. Expression of indoleamine 2,3- ioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons. Glia. 2005; 49 (1): 15–23.
  13. Guillemin G.J., Kerr S.J., Smythe G.A. et al. Kinurenine pathway metabolism in human astrocytes: a paradox for neuronal protection. J. Neurochem. 2001; 78 (4): 842–853.
  14. Quagliariello E., Papa S., Saccone C. et al. Effect of 3-hydroxyanthranilic acid on the mitochondrial respiratory system. Biochem. J. 1964; 91 (1): 137–146.
  15. Lardy H.A. The role of tryptophan metabolites in regulating gluconeogenesis. Am. J. Clin. Nutr. 1971; 24 (7): 764–765.
  16. Yuskaitis C.J., Jope R.S. Glycogen synthase kinase-3 regulates microglial migration, inflammation, and inflammation-induced neurotoxicity. Cell Signal. 2009; 21 (2): 264–273.
  17. Mellor A.L., Munn D.H. Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol. Today. 1999; 20 (10): 469–473.
  18. Moffett J.R., Blinder K.L., Venkateshan C.N. et al. Differential effects of kynurenine and tryptophan treatment on quinolinate immunoreactivity in rat lymphoid and non-lymphoid organs. Cell Tissue Res. 1998; 293 (3): 525–534.
  19. Moffett J.R., Namboodiri M.A. Tryptophan and the immune response. Immunol. Cell Biol. 2003; 81 (4): 247–265.
  20. Carlin J.M., Borden E.C., Sondel P.M. et al. Biologic-response-modifier-induced indoleamine 2,3-dioxygenase activity in human peripheral blood mononuclear cell cultures. J. Immunol. 1987; 139 (7): 2414–2418.
  21. Yasui H., Takai K., Yoshida R. et al. Interferon enhances tryptophan metabolism by inducing pulmonary indoleamine 2,3-dioxygenase: its possible occurrence in cancer patients. Proc. Natl. Acad. Sci. USA. 1986; 83 (17): 6622–6626.
  22. Musso T., Gusella G.L., Brooks A. et al. Interleukin-4 inhibits indoleamine 2,3-dioxygenase expression in human monocytes. Blood. 1994; 83 (5): 1408–1411.
  23. Salter M., Pogson C.I. The role of tryptophan 2,3-dioxygenase in the hormonal control of tryptophan metabolism in isolated rat liver cells. Effects of glucocorticoids and experimental diabetes. Biochem. J. 1985; 229 (2): 499–504.
  24. Kotake Y., Ueda T., Mori T. et al. Abnormal tryptophan metabolism and experimental diabetes by xanthurenic acid (XA). Acta Vitaminol. Enzymol. 1975; 29 (1–6): 236–239.
  25. Buczko P., Stokowska W., Gorska M. et al. Tryptophan metabolites via kynurenine pathway in saliva of diabetic patients. Dent. Med. Probl. 2006; 43: 21–25.
  26. Chiarugi A., Calvani M., Meli E. et al. Synthesis and release of neurotoxic kynurenine metabolites by human monocyte-derived macrophages. J. Neuroimmunol. 2001; 120 (1–2): 190–198.
  27. Pertz H., Back W. Synthesis and resolution of chiral ring-opened serotonin analogs of the 5-hydroxykynuramine type. Pharm. Acta Helv. 1988; 63 (4-5): 128–131.
  28. Guillemin G.J. Quinolinic acid, the inescapable neurotoxin. FEBS J. 2012; 279 (8): 1356–1365.
  29. Okuda S., Nishiyama N., Saito H. et al. 3-Hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and region selectivity. J. Neurochem. 1998; 70 (1): 299–307.
  30. Perkins M.N., Stone T.W. An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res. 1982; 247 (1): 184–187.
  31. Kim J.P., Choi D.W. Quinolinate neurotoxicity in cortical cell culture. Neuroscience. 1987; 23 (2): 423–432.
  32. Zhuravlev A.V. Molekulyarnye mekhanizmy deistviya metabolitov kinureninovogo puti obmena triptofana na glyutamatergicheskuyu i kholinergicheskuyu sistemy neirotransmissii u mutantov drozofily. Avtoref. …diss [Molecular mechanisms of action of metabolites kinureninovogo pathway of tryptophan to glutamatergic and cholinergic neurotransmission system in Drosophila mutants. Author’s abstract]. 2012.
  33. Zhuravlev A.V., Zakharov G.A., Savvafteeva-Popova E.V. Molekulyarnye mekhanizmy deistviya metabolitov kinureninovogo puti obmena triptofana na glyutamatergicheskuyu i kholinergicheskuyu sistemy neirotransmissii u mutantov drozofily. Mat-ly s"ezda. VII Sibirskii s"ezd fiziologov [Molecular mechanisms of action of metabolites kinureninovogo pathway of tryptophan to glutamatergic and cholinergic neurotransmission system in Drosophila mutants. Proceedings of the Congress. 7th Siberian Congress of Physiologists]. 2012. pp. 182–183.
  34. Olney J.W., Labruyere J., Wang G. et al. NMDA antagonist neurotoxicity: mechanism and prevention. Science. 1991; 254 (5037): 1515–1518.
  35. Hilmas C., Pereira E.F., Alkondon M. et al. The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. J. Neurosci. 2001; 21 (19): 7463–7473.
  36. Wu H.Q., Rassoulpour A., Schwarcz R. Kynurenic acid leads, dopamine follows: a new case of volume transmission in the brain? J. Neural. Transm. 2007; 114 (1): 33–41.
  37. Schiepers O.J., Wichers M.C., Maes M. Cytokines and major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2005; 29 (2): 201–217.
  38. Thomas A.J., Davis S., Morris C. et al. Increase in interleukin-1beta in late-life depression. Am. J. Psychiatry. 2005; 162 (1): 175–177.
  39. Raison C.L., Miller A.H. Is depression an inflammatory disorder? Curr. Psychiatry Rep. 2011; 13 (6): 467–475.
  40. Myint A.M., Kim Y.K. Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression. Med. Hypotheses. 2003; 61 (5–6): 519–525.
  41. Appel E., Kolman O., Kazimirsky G. et al. Regulation of GDNF expression in cultured astrocytes by inflammatory stimuli. Neuroreport. 1997; 8 (15): 3309–3312.
  42. Shimizu E., Hashimoto K., Okamura N. et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol. Psychiatry. 2003; 54 (1): 70–75.
  43. Lavoie J., Giguere J.F., Layrargues G.P. et al. Activities of neuronal and astrocytic marker enzymes in autopsied brain tissue from patients with hepatic encephalopathy. Metab. Brain Dis. 1987; 2 (4): 283–290.
  44. Myint A.M., Kim Y.K., Verkerk R. et al. Kynurenine pathway in major depression: evidence of impaired neuroprotection. J. Affect. Disord. 2007; 98 (1–2): 143–151.
  45. Steiner J., Gos T., Bogerts B. et al. Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulated gyrus: evidence for an immune-modulated glutamatergic neurotransmission? J. Neuroinflammation. 2011; 8: 94.
  46. Rajkowska G., Miguel-Hidalgo J.J., Wei J. et al. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol. Psychiatry. 1999; 45 (9): 1085–1098.
  47. Gabbay V., Liebes L., Katz Y. et al. The kynurenine pathway in adolescent depression: preliminary findings from a proton MR spectroscopy study. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2010; 34 (1): 37–44.
  48. Wichers M.C., Koek G.H., Robaeys G. et al. IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol. Psychiatry. 2005; 10 (6): 538–544.
  49. Raison C.L., Dantzer R., Kelly K.W. et al. CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol. Psychiatry. 2000; 15 (4): 393–403.
  50. O’Connor J.C., Lawson M.A., Andre C. et al. Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol. Psychiatry. 2009; 14 (5): 511–522.
  51. O’Connor J.C., Andre C., Wang Y. et al. Interferon-gamma and tumor necrosis factor-alpha mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to Bacillus Calmette-Guerin. J. Neurosci. 2009; 29 (13): 4200–4209.
  52. Mason M., Manning B. Effects of steroid conjugates on availability of pyridoxal phosphate for kynureninase and kynurenine aminotransferase activity. Am. J. Clin. Nutr. 1971; 24 (7): 786–791.
  53. Pocivavsek A., Wu H.-Q., Schwarcz R. et al. Pre- and postnatal exposure to kynurenine causes cognitive deficits in adulthood. Eur. J. Neurosci. 2012; 35 (10): 1605–1612.
  54. Rapaport M.H., McAllister C.G., Pickar D. et al. Elevated levels of soluble interleukin 2 receptors in schizophrenia. Arch. Gen. Psychiatry. 1989; 46 (3): 291–292.
  55. Kim Y.K., Myint A.M., Verkerk R. et al. Cytokine changes and tryptophan metabolites in medication naïve and medication-free schizophrenia patients. Neuropsychobiology. 2009; 59 (2): 123–129.
  56. Potvin S., Stip E., Sepehry A.A. et al. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol. Psychiatry. 2008; 63 (8): 801–808.
  57. Schwarcz R., Rassoulpour A., Wu H.-Q. et al. Increased cortical kynurenate content in schizophrenia. Biol. Psychiatry. 2001; 50 (7): 521–530.
  58. Sathyasaikumar K.V., Stachowski E.K., Schwarcz. et al. Impaired kynurenine pathway metabolism in the prefrontal cortex of individuals with schizophrenia. Schizophr. Bull. 2011; 37 (6): 1147–1156.
  59. Erhardt S., Blennow K., Nordin C. et al. Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci. Lett. 2001; 313 (1-2): 96–98.
  60. Erhardt S., Schwieler L., Engberg G. Kynurenic acid and schizophrenia. Adv. Exp. Med. Biol. 2003; 527: 155–165.
  61. Ceresoli-Borroni G., Rassoulpour A., Wu H.-Q. et al. Chronic neuroleptic treatment reduces endogenous kynurenic acid levels in rat brain. J. Neural. Transm. 2006; 113 (10): 1355–1365.
  62. Andreasen N.C., O’Leary D.S., Flaum M. et al. Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naive patients. Lancet. 1997; 349 (9067): 1730–1734.
  63. Takahashi T., Wood S.J., Soulsby B. et al. Follow-up MRI study of the insular cortex in first-episode psychosis and chronic schizophrenia. Schizophr. Res. 2009; 108 (1–): 49–56.
  64. Copeland C.S., Neale S.A., Salt T.E. Actions of Xanthurenic Acid, a putative endogenous Group II metabotropic glutamate receptor agonist, on sensory transmission in the thalamus. Neuropharmacology. 2012; [Epub ahead of print].
  65. Condray R., Dougherty G.G. Jr., Keshavan M.S. 3-Hydroxykynurenine and clinical symptoms in first-episode neuroleptic-naïve patients with schizophrenia. Int. J. Neuropsychopharmacol. 2011; 14 (6): 756–767.
  66. Myint A.M., Schwarz M., Verkerk R. Imballance of kynurenine metabolites in drug naive schizophrenia. Brain Behav. Immun. 2011; 25 (8): 1576–1581.
  67. Erhardt S., Olsson S.K., Engberg G. Pharmacological manipulation of kynurenic acid: potential in the treatment of psychiatric disorders. CNS Drugs. 2009; 23 (2): 91–101.
  68. Stone T.W., Forrest C.M., Darlington L.G. Kynurenine pathway inhibition as a therapeutic strategy for neuroprotection. FEBS J. 2012; 279 (8): 1386–1397.
  69. Badawy A.A., Morgan C.J. Rapid isocratic liquid chromatographic separation and quantification of tryptophan and six kynurenine metabolites in biological samples with ultraviolet and fluorimetric detection. Int. J. Tryptophan Res. 2010; 3: 175–186.
  70. Sidorova A.A., Kartsova L.A. Study kinureninovogo tryptophan pathway by capillary electrophoresis and mass spectrometry. Zhurn. analitich. khimii = Journal of analytic chemistry. 2011; 66 (3): 329–334.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 1970 "Paediatrician" Publishers LLC



This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies