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Neuropathology of Kynurenine Pathway of Tryptophan Metabolism

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Abstract

The different branches of kynurenine pathways of tryptophan metabolism are the important mechanism to elucidate various neurological and immunological disorders. There is a substantial body of evidence indicating the involvement of kynurenine pathway (KP) in the pathophysiology of some neuropsychiatric and neurodegenerative perturbation. This pathway generates neuro-active compounds, those can interact with neurotransmitters receptors in the central nervous system (CNS). According to some recent studies, there are a strong relation between KP’s related enzymes such as indoleamine 2,3 dioxygenase (IDO) and tryptophan 2,3 dioxygenase (TDO) activation and neurological disease. In this review article, we focus on the level/ratios of different metabolites and precursors such as tryptophan (TRP), 5-hydroxytryptamine (5-HT), kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QUIN) in order to find the link with the KP-induced neuropathologies. Kynurenine metabolism is hypothesized to be one of the key mechanisms that link inflammation and depression. Some factors such as exercise (through PGC-1α), inflammation, stress, and some medication have the remarkable effects on KP. We highlight the role of different causes such as inflammation and stress, Tryptophan-kynurenine pathway with the whole biochemical and organ-specific biochemistry, and the neuropathomechanism of related pathologies. Here, we discuss the relations, the changes, and the mutual effects of KP with major depressive disorders, bipolar disorders, schizophrenia, Parkinson’s, and Alzheimer’s disease.

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Fig. 1

Abbreviations

KP:

Kynurenine pathway

KYN:

Kynurenine

KYNA:

Kynurenic acid

TRP:

Tryptophan

3-HK:

3-Hydroxykynurenine

AA:

Anthranilic acid

XA:

Xanthurenic acid

TDO:

Tryptophan 2, 3 dioxygenase

IDO:

Indoleamine 2, 3 dioxygenase

KAT:

Kynurenine aminotransferase

KMO:

Kynurenine monoxygenase

NAD:

Nicotinamide adenine dinucleotide

BDL:

Bile duct ligation

NMDA:

N-methyl D-aspartate

GSH:

Glutathione

TPH:

Tryptophan hydroxylase

5-HIAA:

5-hydroxyindoleacetic acid

BD:

Bipolar disorders

HD:

Huntington disease

AD:

Alzheimer’s disease

PD:

Parkinson’s disease

MDD:

Major depressive disorders

TLR:

Toll-like receptors

MT:

1-Methyl tryptophan

BDNF:

Brain-derived neurotrophic factor

TrkB:

Tropomycin receptor kinase B

PFC:

Prefrontal cortex

CA3:

Cornu ammonis of hippocampus

MS:

Multiple sclerosis

FNDC5:

Fibronectin type III domain containing 5

CSF:

Cerebrospinal fluid

PPI:

Prepulse Inhibition

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

PIC:

Picolinic acid

References

  1. 1.

    Austin CJD, Rendina LM. Targeting key dioxygenases in tryptophan-kynurenine metabolism for immunomodulation and cancer chemotherapy. Drug Discov Today. 2015;20:609–17.

  2. 2.

    Opitz CA, Heiland I. Dynamics of NAD-metabolism: everything but constant. Biochem Soc Trans. 2015;43:1127–32.

  3. 3.

    Moyer BJ, Rojas IY, Murray IA, Lee S, Hazlett HF, Perdew GH, et al. Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor. Toxicol Appl Pharmacol. 2017;323:74–80.

  4. 4.

    Brandacher G, Hoeller E, Fuchs D, Weiss HG. Chronic immune activation underlies morbid obesity: is IDO a key player? Curr Drug Metab. 2007;8:289–95.

  5. 5.

    Sarkar SA, Wong R, Hackl SI, Moua O, Gill RG, Wiseman A, et al. Induction of indoleamine 2,3-dioxygenase by interferon-gamma in human islets. Diabetes. 2007;56:72–9.

  6. 6.

    Chen W. IDO: more than an enzyme. Nat Immunol. 2011;12:809–11.

  7. 7.

    Bessede A, Gargaro M, Pallotta MT, Matino D, Servillo G, Brunacci C, et al. Aryl hydrocarbon receptor control of a disease tolerance defence pathway. Nature. 2014;511:184–90.

  8. 8.

    Fujigaki H, Yamamoto Y, Saito K. L-tryptophan-kynurenine pathway enzymes are therapeutic target for neuropsychiatric diseases: focus on cell type differences. Neuropharmacology. 2017;112:264–74.

  9. 9.

    Badawy AA-B. Tryptophan availability for kynurenine pathway metabolism across the life span: control mechanisms and focus on aging, exercise, diet and nutritional supplements. Neuropharmacology. 2017;112:248–63.

  10. 10.

    Oxenkrug G. Interferon-gamma - inducible inflammation: contribution to aging and aging-associated psychiatric disorders. Aging Dis. 2011;2:474–86.

  11. 11.

    Raison CL, Dantzer R, Kelley KW, Lawson MA, Woolwine BJ, Vogt G, et al. CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatry. 2010;15:393–403.

  12. 12.

    Baranyi A, Meinitzer A, Breitenecker RJ, Amouzadeh-Ghadikolai O, Stauber R, Rothenhäusler H-B. Quinolinic acid responses during interferon-α-induced depressive symptomatology in patients with chronic hepatitis C infection - a novel aspect for depression and inflammatory hypothesis. PLoS One. 2015;10:e0137022.

  13. 13.

    Steiner J, Walter M, Gos T, Guillemin GJ, Bernstein H-G, Sarnyai Z, et al. Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission? J Neuroinflammation. 2011;8:94.

  14. 14.

    Myint A-M, Kim YK, Verkerk R, Scharpé S, Steinbusch H, Leonard B. Kynurenine pathway in major depression: evidence of impaired neuroprotection. J Affect Disord. 2007;98:143–51.

  15. 15.

    Schwieler L, Samuelsson M, Frye MA, Bhat M, Schuppe-Koistinen I, Jungholm O, et al. Electroconvulsive therapy suppresses the neurotoxic branch of the kynurenine pathway in treatment-resistant depressed patients. J Neuroinflammation. 2016;13:51.

  16. 16.

    Bay-Richter C, Linderholm KR, Lim CK, Samuelsson M, Träskman-Bendz L, Guillemin GJ, et al. A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality. Brain Behav Immun. 2015;43:110–7.

  17. 17.

    Cho HJ, Savitz J, Dantzer R, Teague TK, Drevets WC, Irwin MR. Sleep disturbance and kynurenine metabolism in depression. J Psychosom Res. 2017;99:1–7.

  18. 18.

    Schwarcz R, Bruno JP, Muchowski PJ, Wu H-Q. Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci. 2012;13:465–77.

  19. 19.

    Refaey ME, McGee-Lawrence ME, Fulzele S, Kennedy EJ, Bollag WB, Elsalanty M, et al. Kynurenine, a tryptophan metabolite that accumulates with age, induces bone loss. J Bone Miner Res Off J Am Soc Bone Miner Res. 2017;32:2182–93.

  20. 20.

    Matthews KA, Schott LL, Bromberger JT, Cyranowski JM, Everson-Rose SA, Sowers M. Are there bi-directional associations between depressive symptoms and C-reactive protein in mid-life women? Brain Behav Immun. 2010;24:96–101.

  21. 21.

    Prescott C, Weeks AM, Staley KJ, Partin KM. Kynurenic acid has a dual action on AMPA receptor responses. Neurosci Lett. 2006;402:108–12.

  22. 22.

    Moroni F, Cozzi A, Sili M, Mannaioni G. Kynurenic acid: a metabolite with multiple actions and multiple targets in brain and periphery. J Neural Transm Vienna Austria 1996. 2012;119:133–9.

  23. 23.

    Jiang X, Xu L, Tang L, Liu F, Chen Z, Zhang J, et al. Role of the indoleamine-2,3-dioxygenase/kynurenine pathway of tryptophan metabolism in behavioral alterations in a hepatic encephalopathy rat model. J Neuroinflammation. 2018;15:3.

  24. 24.

    O’Connor JC, André C, Wang Y, Lawson MA, Szegedi SS, Lestage J, 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;29:4200–9.

  25. 25.

    Walker AK, Budac DP, Bisulco S, Lee AW, Smith RA, Beenders B, et al. NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice. Neuropsychopharmacology. 2013;38:1609–16.

  26. 26.

    Heisler JM, O’Connor JC. Indoleamine 2,3-dioxygenase-dependent neurotoxic kynurenine metabolism mediates inflammation-induced deficit in recognition memory. Brain Behav Immun. 2015;50:115–24.

  27. 27.

    Parrott JM, O’Connor JC. Kynurenine 3-monooxygenase: an influential mediator of neuropathology. Front Psychiatry. 2015;6:116.

  28. 28.

    Wejksza K, Rzeski W, Okuno E, Kandefer-Szerszen M, Albrecht J, Turski WA. Demonstration of kynurenine aminotransferases I and II and characterization of kynurenic acid synthesis in oligodendrocyte cell line (OLN-93). Neurochem Res. 2005;30:963–8.

  29. 29.

    Ramírez-Ortega D, Ramiro-Salazar A, González-Esquivel D, Ríos C, Pineda B, Pérez de la Cruz V. 3-Hydroxykynurenine and 3-hydroxyanthranilic acid enhance the toxicity induced by copper in rat astrocyte culture. Oxidative Med Cell Longev. 2017;2017:2371895.

  30. 30.

    Baran H, Staniek K, Bertignol-Spörr M, Attam M, Kronsteiner C, Kepplinger B. Effects of various kynurenine metabolites on respiratory parameters of rat brain, liver and heart mitochondria. Int J Tryptophan Res. 2016;9:17–29.

  31. 31.

    Vazquez S, Garner B, Sheil MM, Truscott RJ. Characterisation of the major autoxidation products of 3-hydroxykynurenine under physiological conditions. Free Radic Res. 2000;32:11–23.

  32. 32.

    Hirrlinger J, Dringen R. The cytosolic redox state of astrocytes: maintenance, regulation and functional implications for metabolite trafficking. Brain Res Rev. 2010;63:177–88.

  33. 33.

    Bryleva EY, Brundin L. Kynurenine pathway metabolites and suicidality. Neuropharmacology. 2017;112:324–30.

  34. 34.

    Fond G, Loundou A, Rabu C, Macgregor A, Lançon C, Brittner M, et al. Ketamine administration in depressive disorders: a systematic review and meta-analysis. Psychopharmacology. 2014;231:3663–76.

  35. 35.

    Maes M, Leonard BE, Myint AM, Kubera M, Verkerk R. The new “5-HT” hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression. Prog Neuro-Psychopharmacol Biol Psychiatry. 2011;35:702–21.

  36. 36.

    Bradley KAL, Case JAC, Khan O, Ricart T, Hanna A, Alonso CM, et al. The role of the kynurenine pathway in suicidality in adolescent major depressive disorder. Psychiatry Res. 2015;227:206–12.

  37. 37.

    Vikelis M, Mitsikostas DD. The role of glutamate and its receptors in migraine. CNS Neurol Disord Drug Targets. 2007;6:251–7.

  38. 38.

    Vécsei L, Majláth Z, Balog A, Tajti J. Drug targets of migraine and neuropathy: treatment of hyperexcitability. CNS Neurol Disord Drug Targets. 2015;14:664–76.

  39. 39.

    Sas K, Szabó E, Vécsei L. Mitochondria, oxidative stress and the kynurenine system, with a focus on ageing and neuroprotection. Molecules Basel Switz. 2018;23.

  40. 40.

    Gasparini CF, Griffiths LR. The biology of the glutamatergic system and potential role in migraine. Int J Biomed Sci. 2013;9:1–8.

  41. 41.

    Behan WM, McDonald M, Darlington LG, Stone TW. Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage: protection by melatonin and deprenyl. Br J Pharmacol. 1999;128:1754–60.

  42. 42.

    Tavares RG, Tasca CI, Santos CE, Wajner M, Souza DO, Dutra-Filho CS. Quinolinic acid inhibits glutamate uptake into synaptic vesicles from rat brain. Neuroreport. 2000;11:249–53.

  43. 43.

    Kemp JA, Foster AC, Leeson PD, Priestley T, Tridgett R, Iversen LL, et al. 7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-D-aspartate receptor complex. Proc Natl Acad Sci U S A. 1988;85:6547–50.

  44. 44.

    Sas K, Robotka H, Rózsa E, Agoston M, Szénási G, Gigler G, et al. Kynurenine diminishes the ischemia-induced histological and electrophysiological deficits in the rat hippocampus. Neurobiol Dis. 2008;32:302–8.

  45. 45.

    Pompili M, Orsolini L, Lamis DA, Goldsmith DR, Nardella A, Falcone G, et al. Suicide prevention in schizophrenia: do long-acting injectable antipsychotics (LAIs) have a role? CNS Neurol Disord Drug Targets. 2017;16:454–62.

  46. 46.

    Jentsch JD, Roth RH. The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology. 1999;20:201–25.

  47. 47.

    Miller CL, Llenos IC, Dulay JR, Weis S. Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder. Brain Res. 2006;1073–1074:25–37.

  48. 48.

    Stewart JC, Rand KL, Muldoon MF, Kamarck TW. A prospective evaluation of the directionality of the depression-inflammation relationship. Brain Behav Immun. 2009;23:936–44.

  49. 49.

    Zepf FD, Stewart RM, Guillemin G, Ruas JL. Inflammation, immunology, stress and depression: a role for kynurenine metabolism in physical exercise and skeletal muscle. Acta Neuropsychiatr. 2016;28:244–5.

  50. 50.

    Agudelo LZ, Femenía T, Orhan F, Porsmyr-Palmertz M, Goiny M, Martinez-Redondo V, et al. Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell. 2014;159:33–45.

  51. 51.

    Cervenka I, Agudelo LZ, Ruas JL. Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health. Science. 2017;357.

  52. 52.

    Wirleitner B, Neurauter G, Schröcksnadel K, Frick B, Fuchs D. Interferon-gamma-induced conversion of tryptophan: immunologic and neuropsychiatric aspects. Curr Med Chem. 2003;10:1581–91.

  53. 53.

    Musso T, Gusella GL, Brooks A, Longo DL, Varesio L. Interleukin-4 inhibits indoleamine 2,3-dioxygenase expression in human monocytes. Blood. 1994;83:1408–11.

  54. 54.

    Kanai M, Nakamura T, Funakoshi H. Identification and characterization of novel variants of the tryptophan 2,3-dioxygenase gene: differential regulation in the mouse nervous system during development. Neurosci Res. 2009;64:111–7.

  55. 55.

    Li J, Wang Y, Zhou R, Zhang H, Yang L, Wang B, et al. Association between tryptophan hydroxylase gene polymorphisms and attention deficit hyperactivity disorder in Chinese Han population. Am J Med Genet Part B Neuropsychiatr Genet. 2006;141B:126–9.

  56. 56.

    Li JS, Han Q, Fang J, Rizzi M, James AA, Li J. Biochemical mechanisms leading to tryptophan 2,3-dioxygenase activation. Arch Insect Biochem Physiol. 2007;64:74–87.

  57. 57.

    Metz R, Smith C, DuHadaway JB, Chandler P, Baban B, Merlo LMF, et al. IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation. Int Immunol. 2014;26:357–67.

  58. 58.

    Saito K, Crowley JS, Markey SP, Heyes MP. A mechanism for increased quinolinic acid formation following acute systemic immune stimulation. J Biol Chem. 1993;268:15496–503.

  59. 59.

    Bender DA. Biochemistry of tryptophan in health and disease. Mol Asp Med. 1983;6:101–97.

  60. 60.

    Salter M, Knowles RG, Pogson CI. Quantification of the importance of individual steps in the control of aromatic amino acid metabolism. Biochem J. 1986;234:635–47.

  61. 61.

    Holmes EW. Determination of serum kynurenine and hepatic tryptophan dioxygenase activity by high-performance liquid chromatography. Anal Biochem. 1988;172:518–25.

  62. 62.

    Takeuchi F, Tsubouchi R, Izuta S, Shibata Y. Kynurenine metabolism and xanthurenic acid formation in vitamin B6-deficient rat after tryptophan injection. J Nutr Sci Vitaminol (Tokyo). 1989;35:111–22.

  63. 63.

    Pawlak D, Tankiewicz A, Matys T, Buczko W. Peripheral distribution of kynurenine metabolites and activity of kynurenine pathway enzymes in renal failure. J Physiol Pharmacol. 2003;54:175–89.

  64. 64.

    Gál EM, Sherman AD. L-kynurenine: its synthesis and possible regulatory function in brain. Neurochem Res. 1980;5:223–39.

  65. 65.

    Heyes MP, Chen CY, Major EO, Saito K. Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types. Biochem J. 1997;326(Pt 2):351–6.

  66. 66.

    Heyes MP, Achim CL, Wiley CA, Major EO, Saito K, Markey SP. Human microglia convert l-tryptophan into the neurotoxin quinolinic acid. Biochem J. 1996;320(Pt 2):595–7.

  67. 67.

    Schwarcz R, Pellicciari R. Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities. J Pharmacol Exp Ther. 2002;303:1–10.

  68. 68.

    Bordelon YM, Chesselet MF, Nelson D, Welsh F, Erecińska M. Energetic dysfunction in quinolinic acid-lesioned rat striatum. J Neurochem. 1997;69:1629–39.

  69. 69.

    Santamaría A, Galván-Arzate S, Lisý V, Ali SF, Duhart HM, Osorio-Rico L, et al. Quinolinic acid induces oxidative stress in rat brain synaptosomes. Neuroreport. 2001;12:871–4.

  70. 70.

    Schwarcz R, Whetsell WO, Mangano RM. Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. Science. 1983;219:316–8.

  71. 71.

    Kim JP, Choi DW. Quinolinate neurotoxicity in cortical cell culture. Neuroscience. 1987;23:423–32.

  72. 72.

    Laugeray A, Launay J-M, Callebert J, Surget A, Belzung C, Barone PR. Peripheral and cerebral metabolic abnormalities of the tryptophan-kynurenine pathway in a murine model of major depression. Behav Brain Res. 2010;210:84–91.

  73. 73.

    Guillemin GJ, Brew BJ, Noonan CE, Takikawa O, Cullen KM. Indoleamine 2,3 dioxygenase and quinolinic acid immunoreactivity in Alzheimer’s disease hippocampus. Neuropathol Appl Neurobiol. 2005;31:395–404.

  74. 74.

    Guillemin GJ, Kerr SJ, Brew BJ. Involvement of quinolinic acid in AIDS dementia complex. Neurotox Res. 2005;7:103–23.

  75. 75.

    Moroni F, Russi P, Lombardi G, Beni M, Carlà V. Presence of kynurenic acid in the mammalian brain. J Neurochem. 1988;51:177–80.

  76. 76.

    Stone TW. Neuropharmacology of quinolinic and kynurenic acids. Pharmacol Rev. 1993;45:309–79.

  77. 77.

    Stone TW, Addae JI. The pharmacological manipulation of glutamate receptors and neuroprotection. Eur J Pharmacol. 2002;447:285–96.

  78. 78.

    Erhardt S, Blennow K, Nordin C, Skogh E, Lindström LH, Engberg G. Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci Lett. 2001;313:96–8.

  79. 79.

    Zanos P, Piantadosi SC, Wu H-Q, Pribut HJ, Dell MJ, Can A, et al. The prodrug 4-chlorokynurenine causes ketamine-like antidepressant effects, but not side effects, by NMDA/glycineB-site inhibition. J Pharmacol Exp Ther. 2015;355:76–85.

  80. 80.

    Goldstein LE, Leopold MC, Huang X, Atwood CS, Saunders AJ, Hartshorn M, et al. 3-Hydroxykynurenine and 3-hydroxyanthranilic acid generate hydrogen peroxide and promote alpha-crystallin cross-linking by metal ion reduction. Biochemistry. 2000;39:7266–75.

  81. 81.

    Schwarcz R, Rassoulpour A, Wu HQ, Medoff D, Tamminga CA, Roberts RC. Increased cortical kynurenate content in schizophrenia. Biol Psychiatry. 2001;50:521–30.

  82. 82.

    Sathyasaikumar KV, Stachowski EK, Wonodi I, Roberts RC, Rassoulpour A, McMahon RP, et al. Impaired kynurenine pathway metabolism in the prefrontal cortex of individuals with schizophrenia. Schizophr Bull. 2011;37:1147–56.

  83. 83.

    Linderholm KR, Skogh E, Olsson SK, Dahl M-L, Holtze M, Engberg G, et al. Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia. Schizophr Bull. 2012;38:426–32.

  84. 84.

    Nilsson LK, Linderholm KR, Engberg G, Paulson L, Blennow K, Lindström LH, et al. Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia. Schizophr Res. 2005;80:315–22.

  85. 85.

    Johansson A-S, Owe-Larsson B, Asp L, Kocki T, Adler M, Hetta J, et al. Activation of kynurenine pathway in ex vivo fibroblasts from patients with bipolar disorder or schizophrenia: cytokine challenge increases production of 3-hydroxykynurenine. J Psychiatr Res. 2013;47:1815–23.

  86. 86.

    Oxenkrug G, van der Hart M, Roeser J, Summergrad P. Anthranilic acid: a potential biomarker and treatment target for schizophrenia. Ann Psychiatry Ment Health. 2016;4.

  87. 87.

    Atlas A, Gisslén M, Nordin C, Lindström L, Schwieler L. Acute psychotic symptoms in HIV-1 infected patients are associated with increased levels of kynurenic acid in cerebrospinal fluid. Brain Behav Immun. 2007;21:86–91.

  88. 88.

    Ravikumar A, Deepadevi KV, Arun P, Manojkumar V, Kurup PA. Tryptophan and tyrosine catabolic pattern in neuropsychiatric disorders. Neurol India. 2000;48:231–8.

  89. 89.

    Fukui S, Schwarcz R, Rapoport SI, Takada Y, Smith QR. Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism. J Neurochem. 1991;56:2007–17.

  90. 90.

    Chang YF, Cauley RK, Chang JD, Rao VV. L-alpha-aminoadipate inhibits kynurenate synthesis in rat brain hippocampus and tissue culture. Neurochem Res. 1997;22:825–9.

  91. 91.

    Speciale C, Wu HQ, Cini M, Marconi M, Varasi M, Schwarcz R. (R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a large and persistent increase in brain kynurenic acid levels in rats. Eur J Pharmacol. 1996;315:263–7.

  92. 92.

    Röver S, Cesura AM, Huguenin P, Kettler R, Szente A. Synthesis and biochemical evaluation of N-(4-phenylthiazol-2-yl)benzenesulfonamides as high-affinity inhibitors of kynurenine 3-hydroxylase. J Med Chem. 1997;40:4378–85.

  93. 93.

    Clunie M, Crone L-A, Klassen L, Yip R. Psychiatric side effects of indomethacin in parturients. Can J Anaesth. 2003;50:586–8.

  94. 94.

    Schwieler L, Erhardt S, Nilsson L, Linderholm K, Engberg G. Effects of COX-1 and COX-2 inhibitors on the firing of rat midbrain dopaminergic neurons--possible involvement of endogenous kynurenic acid. Synapse. 2006;59:290–8.

  95. 95.

    Wonodi I, Stine OC, Sathyasaikumar KV, Roberts RC, Mitchell BD, Hong LE, et al. Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes. Arch Gen Psychiatry. 2011;68:665–74.

  96. 96.

    Sellgren CM, Kegel ME, Bergen SE, Ekman CJ, Olsson S, Larsson M, et al. A genome-wide association study of kynurenic acid in cerebrospinal fluid: implications for psychosis and cognitive impairment in bipolar disorder. Mol Psychiatry. 2016;21:1342–50.

  97. 97.

    Karlsson H. Viruses and schizophrenia, connection or coincidence? Neuroreport. 2003;14:535–42.

  98. 98.

    Canetta SE, Brown AS. Prenatal infection, maternal immune activation, and risk for schizophrenia. Transl Neurosci. 2012;3:320–7.

  99. 99.

    Miller CL, Llenos IC, Dulay JR, Barillo MM, Yolken RH, Weis S. Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia. Neurobiol Dis. 2004;15:618–29.

  100. 100.

    Asp L, Beraki S, Kristensson K, Ogren SO, Karlsson H. Neonatal infection with neurotropic influenza a virus affects working memory and expression of type III Nrg1 in adult mice. Brain Behav Immun. 2009;23:733–41.

  101. 101.

    Liu X-C, Holtze M, Powell SB, Terrando N, Larsson MK, Persson A, et al. Behavioral disturbances in adult mice following neonatal virus infection or kynurenine treatment--role of brain kynurenic acid. Brain Behav Immun. 2014;36:80–9.

  102. 102.

    Carlborg A, Winnerbäck K, Jönsson EG, Jokinen J, Nordström P. Suicide in schizophrenia. Expert Rev Neurother. 2010;10:1153–64.

  103. 103.

    Asberg M. Neurotransmitters and suicidal behavior. The evidence from cerebrospinal fluid studies. Ann N Y Acad Sci. 1997;836:158–81.

  104. 104.

    Barrett TB, Hauger RL, Kennedy JL, Sadovnick AD, Remick RA, Keck PE, et al. Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder. Mol Psychiatry. 2003;8:546–57.

  105. 105.

    Barrett TB, Emberton JE, Nievergelt CM, Liang SG, Hauger RL, Eskin E, et al. Further evidence for association of GRK3 to bipolar disorder suggests a second disease mutation. Psychiatr Genet. 2007;17:315–22.

  106. 106.

    Askland K, Parsons M. Toward a biaxial model of “bipolar” affective disorders: spectrum phenotypes as the products of neuroelectrical and neurochemical alterations. J Affect Disord. 2006;94:15–33.

  107. 107.

    Anguelova M, Benkelfat C, Turecki G. A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders. Mol Psychiatry. 2003;8:574–91.

  108. 108.

    Mahmood T, Silverstone T. Serotonin and bipolar disorder. J Affect Disord. 2001;66:1–11.

  109. 109.

    Serretti A, Lilli R, Lorenzi C, Lattuada E, Cusin C, Smeraldi E. Serotonin transporter gene (5-HTTLPR) and major psychoses. Mol Psychiatry. 2002;7:95–9.

  110. 110.

    Bellivier F, Henry C, Szöke A, Schürhoff F, Nosten-Bertrand M, Feingold J, et al. Serotonin transporter gene polymorphisms in patients with unipolar or bipolar depression. Neurosci Lett. 1998;255:143–6.

  111. 111.

    Hoekstra R, Fekkes D, Loonen AJM, Pepplinkhuizen L, Tuinier S, Verhoeven WMA. Bipolar mania and plasma amino acids: increased levels of glycine. Eur Neuropsychopharmacol. 2006;16:71–7.

  112. 112.

    Myint AM, Kim YK. Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression. Med Hypotheses. 2003;61:519–25.

  113. 113.

    Sheehan DV, Nakagome K, Asami Y, Pappadopulos EA, Boucher M. Restoring function in major depressive disorder: a systematic review. J Affect Disord. 2017;215:299–313.

  114. 114.

    Küster OC, Laptinskaya D, Fissler P, Schnack C, Zügel M, Nold V, et al. Novel blood-based biomarkers of cognition, stress, and physical or cognitive training in older adults at risk of dementia: preliminary evidence for a role of BDNF, irisin, and the kynurenine pathway. J Alzheimers Dis. 2017;59:1097–111.

  115. 115.

    Meier TB, Drevets WC, Teague TK, Wurfel BE, Mueller SC, Bodurka J, et al. Kynurenic acid is reduced in females and oral contraceptive users: implications for depression. Brain Behav Immun. 2018;67:59–64.

  116. 116.

    Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16:626–38.

  117. 117.

    Holsboer F. How can we realize the promise of personalized antidepressant medicines? Nat Rev Neurosci. 2008;9:638–46.

  118. 118.

    Pearson SJ, Reynolds GP. Increased brain concentrations of a neurotoxin, 3-hydroxykynurenine, in Huntington’s disease. Neurosci Lett. 1992;144:199–201.

  119. 119.

    Haroon et al., 2012 - PubMed - NCBI [Internet]. [cited 2018 Aug 14]. Available from: https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/?term=Haroon+et+al.%2C+2012

  120. 120.

    Maddison DC, Giorgini F. The kynurenine pathway and neurodegenerative disease. Semin Cell Dev Biol. 2015;40:134–41.

  121. 121.

    Myint AM, Schwarz MJ, Verkerk R, Mueller HH, Zach J, Scharpé S, et al. Reversal of imbalance between kynurenic acid and 3-hydroxykynurenine by antipsychotics in medication-naïve and medication-free schizophrenic patients. Brain Behav Immun. 2011;25:1576–81.

  122. 122.

    Sperner-Unterweger B, Kohl C, Fuchs D. Immune changes and neurotransmitters: possible interactions in depression? Prog Neuro-Psychopharmacol Biol Psychiatry. 2014;48:268–76.

  123. 123.

    Jeon SW, Kim Y-K. Inflammation-induced depression: its pathophysiology and therapeutic implications. J Neuroimmunol. 2017;313:92–8.

  124. 124.

    Hashimoto K. Inflammatory biomarkers as differential predictors of antidepressant response. Int J Mol Sci. 2015;16:7796–801.

  125. 125.

    Zhang J-C, Yao W, Hashimoto K. Brain-derived neurotrophic factor (BDNF)-TrkB signaling in inflammation-related depression and potential therapeutic targets. Curr Neuropharmacol. 2016;14:721–31.

  126. 126.

    Yang J-J, Wang N, Yang C, Shi J-Y, Yu H-Y, Hashimoto K. Serum interleukin-6 is a predictive biomarker for ketamine’s antidepressant effect in treatment-resistant patients with major depression. Biol Psychiatry. 2015;77:e19–20.

  127. 127.

    Burke TF, Advani T, Adachi M, Monteggia LM, Hensler JG. Sensitivity of hippocampal 5-HT1A receptors to mild stress in BDNF-deficient mice. Int J Neuropsychopharmacol. 2013;16:631–45.

  128. 128.

    Dugan AM, Parrott JM, Redus L, Hensler JG, O’Connor JC. Low-level stress induces production of neuroprotective factors in wild-type but not BDNF+/− mice: interleukin-10 and kynurenic acid. Int J Neuropsychopharmacol. 2015;19:pyv089.

  129. 129.

    Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science. 2006;311:864–8.

  130. 130.

    Jin Y, Sumsuzzman DM, Choi J, Kang H, Lee S-R, Hong Y. Molecular and functional interaction of the myokine irisin with physical exercise and Alzheimer’s disease. Molecules Basel Switz. 2018;23.

  131. 131.

    Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, et al. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab. 2013;18:649–59.

  132. 132.

    Mancuso R, Hernis A, Agostini S, Rovaris M, Caputo D, Fuchs D, et al. Indoleamine 2,3 dioxygenase (IDO) expression and activity in relapsing-remitting multiple sclerosis. PLoS One. 2015;10:e0130715.

  133. 133.

    Lovelace MD, Varney B, Sundaram G, Lennon MJ, Lim CK, Jacobs K, et al. Recent evidence for an expanded role of the kynurenine pathway of tryptophan metabolism in neurological diseases. Neuropharmacology. 2017;112:373–88.

  134. 134.

    Manoharan S, Guillemin GJ, Abiramasundari RS, Essa MM, Akbar M, Akbar MD. The role of reactive oxygen species in the pathogenesis of Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease: a mini review. Oxidative Med Cell Longev. 2016;2016:8590578.

  135. 135.

    Vécsei L, Szalárdy L, Fülöp F, Toldi J. Kynurenines in the CNS: recent advances and new questions. Nat Rev Drug Discov. 2013;12:64–82.

  136. 136.

    Zwilling D, Huang S-Y, Sathyasaikumar KV, Notarangelo FM, Guidetti P, Wu H-Q, et al. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell. 2011;145:863–74.

  137. 137.

    Malinova TS, Dijkstra CD, de Vries HE. Serotonin: a mediator of the gut-brain axis in multiple sclerosis. Mult Scler. 2018;24:1144–50.

  138. 138.

    Anderson G, Rodriguez M. Multiple sclerosis, seizures, and antiepileptics: role of IL-18, IDO, and melatonin. Eur J Neurol. 2011;18:680–5.

  139. 139.

    Rozov SV, Filatova EV, Orlov AA, Volkova AV, Zhloba ARA, Blashko EL, et al. N1-acetyl-N2-formyl-5-methoxykynuramine is a product of melatonin oxidation in rats. J Pineal Res. 2003;35:245–50.

  140. 140.

    Sveinbjornsdottir S. The clinical symptoms of Parkinson’s disease. J Neurochem. 2016;139(Suppl 1):318–24.

  141. 141.

    de Lau LML, Breteler MMB. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006;5:525–35.

  142. 142.

    Lang AE, Lozano AM. Parkinson’s disease. First of two parts. N Engl J Med. 1998;339:1044–53.

  143. 143.

    Ogawa T, Matson WR, Beal MF, Myers RH, Bird ED, Milbury P, et al. Kynurenine pathway abnormalities in Parkinson’s disease. Neurology. 1992;42:1702–6.

  144. 144.

    Chang K-H, Cheng M-L, Tang H-Y, Huang C-Y, Wu Y-R, Chen C-M. Alternations of metabolic profile and kynurenine metabolism in the plasma of Parkinson’s disease. Mol Neurobiol. 2018:1–10.

  145. 145.

    Jauch D, Urbańska EM, Guidetti P, Bird ED, Vonsattel JP, Whetsell WO, et al. Dysfunction of brain kynurenic acid metabolism in Huntington’s disease: focus on kynurenine aminotransferases. J Neurol Sci. 1995;130:39–47.

  146. 146.

    Havelund JF, Andersen AD, Binzer M, Blaabjerg M, Heegaard NHH, Stenager E, et al. Changes in kynurenine pathway metabolism in Parkinson patients with L-DOPA-induced dyskinesia. J Neurochem. 2017;142:756–66.

  147. 147.

    Schwarcz R. Kynurenines and glutamate: multiple links and therapeutic implications. Adv Pharmacol. 2016;76:13–37.

  148. 148.

    Schwarz MJ, Guillemin GJ, Teipel SJ, Buerger K, Hampel H. Increased 3-hydroxykynurenine serum concentrations differentiate Alzheimer’s disease patients from controls. Eur Arch Psychiatry Clin Neurosci. 2013;263:345–52.

  149. 149.

    Amori L, Wu H-Q, Marinozzi M, Pellicciari R, Guidetti P, Schwarcz R. Specific inhibition of kynurenate synthesis enhances extracellular dopamine levels in the rodent striatum. Neuroscience. 2009;159:196–203.

  150. 150.

    Grégoire L, Rassoulpour A, Guidetti P, Samadi P, Bédard PJ, Izzo E, et al. Prolonged kynurenine 3-hydroxylase inhibition reduces development of levodopa-induced dyskinesias in parkinsonian monkeys. Behav Brain Res. 2008;186:161–7.

  151. 151.

    Lewitt PA, Li J, Lu M, Beach TG, Adler CH, Guo L, et al. 3-hydroxykynurenine and other Parkinson’s disease biomarkers discovered by metabolomic analysis. Mov Disord. 2013;28:1653–60.

  152. 152.

    Lim CK, Fernández-Gomez FJ, Braidy N, Estrada C, Costa C, Costa S, et al. Involvement of the kynurenine pathway in the pathogenesis of Parkinson’s disease. Prog Neurobiol. 2017;155:76–95.

  153. 153.

    Kennedy PJ, Cryan JF, Dinan TG, Clarke G. Kynurenine pathway metabolism and the microbiota-gut-brain axis. Neuropharmacology. 2017;112:399–412.

  154. 154.

    Pláteník J, Stopka P, Vejrazka M, Stípek S. Quinolinic acid-iron(ii) complexes: slow autoxidation, but enhanced hydroxyl radical production in the Fenton reaction. Free Radic Res. 2001;34:445–59.

  155. 155.

    Gulaj E, Pawlak K, Bien B, Pawlak D. Kynurenine and its metabolites in Alzheimer’s disease patients. Adv Med Sci. 2010;55:204–11.

  156. 156.

    Ardura-Fabregat A, Boddeke EWGM, Boza-Serrano A, Brioschi S, Castro-Gomez S, Ceyzériat K, et al. Targeting neuroinflammation to treat Alzheimer’s disease. CNS Drugs. 2017;31:1057–82.

  157. 157.

    Braidy N, Grant R, Adams S, Brew BJ, Guillemin GJ. Mechanism for quinolinic acid cytotoxicity in human astrocytes and neurons. Neurotox Res. 2009;16:77–86.

  158. 158.

    Ting KK, Brew BJ, Guillemin GJ. Effect of quinolinic acid on human astrocytes morphology and functions: implications in Alzheimer’s disease. J Neuroinflammation. 2009;6:36.

  159. 159.

    Hartai Z, Juhász A, Rimanóczy A, Janáky T, Donkó T, Dux L, et al. Decreased serum and red blood cell kynurenic acid levels in Alzheimer’s disease. Neurochem Int. 2007;50:308–13.

  160. 160.

    Guillemin GJ, Smythe GA, Veas LA, Takikawa O, Brew BJ. A beta 1-42 induces production of quinolinic acid by human macrophages and microglia. Neuroreport. 2003;14:2311–5.

  161. 161.

    Walker DG, Link J, Lue L-F, Dalsing-Hernandez JE, Boyes BE. Gene expression changes by amyloid beta peptide-stimulated human postmortem brain microglia identify activation of multiple inflammatory processes. J Leukoc Biol. 2006;79:596–610.

  162. 162.

    Okuda S, Nishiyama N, Saito H, Katsuki H. 3-Hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and region selectivity. J Neurochem. 1998;70:299–307.

  163. 163.

    Vazquez S, Aquilina JA, Jamie JF, Sheil MM, Truscott RJW. Novel protein modification by kynurenine in human lenses. J Biol Chem. 2002;277:4867–73.

  164. 164.

    Rahman A, Ting K, Cullen KM, Braidy N, Brew BJ, Guillemin GJ. The excitotoxin quinolinic acid induces tau phosphorylation in human neurons. PLoS One. 2009;4:e6344.

  165. 165.

    Forrest CM, McNair K, Pisar M, Khalil OS, Darlington LG, Stone TW. Altered hippocampal plasticity by prenatal kynurenine administration, kynurenine-3-monoxygenase (KMO) deletion or galantamine. Neuroscience. 2015;310:91–105.

  166. 166.

    Schroecksnadel K, Winkler C, Fuith LC, Fuchs D. Tryptophan degradation in patients with gynecological cancer correlates with immune activation. Cancer Lett. 2005;223:323–9.

  167. 167.

    Schröcksnadel K, Widner B, Bergant A, Neurauter G, Schennach H, Schröcksnadel H, et al. Longitudinal study of tryptophan degradation during and after pregnancy. Life Sci. 2003;72:785–93.

  168. 168.

    Heyes MP, Saito K, Lackner A, Wiley CA, Achim CL, Markey SP. Sources of the neurotoxin quinolinic acid in the brain of HIV-1-infected patients and retrovirus-infected macaques. FASEB J. 1998;12:881–96.

  169. 169.

    Huengsberg M, Winer JB, Gompels M, Round R, Ross J, Shahmanesh M. Serum kynurenine-to-tryptophan ratio increases with progressive disease in HIV-infected patients. Clin Chem. 1998;44:858–62.

  170. 170.

    Look MP, Altfeld M, Kreuzer KA, Riezler R, Stabler SP, Allen RH, et al. Parallel decrease in neurotoxin quinolinic acid and soluble tumor necrosis factor receptor p75 in serum during highly active antiretroviral therapy of HIV type 1 disease. AIDS Res Hum Retrovir. 2000;16:1215–21.

  171. 171.

    Murr C, Gerlach D, Widner B, Dierich MP, Fuchs D. Neopterin production and tryptophan degradation in humans infected by Streptococcus pyogenes. Med Microbiol Immunol. 2001;189:161–3.

  172. 172.

    Huang A, Fuchs D, Widner B, Glover C, Henderson DC, Allen-Mersh TG. Serum tryptophan decrease correlates with immune activation and impaired quality of life in colorectal cancer. Br J Cancer. 2002;86:1691–6.

  173. 173.

    Young SN, Joseph MH, Gauthier S. Studies on kynurenine in human cerebrospinal fluid: lowered levels in epilepsy. J Neural Transm. 1983;58:193–204.

  174. 174.

    Baig S, Halawa I, Qureshi GA. High performance liquid chromatography as a tool in the definition of abnormalities in monoamine and tryptophan metabolites in cerebrospinal fluid from patients with neurological disorders. Biomed Chromatogr. 1991;5:108–12.

  175. 175.

    Heyes MP, Saito K, Devinsky O, Nadi NS. Kynurenine pathway metabolites in cerebrospinal fluid and serum in complex partial seizures. Epilepsia. 1994;35:251–7.

  176. 176.

    Heyes MP, Saito K, Milstien S, Schiff SJ. Quinolinic acid in tumors, hemorrhage and bacterial infections of the central nervous system in children. J Neurol Sci. 1995;133:112–8.

  177. 177.

    Medana IM, Day NPJ, Salahifar-Sabet H, Stocker R, Smythe G, Bwanaisa L, et al. Metabolites of the kynurenine pathway of tryptophan metabolism in the cerebrospinal fluid of Malawian children with malaria. J Infect Dis. 2003;188:844–9.

  178. 178.

    Iłzecka J, Kocki T, Stelmasiak Z, Turski WA. Endogenous protectant kynurenic acid in amyotrophic lateral sclerosis. Acta Neurol Scand. 2003;107:412–8.

  179. 179.

    Theme 3 cognitive and psychological assessment and support. Amyotroph Lateral Scler Frontotemporal Degener. 2014;15(Suppl 1):81–92.

  180. 180.

    Rejdak K, Bartosik-Psujek H, Dobosz B, Kocki T, Grieb P, Giovannoni G, et al. Decreased level of kynurenic acid in cerebrospinal fluid of relapsing-onset multiple sclerosis patients. Neurosci Lett. 2002;331:63–5.

  181. 181.

    Orlikov AB, Prakhye IB, Ryzov IV. Kynurenine in blood plasma and DST in patients with endogenous anxiety and endogenous depression. Biol Psychiatry. 1994;36:97–102.

  182. 182.

    Beal MF, Matson WR, Storey E, Milbury P, Ryan EA, Ogawa T, et al. Kynurenic acid concentrations are reduced in Huntington’s disease cerebral cortex. J Neurol Sci. 1992;108:80–7.

  183. 183.

    Sardar AM, Bell JE, Reynolds GP. Increased concentrations of the neurotoxin 3-hydroxykynurenine in the frontal cortex of HIV-1-positive patients. J Neurochem. 1995;64:932–5.

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Tutakhail, A., Boulet, L., Khabil, S. et al. Neuropathology of Kynurenine Pathway of Tryptophan Metabolism. Curr Pharmacol Rep (2020) doi:10.1007/s40495-019-00208-2

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Keywords

  • Kynurenine pathway
  • KYNs
  • Excitotoxicity
  • Neuropsychiatric diseases
  • Neurodegenerative diseases