Skip to main content

Advertisement

SpringerLink
Log in

The role of the kynurenine metabolism in major depression

  • Basic Neurosciences, Genetics and Immunology - Review article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

There are circumferential evidences that major depression is associated with mild pro-inflammatory state. Both physiological and psychological stress can induce increased production of pro-inflammatory mediators, reactive oxygen species (ROS) and hypothalamo–hypophyseal–adrenal axis disturbances. While both pro-inflammatory mediators and ROS could activate the tryptophan breakdown and kynurenine pathway with a shift toward the neurotoxic arm, chronic hypercortisolism could also enhance tryptophan breakdown and induce neurodegenerative changes. The imbalanced kynurenine metabolism in terms of neuroprotective and neurotoxic effects was demonstrated in major depression, and in drug-induced neuropsychiatric side effects, such as interferon-treated depression. The changes in periphery are shown to be associated with central changes. Those changes might be partly contributed by genetic factors. While some of the currently available antidepressants could reverse the pro-inflammatory state of the depressed patients, these medications could not efficiently improve those metabolic and neurochemical changes within the period that could induce clinical improvement. In this review, the role of kynurenine metabolism which interacts with other neurochemicals is discussed as a major contributing pathophysiological mechanism in major depression. Moreover, the future therapeutic opportunities are also discussed in this review.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Alonso J, Angermeyer MC, Bernert S, Bruffaerts R, Brugha TS, Bryson H et al (2004) Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatr Scand Suppl 21–27

  • Anisman H, Ravindran AV, Griffiths J, Merali Z (1999) Endocrine and cytokine correlates of major depression and dysthymia with typical or atypical features. Mol Psychiatry 4:182–188

    Article  PubMed  CAS  Google Scholar 

  • Bender DA (1989) Effects of a dietary excess of leucine and of the addition of leucine and 2-oxo-isocaproate on the metabolism of tryptophan and niacin in isolated rat liver cells. Br J Nutr 61:629–640

    Article  PubMed  CAS  Google Scholar 

  • Bender DA, McCreanor GM (1985) Kynurenine hydroxylase: a potential rate-limiting enzyme in tryptophan metabolism. Biochem Soc Trans 13:441–443

    PubMed  CAS  Google Scholar 

  • Campuzano O, Castillo-Ruiz MM, Acarin L, Castellano B, Gonzalez B (2008) Distinct pattern of microglial response, cyclooxygenase-2, and inducible nitric oxide synthase expression in the aged rat brain after excitotoxic damage. J Neurosci Res 86:3170–3183

    Article  PubMed  CAS  Google Scholar 

  • Carlin JM, Borden EC, Sondel PM, Byrne GI (1987) Biologic-response-modifier-induced indoleamine 2, 3-dioxygenase activity in human peripheral blood mononuclear cell cultures. J Immunol 139:2414–2418

    PubMed  CAS  Google Scholar 

  • Chen S, Averett NT, Manelli A, Ladu MJ, May W, Ard MD (2005) Isoform-specific effects of apolipoprotein E on secretion of inflammatory mediators in adult rat microglia. J Alzheimers Dis 7:25–35

    PubMed  CAS  Google Scholar 

  • Chiarugi A, Calvani M, Meli E, Traggiai E, Moroni F (2001) Synthesis and release of neurotoxic kynurenine metabolites by human monocyte-derived macrophages. J Neuroimmunol 120:190–198

    Article  PubMed  CAS  Google Scholar 

  • Connor TJ, Leonard BE (1998) Depression, stress and immunological activation: the role of cytokines in depressive disorders. Life Sci 62:583–606

    Article  PubMed  CAS  Google Scholar 

  • Depboylu C, Weihe E, Eiden LE (2011) COX1 and COX2 expression in non-neuronal cellular compartments of the rhesus macaque brain during lentiviral infection. Neurobiol Dis 42:108–115

    Article  PubMed  CAS  Google Scholar 

  • Evans DL, Pedersen CA, Folds JD (1988) Major depression and immunity: preliminary evidence of decreased natural killer cell populations. Prog Neuropsychopharmacol Biol Psychiatry 12:739–748

    Article  PubMed  CAS  Google Scholar 

  • Eynard N, Flachaire E, Lestra C, Broyer M, Zaidan R, Claustrat B et al (1993) Platelet serotonin content and free and total plasma tryptophan in healthy volunteers during 24 hours. Clin Chem 39:2337–2340

    PubMed  CAS  Google Scholar 

  • Fernstrom JD (1977) Effects on the diet on brain neurotransmitters. Metabolism 26:207–223

    Article  PubMed  CAS  Google Scholar 

  • Gabbay V, Liebes L, Katz Y, Liu S, Mendoza S, Babb JS et al (2010) The kynurenine pathway in adolescent depression: preliminary findings from a proton MR spectroscopy study. Prog Neuropsychopharmacol Biol Psychiatry 34:37–44

    Article  PubMed  CAS  Google Scholar 

  • Gal EM, Sherman AD (1980) l-Kynurenine: its synthesis and possible regulatory function in brain. Neurochem Res 5:223–239

    Article  PubMed  CAS  Google Scholar 

  • Grant RS, Kapoor V (1998) Murine glial cells regenerate NAD, after peroxide-induced depletion, using either nicotinic acid, nicotinamide, or quinolinic acid as substrates. J Neurochem 70:1759–1763

    Article  PubMed  CAS  Google Scholar 

  • Grant RS, Naif H, Espinosa M, Kapoor V (2000) IDO induction in IFN-gamma activated astroglia: a role in improving cell viability during oxidative stress. Redox Rep 5:101–104

    Article  PubMed  CAS  Google Scholar 

  • Guillemin GJ, Smith DG, Kerr SJ, Smythe GA, Kapoor V, Armati PJ et al (2000) Characterisation of kynurenine pathway metabolism in human astrocytes and implications in neuropathogenesis. Redox Rep 5:108–111

    Article  PubMed  CAS  Google Scholar 

  • Guillemin GJ, Kerr SJ, Smythe GA, Smith DG, Kapoor V, Armati PJ et al (2001) Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection. J Neurochem 78:842–853

    Article  PubMed  CAS  Google Scholar 

  • Guillemin GJ, Smythe G, Takikawa O, Brew BJ (2005) Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons. Glia 49:15–23

    Article  PubMed  Google Scholar 

  • Heyes MP, Saito K, Crowley JS, Davis LE, Demitrack MA, Der M et al (1992) Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. Brain 115:1249–1273

    Article  PubMed  Google Scholar 

  • Heyes MP, Saito K, Major EO, Milstien S, Markey SP, Vickers JH (1993) A mechanism of quinolinic acid formation by brain in inflammatory neurological disease. Attenuation of synthesis from l-tryptophan by 6-chlorotryptophan and 4-chloro-3-hydroxyanthranilate. Brain 116:1425–1450

    PubMed  Google Scholar 

  • Heyes MP, Achim CL, Wiley CA, Major EO, Saito K, Markey SP (1996) Human microglia convert l-tryptophan into the neurotoxin quinolinic acid. Biochem J 320:595–597

    PubMed  CAS  Google Scholar 

  • Hilmas C, Pereira EF, Alkondon M, Rassoulpour A, Schwarcz R, Albuquerque EX (2001) The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. J Neurosci 21:7463–7473

    PubMed  CAS  Google Scholar 

  • Hosoda S, Takimura H, Shibayama M, Kanamura H, Ikeda K, Kumada H (2000) Psychiatric symptoms related to interferon therapy for chronic hepatitis C: clinical features and prognosis. Psychiatry Clin Neurosci 54:565–572

    Article  PubMed  CAS  Google Scholar 

  • Irwin M, Smith TL, Gillin JC (1987) Low natural killer cytotoxicity in major depression. Life Sci 41:2127–2133

    Article  PubMed  CAS  Google Scholar 

  • Kaestner F, Hettich M, Peters M, Sibrowski W, Hetzel G, Ponath G et al (2005) Different activation patterns of proinflammatory cytokines in melancholic and non-melancholic major depression are associated with HPA axis activity. J Affect Disord 87:305–311

    Article  PubMed  CAS  Google Scholar 

  • Kim JP, Choi DW (1987) Quinolinate neurotoxicity in cortical cell culture. Neuroscience 23:423–432

    Article  PubMed  CAS  Google Scholar 

  • Kim YK, Suh IB, Kim H, Han CS, Lim CS, Choi SH et al (2002) The plasma levels of interleukin-12 in schizophrenia, major depression, and bipolar mania: effects of psychotropic drugs. Mol Psychiatry 7:1107–1114

    Article  PubMed  CAS  Google Scholar 

  • Knox WE (1951) Two mechanisms which increase in vivo the liver tryptophan peroxidase activity: specific enzyme adaptation and stimulation of the pituitary adrenal system. Br J Exp Pathol 32:462–469

    PubMed  CAS  Google Scholar 

  • Lanquillon S, Krieg JC, Bening-Abu-Shach U, Vedder H (2000) Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology 22:370–379

    Article  PubMed  CAS  Google Scholar 

  • Lapin IP, Oxenkrug GF (1969) Intensification of the central serotoninergic processes as a possible determinant of the thymoleptic effect. Lancet 1:132–136

    Article  PubMed  CAS  Google Scholar 

  • Leklem JE (1971) Quantitative aspects of tryptophan metabolism in humans and other species: a review. Am J Clin Nutr 24:659–672

    PubMed  CAS  Google Scholar 

  • Maes M (1994) Cytokines in major depression. Biol Psychiatry 36:498–499 (letter; comment)

    Article  PubMed  CAS  Google Scholar 

  • Maes M, Lambrechts J, Bosmans E, Jacobs J, Suy E, Vandervorst C et al (1992a) Evidence for a systemic immune activation during depression: results of leukocyte enumeration by flow cytometry in conjunction with monoclonal antibody staining. Psychol Med 22:45–53

    Article  PubMed  CAS  Google Scholar 

  • Maes M, Stevens W, DeClerck L, Bridts C, Peeters D, Schotte C et al (1992b) Immune disorders in depression: higher T helper/T suppressor-cytotoxic cell ratio. Acta Psychiatr Scand 86:423–431

    Article  PubMed  CAS  Google Scholar 

  • Maes M, Song C, Lin AH, Bonaccorso S, Kenis G, de Jongh R et al (1999) Negative immunoregulatory effects of antidepressants: inhibition of interferon-gamma and stimulation of interleukin-10 secretion. Neuropsychopharmacology 20:370–379

    Article  PubMed  CAS  Google Scholar 

  • Mangoni A (1974) The “kynurenine shunt” and depression. Adv Biochem Psychopharmacol 11:293–298

    PubMed  CAS  Google Scholar 

  • Mathers C, Loncar D (2005) Updated projection of global mortality and burden of disease, 2002–2030: data sources, methods and results. WHO, Geneva

    Google Scholar 

  • Mellor AL, Munn DH (1999) Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol Today 20:469–473

    Article  PubMed  CAS  Google Scholar 

  • Mikova O, Yakimova R, Bosmans E, Kenis G, Maes M (2001) Increased serum tumor necrosis factor alpha concentrations in major depression and multiple sclerosis. Eur Neuropsychopharmacol 11:203–208

    Article  PubMed  CAS  Google Scholar 

  • Miller CL, Llenos IC, Dulay JR, Barillo MM, Yolken RH, Weis S (2004) Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia. Neurobiol Dis 15:618–629

    Article  PubMed  CAS  Google Scholar 

  • Moffett JR, Namboodiri MA (2003) Tryptophan and the immune response. Immunol Cell Biol 81:247–265

    Article  PubMed  CAS  Google Scholar 

  • Moffett JR, Blinder KL, Venkateshan CN, Namboodiri MA (1998) Differential effects of kynurenine and tryptophan treatment on quinolinate immunoreactivity in rat lymphoid and non-lymphoid organs. Cell Tissue Res 293:525–534

    Article  PubMed  CAS  Google Scholar 

  • Müller N, Schwarz MJ, Dehning S, Douhet A, Cerovecki A, Goldstein-Müller B et al (2006) The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry 11:680–684

    Article  PubMed  Google Scholar 

  • Musso T, Gusella GL, Brooks A, Longo DL, Varesio L (1994) Interleukin-4 inhibits indoleamine 2,3-dioxygenase expression in human monocytes. Blood 83:1408–1411

    PubMed  CAS  Google Scholar 

  • Myint AM, Kim YK (2003) Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression. Med Hypotheses 61:519–525

    Article  PubMed  CAS  Google Scholar 

  • Myint AM, Leonard BE, Steinbusch HW, Kim YK (2005) Th1, Th2, and Th3 cytokine alterations in major depression. J Affect Disord 88:167–173

    Article  PubMed  CAS  Google Scholar 

  • Myint AM, Kim YK, Verkerk R, Scharpe S, Steinbusch H, Leonard B (2007) Kynurenine pathway in major depression: evidence of impaired neuroprotection. J Affect Disord 98:143–151

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Perkins MN, Stone TW (1982) An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res 247:184–187

    Article  PubMed  CAS  Google Scholar 

  • Pertz H, Back W (1988) Synthesis and resolution of chiral ring-opened serotonin analogs of the 5-hydroxykynuramine type. Pharm Acta Helv 63:128–131

    PubMed  CAS  Google Scholar 

  • Pocivavsek A, Wu HQ, Potter MC, Elmer GI, Pellicciari R, Schwarcz R (2011) Fluctuations in endogenous kynurenic acid control hippocampal glutamate and memory. Neuropsychopharmacology 36:2357–2367

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY et al (1999) Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry 45:1085–1098

    Article  PubMed  CAS  Google Scholar 

  • Salter M, Pogson CI (1985) 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 229:499–504

    PubMed  CAS  Google Scholar 

  • Schiepers OJ, Wichers MC, Maes M (2005) Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry 29:201–217

    Article  PubMed  CAS  Google Scholar 

  • Schwarcz R, Whetsell WO Jr, Mangano RM (1983) Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. Science 219:316–318

    Article  PubMed  CAS  Google Scholar 

  • Sluzewska A, Rybakowski JK, Laciak M, Mackiewicz A, Sobieska M, Wiktorowicz K (1995) Interleukin-6 serum levels in depressed patients before and after treatment with fluoxetine. Ann N Y Acad Sci 762:474–476

    Article  PubMed  CAS  Google Scholar 

  • Sluzewska A, Rybakowski J, Bosmans E, Sobieska M, Berghmans R, Maes M et al (1996) Indicators of immune activation in major depression. Psychiatry Res 64:161–167

    Article  PubMed  CAS  Google Scholar 

  • Smith RS (1991) The macrophage theory of depression. Med Hypotheses 35:298–306

    Article  PubMed  CAS  Google Scholar 

  • Steiner J, Bielau H, Brisch R, Danos P, Ullrich O, Mawrin C et al (2008) Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide. J Psychiatr Res 42:151–157

    Article  PubMed  Google Scholar 

  • Thomas AJ, Davis S, Morris C, Jackson E, Harrison R, O’Brien JT (2005) Increase in interleukin-1beta in late-life depression. Am J Psychiatry 162:175–177

    Article  PubMed  Google Scholar 

  • Watanabe Y, Fujiwara M, Yoshida R, Hayaishi O (1980) Stereospecificity of hepatic l-tryptophan 2,3-dioxygenase. Biochem J 189:393–405

    PubMed  CAS  Google Scholar 

  • Wichers MC, Koek GH, Robaeys G, Verkerk R, Scharpe S, Maes M (2005) IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry 10:538–544

    Article  PubMed  CAS  Google Scholar 

  • Yasui H, Takai K, Yoshida R, Hayaishi O (1986) Interferon enhances tryptophan metabolism by inducing pulmonary indoleamine 2,3-dioxygenase: its possible occurrence in cancer patients. Proc Natl Acad Sci USA 83:6622–6626

    Article  PubMed  CAS  Google Scholar 

  • Yuwiler A, Oldendorf WH, Geller E, Braun L (1977) Effect of albumin binding and amino acid competition on tryptophan uptake into brain. J Neurochem 28:1015–1023

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The work of the authors is partly funded by European Collaborative Research Project MOODINFLAME.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University, Nussbaumstr. 7, 80336, Munich, Germany

    Aye-Mu Myint, Markus J. Schwarz & Norbert Müller

Authors
  1. Aye-Mu Myint
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Markus J. Schwarz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Norbert Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Norbert Müller.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Myint, AM., Schwarz, M.J. & Müller, N. The role of the kynurenine metabolism in major depression. J Neural Transm 119, 245–251 (2012). https://doi.org/10.1007/s00702-011-0741-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-011-0741-3

Keywords

Search

Navigation