Cited by 1,530Tryptophan and brain disordersAmino Acid Enzymes and MetabolismNeuroinflammation and Neurodegeneration Mechanisms

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Kynurenines in the mammalian brain: when physiology meets pathology

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Schwarcz, Robert, Bruno, John P., Muchowski, Paul J., Wu, Hui-Qiu·2012·Nature Reviews Neuroscience

DOI 10.1038/nrn3257PMC PMC3681811

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Abstract

The essential amino acid tryptophan is not only a precursor of serotonin but is also degraded to several other neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine and quinolinic acid. The synthesis of these metabolites is regulated by an enzymatic cascade, known as the kynurenine pathway, that is tightly controlled by the immune system. Dysregulation of this pathway, resulting in hyper-or hypofunction of active metabolites, is associated with neurodegenerative and other neurological disorders, as well as with psychiatric diseases such as depression and schizophrenia. With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions.

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Modeling the Interaction between Quinolinate and the Receptor for Advanced Glycation End Products (RAGE): Relevance for Early Neuropathological Processes
Serratos, I. N., Castellanos, P., Pastor, N., Millán‐Pacheco, C., Rembao, D., Pérez‐Montfort, R., Cabrera, N., Reyes‐Espinosa, F., Díaz-Garrido, P., López-Macay, Á., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0120221 · Cited by 21
The IDO genetic polymorphisms and postpartum depressive symptoms: an association study in Chinese parturients who underwent cesarean section
Duan, K., Wang, S., Yin, J., Li, X., Ma, J., Huang, Z., Zhou, Y., Yu, H., Yang, M., Zhou, H., et al. (2018) · Archives of Women s Mental Health · doi:10.1007/s00737-018-0898-y · Cited by 21
“Moreover, KYN is able to cross the blood-brain barrier via neutral transporters, with about 60% of central KYN being peripherally derived (Gál and Sherman 1980; Schwarcz et al. 2012).”
Background
Encephalitis and aseptic meningitis: short-term and long-term outcome, quality of life and neuropsychological functioning
Quist-Paulsen, E., Ormaasen, V., Kran, A.-M. B., Dunlop, O., Ueland, P. M., Ueland, T., Eikeland, R., Aukrust, P., & Nordenmark, T. H. (2019) · Scientific Reports · doi:10.1038/s41598-019-52570-2 · Cited by 20
Chronic stress induces behavioural changes through increased kynurenic acid by downregulation of kynurenine‐3‐monooxygenase with microglial decline
Hasegawa, M., Kunisawa, K., Wulaer, B., Kubota, H., Kurahashi, H., Sakata, T., Ando, H., Fujigaki, S., Fujigaki, H., Yamamoto, Y., et al. (2024) · British Journal of Pharmacology · doi:10.1111/bph.17407 · Cited by 20
“3-Hydroxykynurenine (3-HK) is metabolised to 3-hydroxyanthranilic acid (3-HAA) by kynureninase (Schwarcz et al., 2012).”
Quinolinic acid potentially links kidney injury to brain toxicity
Saliba, A., Debnath, S., Tamayo, I. M., Lee, H. J., Ragi, N., Das, F., Montellano, R., Tůmová, J., Maddox, M., Trevino, E., et al. (2025) · JCI Insight · doi:10.1172/jci.insight.180229 · Cited by 23
“As inflammation triggers metabolism of KYN within the brain to generate oxidative and neurochemically active metabolites (22–24), we performed targeted bulk metabolomics analysis in the brain cortex of Mdm2 -cKO versus control mice, focusing on Trp metabolites.”
The Effect of Tryptophan 2,3-Dioxygenase Inhibition on Kynurenine Metabolism and Cognitive Function in the APP23 Mouse Model of Alzheimer’s Disease
Sorgdrager, F. J. H., van der Ley, C. P., van Faassen, M. H. J. R., Calus, E., Nollen, E. A. A., Kema, I. P., Dam, D. V., & Deyn, P. D. (2020) · International Journal of Tryptophan Research · doi:10.1177/1178646920972657 · Cited by 19
Effects of stress associated with academic examination on the kynurenine pathway profile in healthy students
Myint, K., Jacobs, K. R., Myint, A.-M., Lam, S. K., Henden, L., Hoe, S.-Z., & Guillemin, G. J. (2021) · PLoS ONE · doi:10.1371/journal.pone.0252668 · Cited by 22
Cytokine profile in drug-naïve panic disorder patients
Quagliato, L. A., & Nardi, A. E. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-01835-y · Cited by 20
“Tryptophan can be degraded into kynurenine by activation of these cell types, which can lead to PD symptoms by reducing the availability of the necessary precursor for serotonin synthesis, causing disruption of serotonergic neurotransmission [26].”
Background
Volumetric Absorptive Microsampling (VAMS) for Targeted LC-MS/MS Determination of Tryptophan-Related Biomarkers
Protti, M., Cirrincione, M., Mandrioli, R., Rudge, J., Regazzoni, L., Valsecchi, V., Volpi, C., & Mercolini, L. (2022) · Molecules · doi:10.3390/molecules27175652 · Cited by 21
“The KYN pathway has been implicated in the pathophysiology of several diseases including neurodegenerative disorders [1], cancer, infection [2], autoimmune disorders [3] and psychiatric disorders [4].”
Background
A kynurenine pathway enzyme aminocarboxymuconate-semialdehyde decarboxylase may be involved in treatment-resistant depression, and baseline inflammation status of patients predicts treatment response: a pilot study
Yılmaz, N. S., Şen, B., Karadag, R. F., Aslan, S., Ertek, İ. E., Bozkurt, A., Çiçek, S., Bolu, A., Ucar, H., Koçak, C., et al. (2022) · Journal of Neural Transmission · doi:10.1007/s00702-022-02553-x · Cited by 20
“HK may be metabolized to HAA with Kynu, or to XA via KAT (Schwarcz et al.”
BackgroundMethodInfluential
Kynurenine pathway dynamics in patients with schizophrenia spectrum disorders across the disease trajectory
Kuuskmäe, C., Philips, M., Kilk, K., Haring, L., Kangro, R., Seppo, I., Zilmer, M., & Vasar, E. (2023) · Psychiatry Research · doi:10.1016/j.psychres.2023.115423 · Cited by 22
A review of chromatographic methods for bioactive tryptophan metabolites, kynurenine, kynurenic acid, quinolinic acid, and others, in biological fluids
Fukushima, T., Umino, M., Sakamoto, T., & Onozato, M. (2022) · Biomedical Chromatography · doi:10.1002/bmc.5308 · Cited by 20
The crystal structure of human quinolinic acid phosphoribosyltransferase in complex with its inhibitor phthalic acid
Malik, S. S., Patterson, D. N., Ncube, Z., & Toth, E. A. (2013) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.24406 · Cited by 20
Inhibitors of the kynurenine pathway as neurotherapeutics: a patent review (2012–2015)
Zádori, D., Veres, G., Szalárdy, L., Klivènyi, P., Fülöp, F., Toldi, J., & Vécsei, L. (2016) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2016.1189531 · Cited by 21
Protein-derived cofactors: chemical innovations expanding enzyme catalysis
Graciano, A., & Liu, A. (2025) · Chemical Society Reviews · doi:10.1039/d4cs00981a · Cited by 20
Targeting the kynurenine pathway in gliomas: Insights into pathogenesis, therapeutic targets, and clinical advances
Krupa, M. M., Pienkowski, T., Tankiewicz‐Kwedlo, A., & Łysoń, T. (2025) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2025.189343 · Cited by 21
Improved LC-MS/MS method for the determination of 42 neurologically and metabolically important molecules in urine
Galla, Z., Rácz, G., Grecsó, N., Baráth, Á., Kósa, M., Bereczki, C., & Monostori, P. B. (2021) · Journal of Chromatography B · doi:10.1016/j.jchromb.2021.122846 · Cited by 19
Increasing plasma L-kynurenine impairs mitochondrial oxidative phosphorylation prior to the development of atrophy in murine skeletal muscle: A pilot study
Palzkill, V. R., Thome, T., Murillo, A., Khattri, R. B., & RYAN, T. E. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.992413 · Cited by 19
“Kynurenines have long been known to have neurobiological effects and elevated kynurenines have been linked with numerous neurological conditions (Hilmas et al., 2001; Schwarcz et al., 2012; Agudelo et al., 2014; Breda et al., 2016; Platten et al., 2019).”
Background
Pharmacological and physiological roles of adipokines and myokines in metabolic-related dementia
Arjunan, A., & Song, J. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114847 · Cited by 20
The Probiotic Lactobacillus reuteri Preferentially Synthesizes Kynurenic Acid from Kynurenine
Schwarcz, R. M., Foo, A., Sathyasaikumar, K. V., & Notarangelo, F. M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25073679 · Cited by 19
Self-citation
Elevated serum kynurenic acid in individuals with first-episode psychosis and insufficient response to antipsychotics
Hatzimanolis, A., Foteli, S., Xenaki, L., Selaković, M., Dimitrakopoulos, S., Vlachos, I. I., Kosteletos, I., Soldatos, R. F., Gazouli, M., Chatzipanagiotou, S., et al. (2024) · Schizophrenia · doi:10.1038/s41537-024-00483-z · Cited by 22
“Multiple reports have demonstrated peripheral as well as brain KP metabolite differences in individuals with schizophrenia 28,33,35,36,40,42,70 , which might be induced by immune-in ﬂ ammatory processes 24,32 .”
BackgroundInfluential
Plasma levels of IL‐1Ra are associated with schizophrenia
Zhou, Y., Peng, W., Wang, J., Zhou, W., Zhou, Y., & Ying, B. (2018) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12794 · Cited by 21
“Excessive KYNA would then bring about increased inhibition of the α7 nicotinic acetylcholine receptors (α7nAChR), subsequently causing an imbalance in glutamate, dopamine, and acetylcholine systems, all of which have been linked to SCZ pathology.(13) Altogether, these studies were in accordance with the immune/inflamm…”
Result
RETRACTED: Placental serotonin systems in pregnancy metabolic complications associated with maternal obesity and gestational diabetes mellitus
Murthi, P., & Vaillancourt, C. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2019.01.017 · Cited by 19
Retracted
Decreased kynurenine pathway potentiate resilience to social defeat effect on cocaine reward
Giménez‐Gómez, P., Ballestín, R., de Biedma‐Elduayen, L. G., Vidal, R., Perez, C. F., Reguilón, M. D., O’Shea, E., Miñarro, J., Colado, M. I., & Rodríguez‐Arias, M. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108753 · Cited by 19
HIV-associated neurocognitive disorder: key implications of the microbiota-gut-brain axis
Hu, A., Zaongo, S. D., Harypursat, V., Wang, X., Ouyang, J., & Chen, Y. (2024) · Frontiers in Microbiology · doi:10.3389/fmicb.2024.1428239 · Cited by 18
“Fluctuating levels of kynurenine pathway metabolites, including kynurenine, kynurenic acid, 3-hydroxyanthranilic acid (3-HAA), 3-hydroxykynurenine (3-HK), and the neurotoxic quinolinic acid are associated with many neurologic and psychiatric disorders (Schwarcz et al., 2012; Kennedy et al., 2017).”
Background
Microplastics Accumulation Induces Kynurenine-Derived Neurotoxicity in Cerebral Organoids and Mouse Brain
Park, S. B., Jo, J. H., Kim, S. S., Jung, W. H., Bae, M. A., Koh, B., & Kim, K. Y. (2025) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2024.185 · Cited by 20
“In an inflammatory state, the kynurenic pathway becomes more activated, leading to the production of neurotoxic molecules such as 3-HK and quinolinic acid (QA) (Guidetti et al ., 2000; Zinger et al ., 2011; Schwarcz et al ., 2012).”
Tryptophan metabolism: From physiological functions to key roles and therapeutic targets in cancer (Review)
Zhao, J., Bai, X., Du, J., Chen, Y., Guo, X., Zhang, J., Gan, J., Wu, P., Chen, S., Zhang, X., et al. (2025) · Oncology Reports · doi:10.3892/or.2025.8919 · Cited by 20
“The products of this pathway include Kyn, nicotinic acid, and nicotinamide, which ultimately enter the nicotinamide adenine dinucleotide (NAD + ) synthesis pathway to produce essential redox‑regulating molecules for cells (4).”
Structure of the PLP-Form of the Human Kynurenine Aminotransferase II in a Novel Spacegroup at 1.83 Å Resolution
Nematollahi, A., Sun, G., Harrop, S. J., Hanrahan, J. R., & Church, W. B. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17040446 · Cited by 19
Kynurenine pathway in post-mortem prefrontal cortex and cerebellum in schizophrenia: relationship with monoamines and symptomatology
Afia, A. B., Vila, È., MacDowell, K. S., Ormazábal, A., Leza, J. C., Haro, J. M., Artuch, R., Ramos, B., & García‐Bueno, B. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02260-6 · Cited by 20
3,3′-Diindolylmethane and 1,4-dihydroxy-2-naphthoic acid prevent chronic mild stress induced depressive-like behaviors in female mice
Madison, C. A., Kuempel, J., Albrecht, G. L., Hillbrick, L., Jayaraman, A., Safe, S. H., Chapkin, R. S., & Eitan, S. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.04.106 · Cited by 17
Tryptophan Challenge in Healthy Controls and People with Schizophrenia: Acute Effects on Plasma Levels of Kynurenine, Kynurenic Acid and 5-Hydroxyindoleacetic Acid
Sathyasaikumar, K. V., Notarangelo, F. M., Kelly, D. L., Rowland, L. M., Hare, S., Chen, S., Chen, M., Buchanan, R. W., & Schwarcz, R. M. (2022) · Pharmaceuticals · doi:10.3390/ph15081003 · Cited by 18
“Future studies should explore possible abnormal consequences of increased kynurenine levels with respect to AhR function [35] and of elevated levels of neuroactive kynurenine metabolites other than KYNA [12] in the brain of persons with SZ.”
BackgroundSelf-citation
A Novel Aryl Hydrocarbon Receptor Antagonist HBU651 Ameliorates Peripheral and Hypothalamic Inflammation in High-Fat Diet-Induced Obese Mice
Kang, S., Lee, A. G., Im, S., Oh, S. J., Yoon, H. J., Park, J. H., & Pak, Y. K. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232314871 · Cited by 18
“Indeed, AhR is abundantly expressed in lung, liver [38], various brain regions [37,39], and barrier tissues, such as the skin, lungs, gut, and mucosa [40].”
Background
Alpha‐Asarone modulates kynurenine disposal in muscle and mediates resilience to stress‐induced depression via PGC ‐1α induction
Yan, A. L., Liu, C., Xu, S. L., Qian, Y., Song, P., Wei, M., & Liu, B. (2022) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14030 · Cited by 17
Towards a multilevel model of major depression: genes, immuno-metabolic function, and cortico-striatal signaling
Paul, E. R., Östman, L., Heilig, M. A., Mayberg, H. S., & Hamilton, J. P. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02466-7 · Cited by 17
“Pro-inflammatory cytokines, such as interferon-gamma, activate IDO1 and TDO2 [46], reducing the bioavailability of tryptophan to convert to serotonin.”
BackgroundInfluential
Therapeutic modulation of the kynurenine pathway in severe mental illness and comorbidities: A potential role for serotonergic psychedelics
Campanale, A., Inserra, A., & Comai, S. (2024) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2024.111058 · Cited by 19
“While kynurenine (KYN) can cross the blood-brain barrier (BBB) through the large neutral amino acid transporter (LAT1) (Fukui et al., 1991), KYNA and QA normally do not cross the BBB significantly (Savitz, 2020; Schwarcz et al., 2012).”
BackgroundInfluential
The Genetic Link between Parkinson’s Disease and the Kynurenine Pathway Is Still Missing
Török, N., Maszlag-Török, R., Szolnoki, Z., Somogyvári, F., Klivènyi, P., & Vécsei, L. (2015) · Parkinson s Disease · doi:10.1155/2015/474135 · Cited by 18
Decreased levels of kynurenic acid in prefrontal cortex in a genetic animal model of depression
Liu, X.-C., Erhardt, S., Goiny, M., Engberg, G., & Mathé, A. A. (2016) · Acta Neuropsychiatrica · doi:10.1017/neu.2016.31 · Cited by 18
Astroglia, Glutamatergic Transmission and Psychiatric Diseases
Verkhratsky, A., Steardo, L., Peng, L., & Parpura, V. (2016) · Advances in neurobiology · doi:10.1007/978-3-319-45096-4_12 · Cited by 18
Postpartum fluoxetine increased maternal inflammatory signalling and decreased tryptophan metabolism: Clues for efficacy
Qiu, W., Duarte‐Guterman, P., Eid, R. S., Go, K. A., Lamers, Y., & Galea, L. A. M. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108174 · Cited by 18
3-Hydroxykynurenine in Regulation of Drosophila Behavior: The Novel Mechanisms for Cardinal Phenotype Manifestations
Zhuravlev, A. V., Vetrovoy, O. V., Ivanova, P. N., & Savvateeva-Popova, E. V. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00971 · Cited by 18
“The imbalance of kynurenines in nervous system has been observed during neurodegenerative disorders, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases (Schwarcz et al., 2012).”
Background
Kynurenine Metabolism in the Fat Body Non-autonomously Regulates Imaginal Disc Repair in Drosophila
Kashio, S., & Miura, M. (2020) · iScience · doi:10.1016/j.isci.2020.101738 · Cited by 16

Authors: Schwarcz, R., Bruno, J. P., Muchowski, P. J., & Wu, H.-Q.
Affiliations: University of Maryland, Baltimore (US)
The Ohio State University (US)
University of California, San Francisco (US)
Corresponding author: Schwarcz, Robert
ORCID: Schwarcz, Robert
Bruno, John P.
Wu, Hui-Qiu
Venue: Nature Reviews Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2012-06-08
Volume: 13
Issue: 7
Pages: 465-477
ISSN: 1471-003X (ISSN-L)
1471-0048
DOI: 10.1038/nrn3257
PMC: PMC3681811
OpenAlex: W2060050678
Cited by: 1,530
References: 215
Citations by year: 2026: 157 · 2025: 137 · 2024: 124 · 2023: 98 · 2022: 118 · 2021: 145 · 2020: 132 · 2019: 95 · 2018: 83 · 2017: 96 · 2016: 98 · 2015: 105 · 2014: 64 · 2013: 63 · 2012: 13
FWCI: 5.11
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.springer.com/tdm (tdm)
Locations: Nature reviews. Neuroscience (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute of Mental Health (R01MH083729)
National Institute of Neurological Disorders and Stroke (R01NS057715)
Topics: Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: kynurenine pathway, tryptophan metabolism, kynurenic acid, 3-hydroxykynurenine, quinolinic acid, neuroactive metabolites, neurodegenerative diseases, depression, schizophrenia, therapeutic targeting
MeSH terms: Animals, Brain, Humans, Kynurenine, Nervous System Diseases, Signal Transduction

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Kynurenines in the mammalian brain: when physiology meets pathology

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