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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Method
Is the Enzyme ACMSD a Novel Therapeutic Target in Parkinson’s Disease?
Rajamani, K. T., Li, P., Galvis, M. L. E., Labrie, V., Brundin, P., & Brundin, L. (2017) · Journal of Parkinson s Disease · doi:10.3233/jpd-171240 · Cited by 36
“Picolinic acid is a stable end-product formed from AMS that is not further metabo- lized.”
Background
Targeting tryptophan catabolic kynurenine pathway enhances antitumor immunity and cytotoxicity in multiple myeloma
Ray, A., Song, Y. Y., Du, T., Tai, Y., Chauhan, D., & Anderson, K. C. (2019) · Leukemia · doi:10.1038/s41375-019-0558-x · Cited by 35
Autism and Migraine: An Unexplored Association?
Vetri, L. (2020) · Brain Sciences · doi:10.3390/brainsci10090615 · Cited by 38
“Both systemic and central proinflammatory immune stimuli contribute to the activation of the cerebral kynurenine pathway that was involved in several neurological disorders [63].”
Background
Importance of the dysregulation of the kynurenine pathway on cognition in schizophrenia: a systematic review of clinical studies
Sapienza, J., Spangaro, M., Guillemin, G. J., Comai, S., & Bosia, M. (2022) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-022-01519-0 · Cited by 35
Biomarkers in the cerebrospinal fluid of patients with psychotic disorders compared to healthy controls: a systematic review and meta-analysis
Rømer, T. B., Jeppesen, R., Christensen, R. H. B., & Benros, M. E. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02059-2 · Cited by 33
Levels in neurotransmitter precursor amino acids correlate with mental health in patients with breast cancer
Hüfner, K., Oberguggenberger, A., Kohl, C. A., Geisler, S. B., Gamper, E., Meraner, V., Egeter, J., Hubalek, M., Beer, B., Fuchs, D., et al. (2015) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2015.06.001 · Cited by 34
Neuropeptide Y administration reverses tricyclic antidepressant treatment-resistant depression induced by ACTH in mice
Antunes, M. S., Ruff, J. R., Janner, D. E., Piêgas, M. B., de Brito, M. L. O., Rocha, K. M. A., de Gomes, M. G., Goes, A. T. R., Souza, L. C., Donato, F., et al. (2015) · Hormones and Behavior · doi:10.1016/j.yhbeh.2015.05.018 · Cited by 34
Effect of VGLUT inhibitors on glutamatergic synaptic transmission in the rodent hippocampus and prefrontal cortex
Neale, S. A., Copeland, C. S., & Salt, T. E. (2013) · Neurochemistry International · doi:10.1016/j.neuint.2013.10.001 · Cited by 35
Effect of Psychobiotics on Psychometric Tests and Inflammatory Markers in Major Depressive Disorder: Meta-Analysis of Randomized Controlled Trials with Meta-Regression
Misera, A., Liśkiewicz, P., Łoniewski, I., Skonieczna-Żydecka, K., & Samochowiec, J. (2021) · Pharmaceuticals · doi:10.3390/ph14100952 · Cited by 34
“Some kynurenine catabolites may have a role in patients with MDD due to its neurotoxic and neurodegenerative effects [40].”
Background
Correlations between kynurenines in plasma and CSF, and their relation to markers of Alzheimer's disease pathology
Bakker, L., Köhler, S., Eussen, S. J. P. M., Choe, K., van den Hove, D. L. A., Kenis, G., Rutten, B. P. F., Ulvik, A., Ueland, P. M., Verhey, F. R. J., et al. (2023) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2023.04.015 · Cited by 37
Maternal high-fat diet-induced microbiota changes are associated with alterations in embryonic brain metabolites and adolescent behaviour
Ratsika, A., Codagnone, M. G., Bastiaanssen, T. F. S., Sardá, F. A. H., Lynch, C. M. K., Ventura‐Silva, A. P., Rosell‐Cardona, C., Caputi, V., Stanton, C., Fülling, C., et al. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.07.020 · Cited by 36
“Upregulation of the kynurenine pathway in the brain is linked to increased neuronal excitotoxicity, cognitive decline, and neurodegenerative disorders (Gheorghe et al., 2019; O ’ Mahony et al., 2015; Potter et al., 2010; Schwarcz et al., 2012).”
Background
Role of Probiotics in Depression: Connecting Dots of Gut-Brain-Axis Through Hypothalamic-Pituitary Adrenal Axis and Tryptophan/Kynurenic Pathway involving Indoleamine-2,3-dioxygenase
Tiwari, S., & Paramanik, V. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-04708-9 · Cited by 37
Structural Insights into the Quaternary Catalytic Mechanism of Hexameric Human Quinolinate Phosphoribosyltransferase, a Key Enzyme in de novo NAD Biosynthesis
Youn, H., Kim, T., Kim, M., Kang, G. B., Kang, J. Y., Lee, J., An, J. Y., Park, K. R., Lee, Y. J., Im, Y. J., et al. (2016) · Scientific Reports · doi:10.1038/srep19681 · Cited by 34
Involvement of Host Defense Mechanisms against Toxoplasma gondii Infection in Anhedonic and Despair-Like Behaviors in Mice
Mahmoud, M. E., Fereig, R. M., & Nishikawa, Y. (2017) · Infection and Immunity · doi:10.1128/iai.00007-17 · Cited by 35
Structural Basis for Inhibitor-Induced Hydrogen Peroxide Production by Kynurenine 3-Monooxygenase
Kim, H. T., Na, B. K., Chung, J., Kim, S., Kwon, S. K., Cha, H., Son, J., Cho, J. M., & Hwang, K. Y. (2018) · Cell chemical biology · doi:10.1016/j.chembiol.2018.01.008 · Cited by 36
Untargeted 1H NMR-Based Metabolomics Analysis of Urine and Serum Profiles after Consumption of Lentils, Chickpeas, and Beans: An Extended Meal Study To Discover Dietary Biomarkers of Pulses
Madrid-Gambín, F., Brunius, C. F., Garcia‐Aloy, M., Estruel‐Amades, S., Landberg, R., & Andrés‐Lacueva, C. (2018) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.8b00047 · Cited by 35
Linking phencyclidine intoxication to the tryptophan‐kynurenine pathway: Therapeutic implications for schizophrenia
Fujigaki, H., Mouri, A., Yamamoto, Y., Nabeshima, T., & Saito, K. (2019) · Neurochemistry International · doi:10.1016/j.neuint.2019.02.001 · Cited by 29
“PCP was initially used as a surgical anesthetic, but due to its side effects (e.g., post-operative psychosis, severe anxiety, and dysphoria), its use in clinical studies was discontinued in 1965, and PCP https://doi.org/10.1016/j.neuint.2019.02.001 Received 31 October 2018; Received in revised form 17 January 2019; Ac…”
Influential
The ‘Yin’ and the ‘Yang’ of the kynurenine pathway: excitotoxicity and neuroprotection imbalance in stress-induced disorders
Barone, P. R. (2019) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000477 · Cited by 37
“…in mice (Parikh et al., 2010), and KYNA would exert its antiglutamatergic action mainly by its antagonistic effect on α7-nAChRs (see Albuquerque and Schwarcz, 2012; Wu et al., 2014 for critical reviews), as shown in unanesthetized rats (Wu et al., 2010), and by a direct antagonist effect on the…”
Background
Mood‐Stabilizing Antiepileptic Treatment Response in Bipolar Disorder: A Genome‐Wide Association Study
Ho, A. M., Coombes, B. J., Nguyen, T. T. L., Liu, D., McElroy, S. L., Singh, B., Nassan, M. M., Colby, C. L., Larrabee, B. R., Weinshilboum, R. M., et al. (2020) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1982 · Cited by 34
“Furthermore, SNPs in THSD7A have also been reported to be associated with plasma concentrations of kynurenine(31) and kynurenic acid,(32) two metabolites known to influence glutamatergic neurotransmission.(33) Finally, THSD7A protein expression has been shown to be altered in responders to antipsychotic drug therapy.”
Background
Basal myokine levels are associated with quality of life and depressed mood in older adults
Mucher, P., Batmyagmar, D., Perkmann, T., Repl, M., Radakovics, A., Ponocny‐Seliger, E., Lukas, I., Fritzer‐Szekeres, M., Lehrner, J. P., Knogler, T., et al. (2021) · Psychophysiology · doi:10.1111/psyp.13799 · Cited by 34
“The conversion to kynurenic acid prevents the molecule from crossing the blood- brain barrier (Schwarcz et al., 2012).”
Background
Kynurenine‐3‐monooxygenase (KMO): From its biological functions to therapeutic effect in diseases progression
Chen, Y., Zhang, J., Yang, Y., Xiang, K., Li, H., Sun, D., & Chen, L. (2022) · Journal of Cellular Physiology · doi:10.1002/jcp.30876 · Cited by 36
The Prevention and Treatment of Delirium in Elderly Patients Following Hip Fracture Surgery
Martocchia, A., Curto, M., Comite, F., Scaccianoce, S., Girardi, P., Ferracuti, S., Nicoletti, F., Falaschi, P., & Bentham Science Publisher Orthogeriatric Group (2015) · Recent Patents on CNS Drug Discovery · doi:10.2174/1574889810666150216152624 · Cited by 37
Existing and Future Strategies to Manipulate the Gut Microbiota With Diet as a Potential Adjuvant Treatment for Psychiatric Disorders
Ross, F. C., Mayer, D. E., Gupta, A., Gill, C. I. R., Rio, D. D., Cryan, J. F., Lavelle, A., Ross, R. P., Stanton, C., & Mayer, E. A. (2023) · Biological Psychiatry · doi:10.1016/j.biopsych.2023.10.018 · Cited by 35
CD40-TNF activation in mice induces extended sickness behavior syndrome co-incident with but not dependent on activation of the kynurenine pathway
Cathomas, F., Fuertig, R., Sigrist, H., Newman, G. N., Hoop, V., Bizzozzero, M. R., Mueller, A., Luippold, A. H., Ceci, A., Hengerer, B., et al. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.06.184 · Cited by 33
Peripheral kynurenine-3-monooxygenase deficiency as a potential risk factor for metabolic syndrome in schizophrenia patients
Oxenkrug, G. F., van der Hart, M., Roeser, J., & D, P. S. M. (2017) · Integrative Clinical Medicine · doi:10.15761/icm.1000105 · Cited by 33
Targeted metabolome profiling by dual-probe microdialysis sampling and treatment using Gardenia jasminoides for rats with type 2 diabetes
Wang, L., Pi, Z., Liu, S., Liu, Z., & Song, F. (2017) · Scientific Reports · doi:10.1038/s41598-017-10172-w · Cited by 33
Psychosocial stress and inflammation driving tryptophan breakdown in children and adolescents: A cross-sectional analysis of two cohorts
Michels, N., Clarke, G. A., Olavarría‐Ramírez, L., Gómez‐Martínez, S., Díaz, L. E., Marcos, A., Widhalm, K., & Carvalho, L. A. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.05.013 · Cited by 34
Differential effects on blood and cerebrospinal fluid immune protein markers and kynurenine pathway metabolites from aerobic physical exercise in healthy subjects
Isung, J., Granqvist, M., Trepci, A., Huang, J., Schwieler, L., Kierkegaard, M., Erhardt, S., Jokinen, J., & Piehl, F. (2021) · Scientific Reports · doi:10.1038/s41598-021-81306-4 · Cited by 33
Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial
Millischer, V., Heinzl, M. W., Faka, A., Resl, M., Trepci, A., Klammer, C., Egger, M., Dieplinger, B., Clodi, M., & Schwieler, L. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02196-x · Cited by 36
“1) and thereby induces tryptophan degradation [16].”
Effects of Various Kynurenine Metabolites on Respiratory Parameters of Rat Brain, Liver and Heart Mitochondria
Baran, H., Staniek, K., Bertignol-Spörr, M., Attam, M., Kronsteiner, C., & Kepplinger, B. (2016) · International Journal of Tryptophan Research · doi:10.4137/ijtr.s37973 · Cited by 33
IUPHAR review: Microbiota-gut-brain axis and its role in neuropsychiatric disorders
Lee, S.-H., Han, C., & Shin, C. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107749 · Cited by 38
Quantitative analysis of phenylalanine, tyrosine, tryptophan and kynurenine in rat model for tauopathies by ultra-high performance liquid chromatography with fluorescence and mass spectrometry detection
Galba, J., Michalicová, A., Parrák, V., Novák, M., & Kováč, A. (2015) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2015.08.026 · Cited by 34
Changes in brain kynurenine levels via gut microbiota and gut‐barrier disruption induced by chronic ethanol exposure in mice
Giménez‐Gómez, P., Pérez‐Hernández, M., O’Shea, E., Caso, J. R., Martín‐Hernández, D., Alou, L., Gómez-Lus, M. L., Gutiérrez‐López, M. D., & Colado, M. I. (2019) · The FASEB Journal · doi:10.1096/fj.201900491rr · Cited by 34
“In recent years dysregulation of the Kyn pathway has been linked to neurodegenerative, psychiatric, and neurologic disorders (8, 9).”
Background
Kynurenines and the Endocannabinoid System in Schizophrenia: Common Points and Potential Interactions
Zádor, F., Nagy-Grócz, G., Kékesi, G., Dvorácskó, S., Szűcs, E., Tömböly, C., Horváth, G., Benyhe, S., & Vécsei, L. (2019) · Molecules · doi:10.3390/molecules24203709 · Cited by 33
“The KYNA hypothesis of schizophrenia has been studied and reviewed previously by numerous authors [2,4,26,54,55].”
Background
Immune-Kynurenine Pathways and the Gut Microbiota-Brain Axis in Anxiety Disorders
Evrensel, A., Ünsalver, B. Ö., & Ceylan, M. E. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-981-32-9705-0_10 · Cited by 35
Prenatal THC exposure raises kynurenic acid levels in the prefrontal cortex of adult rats
Beggiato, S., Ieraci, A., Tomasini, M. C., Schwarcz, R. M., & Ferraro, L. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.109883 · Cited by 32
“In spite of the fact that both THC and KYNA affect major neurotransmitters including glutamate, acetylcholine and dopamine, and can influence learning, memory and other cognitive functions in adult rodents (Zou and Kumar, 2018; Schwarcz et al., 2012), only very few studies have so far shown mutual interactions between…”
BackgroundSelf-citation
Thymoquinone Loaded Solid Lipid Nanoparticles Demonstrated Antidepressant-Like Activity in Rats via Indoleamine 2, 3- Dioxygenase Pathway
Alam, M. M., Zameer, S., Najmi, A. K., Ahmad, F. J., Imam, S. S., & Akhtar, M. (2020) · Drug Research · doi:10.1055/a-1131-7793 · Cited by 32
Bidirectional communication between mast cells and the gut-brain axis in neurodegenerative diseases: Avenues for therapeutic intervention
Bhuiyan, P., Chen, Y., Karim, M., Dong, H., & Qian, Y. (2021) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2021.04.010 · Cited by 33
Toward a neuroprotective shift: Eight weeks of high intensity interval training reduces the neurotoxic kynurenine activity concurrently to impulsivity in emotionally impulsive humans – A randomized controlled trial
Javelle, F., Bloch, W., Knoop, A., Guillemin, G. J., & Zimmer, P. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.04.020 · Cited by 35

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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