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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“Other examples of systems involved in anxiety with the potential for measurement of blood or CSFbased biomarkers include the kynurenine system (Schwarcz et al., 2012), serine racemase system (Basu et al., 2009) and neuropeptides such as orexin (Flores et al., 2015).”
Background
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“KYN can be further metabolized along different pathways, into either kynurenic acid (KYNA) or quinolinic acid (QUINO) and ultimately into oxidized nicotinamide-adenine-dinucleotideþ (Schwarcz et al., 2012), which induce opposite effects.”
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Background
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Background
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Mingoti, M. E. D., Bertollo, A. G., de Oliveira, T., & Ignácio, Z. M. (2023) · Advances in experimental medicine and biology · doi:10.1007/978-981-19-7376-5_8 · Cited by 12
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“, (Raison et al., 2010; Schwarcz et al., 2012) however the kynurenine pathway timeline in the periphery does not necessarily coincide with the kynurenine pathway timeline in the brain (Kindler et al.”
Background
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“Activated microglia and macrophages are producing a spectrum of kynurenines, including quinolinic acid (QA), which is an N -methyl- D -aspartate (NMDA) receptor agonist and a pro-oxidant [15].”
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“15 High-calorie diet (HCD) has been shown to disrupt tryptophan metabolism, which contributes to inflammation, increased excitatory neurotransmission 16–19 and leads to impaired mitochondrial function and fat accumulation in the liver.”
Background
Repeated Administration of D-Amphetamine Induces Distinct Alterations in Behavior and Metabolite Levels in 129Sv and Bl6 Mouse Strains
Vanaveski, T., Narvik, J., Innos, J., Philips, M., Ottas, A., Plaas, M., Haring, L., Zilmer, M., & Vasar, E. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00399 · Cited by 12
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Effect of Kynurenic Acid on Pupae Viability of Drosophila melanogaster cinnabar and cardinal Eye Color Mutants with Altered Tryptophan-Kynurenine Metabolism
Navrotskaya, V., Wnorowski, A., Turski, W. A., & Oxenkrug, G. F. (2018) · Neurotoxicity Research · doi:10.1007/s12640-018-9891-5 · Cited by 12
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Plasma Anthranilic Acid and Leptin Levels Predict HAM-D Scores in Depressed Women
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“QUIN is eventually converted to nicotine adenine dinucleotide (NAD) [8,15].”
Background
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“Abbreviations: 3-HK 3-hydroxykynurenine, AA anthranilic acid, AD Alzheimer’s disease, CU cognitively unimpaired, KA kynurenic acid, Kyn kynurenine, Pic picolinic acid, Trp trypthophan, QA quinolinic acid [5, 12, 49], possibly modified by APOE ε4 genotype [50].”
Background
The effect of Vagus nerve stimulation ( VNS ) on seizure control, cognitive function, and quality of life in individuals with drug‐resistant epilepsy: A systematic review article
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“Dysregulation of Kyn and its downstream metabolites, which leads to an imbalance in Kyn metabolite levels in the brain, has been associated with neurodegenerative conditions and psychological disorders, including schizophrenia and depression [56].”
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“78 In contrast, the oxidative branch of the pathway resulting in the formation of 3HK and QUIN is predominantly active in microglia and is associated with oxidative damage due to interaction with iron (Fe II), 79 which promotes the generation of ROS and reactive nitrogen species.”
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“ACMS is rapidly converted to quinolinic acid (QA) by the non-enzymatic reaction or to 2-aminomuconic semialdehyde (AMS) [17].”
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“…positive results in other related parameters in this study [59]: an improvement in cognitive functions along with a decreased kynurenine concentration and an increase in 3-hydroxy-kynurenine to kynurenine ratio, which could be considered contributing factors to cognitive improvement [63,95].”
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“In contrast, individuals with a low KAT activity can activate alternative anti-inflammatory pathways through moderate-intensity continuous exercise (MICE) [52].”
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Kynurenine pathway metabolites and therapeutic response to olanzapine in female patients with schizophrenia: A longitudinal study
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Seasonal Changes in Serum Metabolites in Multiple Sclerosis Relapse
Martynova, E. V., Хайбуллин, Т. И., Salafutdinov, I. I., Markelova, M., Laikov, A. V., Lopukhov, L. V., Liu, R., Sahay, K., Goyal, M., Baranwal, M., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043542 · Cited by 14
“We also demonstrated seasonal changes in serum level of L-Kynurenine and quinolinic acid, tryptophan metabolism products [82].”
Background
Glial-Neuronal Interaction in Synapses: A Possible Mechanism of the Pathophysiology of Bipolar Disorder
Wartchow, K. M., Scaini, G., & Quevedo, J. (2023) · Advances in experimental medicine and biology · doi:10.1007/978-981-19-7376-5_9 · Cited by 12
The association between inflammation and kynurenine pathway metabolites in electroconvulsive therapy for schizophrenia: Implications for clinical efficacy
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Cerebrospinal fluid monoamine metabolite concentrations as intermediate phenotypes between glutamate-related genes and psychosis
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Animal Models for Depression Associated with HIV-1 Infection
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New prospects for antipsychotic treatment - the role of the kynurenine pathway
Karakuła‐Juchnowicz, H., Flis, M., Szymona, K., Kuczyńska, M., Stelmach, E., & Kowal-Popczak, A. (2014) · Psychiatria Polska · doi:10.12740/pp/25520 · Cited by 11
Polymorphism of Kynurenine Pathway-Related Genes, Kynurenic Acid, and Psychopathological Symptoms in HIV
Douet, V., Tanizaki, N., Franke, A. A., Li, X., & Chang, L. (2016) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-016-9668-7 · Cited by 11
Effect of Kynurenic Acid on Development and Aging in Wild Type and Vermilion Mutants of Drosophila Melanogaster
Navrotskaya, V., & Oxenkrug, G. F. (2016) · Pharmacology Drug Development & Therapeutics · doi:10.15761/pddt.1000104 · Cited by 11
C-reactive protein is associated with severity of thought and language dysfunction in patients with schizophrenia
Chang, C.-H., Lane, H., Liu, C., Cheng, P.-C., Chen, S.-J., & Lin, C. (2019) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s223278 · Cited by 11
Use of Nutraceutical Ingredient Combinations in the Management of Tension-Type Headaches with or without Sleep Disorders
Curatolo, P., & Moavero, R. (2021) · Nutrients · doi:10.3390/nu13051631 · Cited by 6
“tive molecules, which act as antagonists of NMDA (N-methyl-D-aspartate) receptors [38].”
Background
The mechanism of the neuroprotective effect of zinc against cadmium-induced behavioral impairments in male Wister rats: Focus on tryptophan degradation pathway, oxidative-inflammatory stress, and histologic evidence
Ebokaiwe, A. P., Ushang, O. R., Chimezie, I. P., & Nvene, C. (2022) · Toxicology · doi:10.1016/j.tox.2022.153191 · Cited by 11
Kynurenic Acid Induces Impairment of Oligodendrocyte Viability: On the Role of Glutamatergic Mechanisms
Langner, E., Lemieszek, M. K., Kwiecień, J. M., Rajtar, G., Rzeski, W., & Turski, W. A. (2016) · Neurochemical Research · doi:10.1007/s11064-016-2009-7 · Cited by 11
Comprehensive behavioral analysis of indoleamine 2,3‐dioxygenase knockout mice
Hirata, N., Hattori, S., Shoji, H., Funakoshi, H., & Miyakawa, T. (2018) · Neuropsychopharmacology Reports · doi:10.1002/npr2.12019 · Cited by 10
“2018;38:133–144. wileyonlinelibrary.com/journal/nppr | 133 3-hydroxykynurenie,3 kynurenic acid (KYNA),4–6 and quinolinic acid (QUIN).7,8 Generally, more than 95% of dietary, Trp is metabolized along the KP to produce neuroactive KYNA and QUIN, and only a small amount of it is converted to serotonin.9 Dysfunction of th…”
BackgroundInfluential
Kynurenic Acid Protects Against Reactive Glial-associated Reductions in the Complexity of Primary Cortical Neurons
O’Reilly, K., O’Farrell, K., Midttun, Ø., Rakovets, Y., David‐Bercholz, J., & Harkin, A. (2021) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-020-09976-x · Cited by 12
The histone deacetylases Rpd3 and Hst1 antagonistically regulate de novo NAD+ metabolism in the budding yeast Saccharomyces cerevisiae
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“For instance, intermediates of de novo metabolism have been associated with both beneficial and adverse influences on neurological health (16, 46, 47) and have also been shown to interact with immune signaling (16, 46–49).”
Background
Kynureninase Promotes Immunosuppression and Predicts Survival in Glioma Patients: In Silico Data Analyses of the Chinese Glioma Genome Atlas (CGGA) and of the Cancer Genome Atlas (TCGA)
de la Cruz, G. P., de la Cruz, V. P., Cossio, J. Á. N., Cervantes, G. I. V., Salazar, A., Orozco‐Morales, M., & Pineda, B. (2023) · Pharmaceuticals · doi:10.3390/ph16030369 · Cited by 10
The association between 5-HT1A binding and temporal lobe epilepsy: A meta-analysis of molecular imaging studies
Cai, L., Xu, Z., Luo, H., He, Q., Diao, L., Gui, X., & Wei, L. (2023) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2023.109354 · Cited by 10
Benzo[a]pyrene exposure induces anxiety-like behaviors in the mice through brain metabolic alterations
Li, F., Xie, L., Xiao, Q., Li, J., Zhong, H., Xu, X., Tu, J., & Luo, Q. (2024) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2024.176215 · Cited by 11
A comparative study on the antioxidant and antiglycation properties of different vitamin D forms
Pawlukianiec, C., Lauko, K. K., Michalak, D., Żendzian‐Piotrowska, M., Zalewska, A., & Maciejczyk, M. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.117263 · Cited by 11
Peripheral tryptophan-kynurenine pathway dysfunction in first-episode schizophrenia
Li, M., Wu, Y., Xu, Y., Huang, X., Gao, K., Hu, N., Zhu, S., Wang, C., & Liang, S. (2025) · Scientific Reports · doi:10.1038/s41598-025-86390-4 · Cited by 13
Gut Microbial Control of Neurotransmitters and Their Relation to Neurological Disorders: A Comprehensive Review
Gurow, K., Joshi, D. C., Gwasikoti, J., & Joshi, N. (2025) · Hormone and Metabolic Research · doi:10.1055/a-2536-1421 · Cited by 12
“There are numerous associations between changes in this system and disease [20].”
The anti-inflammation pharmacodynamics of lithium: Therapy of bipolar disorder
Zhou, Y., Zheng, W., Guo, F., Wu, S., & Zhong, C. (2025) · Journal of Psychopharmacology · doi:10.1177/02698811251326942 · Cited by 11
Identification of candidate genes and SNPs associated with growth traits by genome-wide association study (GWAS) in sea cucumber (Apostichopus japonicus)
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Kynurenine pathway dysregulation in cognitive impairment and dementia: a systematic review and meta-analysis
Choe, K., Bakker, L., van den Hove, D., Eussen, S. J. P. M., Kenis, G., Ramakers, I. H. G. B., Verhey, F. R. J., Rutten, B. P. F., & Köhler, S. (2025) · GeroScience · doi:10.1007/s11357-025-01636-3 · Cited by 12
“This suggests that during (neuro)inflammation, astrocytes may upregulate the production of KA to mitigate neurotoxicity [148].”
Histone deacetylase SIRT6 regulates tryptophan catabolism and prevents metabolite imbalance associated with neurodegeneration
Kaluski-Kopatch, S., Stein, D., García-Venzor, A., Campos, A. M. F., Planque, M., Goldstein, B., Allende-Becerra, E. D., Smirnov, D., Zaretsky, A., Eremenko, E., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-67021-y · Cited by 12
“Nosigni ﬁ cantchangeswereobservedintheexpressionlevels of Kynurenine aminotransferase ( Kyat ) family including Aadat , which predominantly express in the brain 60,61 , Got , Ccbl1 , and Ccbl2 (Fig.”
Effects of l-tryptophan on l-DOPA-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque model of Parkinson's disease
Ko, W. K. D., Li, Q., & Bézard, E. (2014) · Neuroscience Letters · doi:10.1016/j.neulet.2014.02.027 · Cited by 10
Psychological Stresses in Children Trigger Cytokine- and Kynurenine Metabolite-Mediated Abdominal Pain and Proinflammatory Changes
Myint, K., Jacobs, K. R., Myint, A.-M., Lam, S. K., Lim, Y. A. L., Boey, C. C. M., Hoe, S.-Z., & Guillemin, G. J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.702301 · Cited by 10
Distinct Lipidomic Signatures in People Living With HIV: Combined Analysis of ACTG 5260s and MACS/WIHS
Jao, J. K., Balmert, L. C., Sun, S., McComsey, G. A., Brown, T. T., Tien, P. C., Currier, J. S., Stein, J. H., Qiu, Y., LeRoith, D., et al. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab663 · Cited by 11
Differential Levels of Tryptophan–Kynurenine Pathway Metabolites in the Hippocampus, Anterior Temporal Lobe, and Neocortex in an Animal Model of Temporal Lobe Epilepsy
Dey, S., Dubey, V., Dixit, A. B., Tripathi, M., Chandra, P. S., & Banerjee, J. (2022) · Cells · doi:10.3390/cells11223560 · Cited by 10
“The increased IDO activity is an Indication of an abnormal tryptophan–kynurenine pathway and an imbalance between kynurenic acid and quinolinic acid, documented in various neurological disorders [3].”
Background
Folic Acid and Vitamin B12 Prevent Deleterious Effects of Rotenone on Object Novelty Recognition Memory and Kynu Expression in an Animal Model of Parkinson’s Disease
Kretzschmar, G. C., Targa, A., Soares‐Lima, S. C., dos Santos, P. I., Rodrigues, L. S., Macedo, D. A., Pinto, L. F. R., Lima, M. M. S., & Boldt, A. B. W. (2022) · Genes · doi:10.3390/genes13122397 · Cited by 10
“Within the KP, KYN results from the tryptophan metabolism [52], and KYNU is one of the enzymes responsible for KYN and 3-hydroxykynurenine (3-HK) processing.”
The kynurenine pathway in traumatic brain injuries and concussion
Dehhaghi, M., Heng, B., & Guillemin, G. J. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1210453 · Cited by 10
“Among KP metabolites, KYNA and QUIN due to their polar properties and lack of transportation systems cannot cross the blood-brain barrier (BBB), while other KP metabolites cross the BBB through active transportation and passive diffusion (36, 37).”
Background
The Efficacy of Chaihu-Guizhi-Ganjiang Decoction on Chronic Non-Atrophic Gastritis with Gallbladder Heat and Spleen Cold Syndrome and Its Metabolomic Analysis: An Observational Controlled Before-After Clinical Trial
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“41,42 Thus, two metabolic hypotheses were predicted for CGGD treatment: (1) the level of kynurenine transported across the BBB was decreased, and(2) the level of tryptophan in the brain converted into kynurenine was decreased.”
Background
Anthranilic Acid, a GPR109A Agonist, and Schizophrenia
Oxenkrug, G. F., & Forester, B. P. (2024) · International Journal of Tryptophan Research · doi:10.1177/11786469241239125 · Cited by 13
Role of Kynurenine Pathway in Insulin Resistance: Toward Kynurenine Hypothesis of Insulin Resistance and Diabetes
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Overview of the Kynurenine Pathway of Tryptophan Metabolism
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Effect of quinolinic acid – A uremic toxin from tryptophan metabolism – On hemostatic profile in rat and mouse thrombosis models
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“At the same time, tryptophan is degraded by kynurenine transformations, which generates a number of intermediate metabolites with high biological activity with regard to glutamatergic receptors, such as kynurenine, quinolinic acid and kynurenic acid [26].”
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Multisensory Integration in Caenorhabditis elegans in Comparison to Mammals
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Role of Inflammation in Psychiatric Disease
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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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