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

The DOI matches its Crossref record; 213 of the 215 references it cites were found in a registry or an index.

Kynurenines in the mammalian brain: when physiology meets pathology

Open access

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

DOI 10.1038/nrn3257PMC PMC3681811

Open this paper in CoChat — free account

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1038/nrn3257

Cites

213 of 213 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans: Psychotomimetic, Perceptual, Cognitive, and Neuroendocrine Responses
Krystal, J. H. (1994) · Archives of General Psychiatry · doi:10.1001/archpsyc.1994.03950030035004 · Cited by 3,330
Ido expression by dendritic cells: tolerance and tryptophan catabolism
Mellor, A. L., & Munn, D. H. (2004) · Nature Reviews Immunology · doi:10.1038/nri1457 · Cited by 2,341
An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor
Opitz, C. A., Litzenburger, U. M., Sahm, F., Ott, M., Tritschler, I., Trump, S., Schumacher, T., Jestaedt, L., Schrenk, D., Weller, M., et al. (2011) · Nature · doi:10.1038/nature10491 · Cited by 1,898
Mammalian nicotinic acetylcholine receptors: from structure to function
Albuquerque, E. X., Pereira, E. F. R., Alkondon, M., & Rogers, S. W. (2009) · Physiological Reviews · doi:10.1152/physrev.00015.2008 · Cited by 1,724
Blockade of N -Methyl-D-Aspartate Receptors May Protect Against Ischemic Damage in the Brain
Simon, R. P., Swan, J. H., Griffiths, T., & Meldrum, B. S. (1984) · Science · doi:10.1126/science.6093256 · Cited by 1,682
Microglia in neurodegenerative disease
Perry, V. H., Nicoll, J. A. R., & Holmes, C. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2010.17 · Cited by 1,543
The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate
Anis, N. A., Berry, S. C., Burton, N. R., & Lodge, D. (1983) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1983.tb11031.x · Cited by 1,399
Quinolinic Acid: An Endogenous Metabolite That Produces Axon-Sparing Lesions in Rat Brain
Schwarcz, R. M., Whetsell, W. O., & Mangano, R. M. (1983) · Science · doi:10.1126/science.6849138 · Cited by 1,269
Self-citation
Lesion of striatal neurons with kainic acid provides a model for Huntington's chorea
Coyle, J. T., & Schwarcz, R. M. (1976) · Nature · doi:10.1038/263244a0 · Cited by 1,255
Self-citation
Subanesthetic Doses of Ketamine Stimulate Psychosis in Schizophrenia
Lahti, A., Koffel, B., Laporte, D., & Tamminga, C. (1995) · Neuropsychopharmacology · doi:10.1016/0893-133x(94)00131-i · Cited by 965

Show all 215 references

Sorted by citations

Items 801–900 of 1,002

Involvement of Kynurenine Metabolism in Bipolar Disorder: An Updated Review
Zhang, P., Huang, H., Gao, X., Jiang, J., Xi, C., Wu, L., Fu, Y., Lai, J., & Hu, S. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.677039 · Cited by 18
Depression, Estrogens, and Neuroinflammation: A Preclinical Review of Ketamine Treatment for Mood Disorders in Women
Gagne, C., Piot, A., & Brake, W. G. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.797577 · Cited by 18
“The kynurenine pathway is controlled by the immune system, with the synthesis of certain downstream metabolites, like QUIN, occurring within microglia (120, 121).”
Background
Adapting to oxygen: 3-Hydroxyanthrinilate 3,4-dioxygenase employs loop dynamics to accommodate two substrates with disparate polarities
Yang, Y., Liu, F., & Liu, A. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.002698 · Cited by 19
Early life stress from allergic dermatitis causes depressive-like behaviors in adolescent male mice through neuroinflammatory priming
Hashimoto, O., Kuniishi, H., Nakatake, Y., Yamada, M., Wada, K., & Sekiguchi, M. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.09.013 · Cited by 17
Acute exercise boosts NAD+ metabolism of human peripheral blood mononuclear cells
Walzik, D., Joisten, N., Schenk, A., Trebing, S., Schaaf, K., Metcalfe, A. J., Spiliopoulou, P., Hiefner, J., McCann, A., Watzl, C., et al. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.11.004 · Cited by 16
Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS
Che, X., Ranjan, A. K., Guo, C., Zhang, K., Goldsmith, R., Levine, S. M., Moneghetti, K. J., Zhai, Y., Ge, L., Mishra, N., et al. (2025) · npj Metabolic Health and Disease · doi:10.1038/s44324-025-00079-w · Cited by 23
“Whereas KYN exhibits depressogenic properties, KYNA is neuroprotective 47 .”
Perturbational Profiling of Metabolites in Patient Fibroblasts Implicates α-Aminoadipate as a Potential Biomarker for Bipolar Disorder
Huang, J., Berkovitch, S. S., Iaconelli, J., Watmuff, B., Park, H., Chattopadhyay, S., McPhie, D. L., Öngür, D., Cohen, B. M., Clish, C. B., et al. (2016) · Complex Psychiatry · doi:10.1159/000446654 · Cited by 17
Hepatocyte-intrinsic type I interferon signaling reprograms metabolism and reveals a novel compensatory mechanism of the tryptophan-kynurenine pathway in viral hepatitis
Lercher, A., Popa, A., Viczenczová, C., Kosack, L., Klavins, K., Agerer, B., Opitz, C. A., Lanz, T. V., Platten, M., & Bergthaler, A. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1008973 · Cited by 20
“This includes the essential amino acid tryptophan, where serum availability is associated with neurologic dysfunctions and inflammation [31,43].”
Background
URB597 Prevents the Short-Term Excitotoxic Cell Damage in Rat Cortical Slices: Role of Cannabinoid 1 Receptors
Chavira-Ramos, K., Orozco‐Morales, M., Karasu, Ç., Tinkov, A. A., Aschner, M., Santamarı́a, A., & Colín-González, A. L. (2020) · Neurotoxicity Research · doi:10.1007/s12640-020-00301-1 · Cited by 17
The Role of The Gut Microbiome in Parkinson’s Disease
Gallop, A., Weagley, J. S., Paracha, S.-U.-R., & Grossberg, G. T. (2021) · Journal of Geriatric Psychiatry and Neurology · doi:10.1177/08919887211018268 · Cited by 18
A Potential Interface between the Kynurenine Pathway and Autonomic Imbalance in Schizophrenia
Büki, A., Kékesi, G., Horváth, G., & Vécsei, L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221810016 · Cited by 18
“The role of KP disruption in schizophrenia has already been established [119,120,143].”
Background
Changes in cortical gene expression in the muscarinic M1 receptor knockout mouse: potential relevance to schizophrenia, Alzheimer’s disease and cognition
Dean, B., & Scarr, E. (2021) · Schizophrenia · doi:10.1038/s41537-021-00174-z · Cited by 17
Association between microglial activation and serum kynurenine pathway metabolites in multiple sclerosis patients
Saraste, M., Matilainen, M., Rajda, C., Galla, Z., Sucksdorff, M., Vécsei, L., & Airas, L. M. (2022) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2022.103667 · Cited by 19
“TRP metabolites seem to limit CNS inflammation via microglial and astrocytic aryl-hydrocarbon receptor (AHR) activation, which brings further complexity to the association between the kynurenine pathway and MS progression (Rothhammer et al., 2018).”
BackgroundInfluential
Analog of kynurenic acid decreases tau pathology by modulating astrogliosis in rat model for tauopathy
Majerová, P., Olešová, D., Golisova, G., Buralova, M., Michalicová, A., Vegh, J., Piešťanský, J., Bhide, M. R., Hanes, J., & Kováč, A. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113257 · Cited by 17
The Involvement of Kynurenine Pathway in Neurodegenerative Diseases
Martins, L. B., Silveira, A. L. M., & Teixeira, A. L. (2022) · Current Neuropharmacology · doi:10.2174/1570159x20666220922153221 · Cited by 18
“KYNA is an antagonist of the ionotropic excitatory amino acid receptors [N-methyl D-aspartate (NMDA), kainate, and AMPA receptors] and plays a role as a free radical scavenger, being implicated in neuroprotection [9].”
Alterations in rat prefrontal cortex kynurenic acid levels are involved in the enduring cognitive dysfunctions induced by tetrahydrocannabinol exposure during the adolescence
Beggiato, S., Ieraci, A., Zuccarini, M., Iorio, P. D., Schwarcz, R. M., & Ferraro, L. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.996406 · Cited by 17
Self-citation
Moxibustion alleviates depression-like behavior in rats with Crohn’s disease by inhibiting the kynurenine pathway metabolism in the gut-brain axis
Bao, C., Huang, J., Wu, H., Ma, Y., Zhou, H., Chen, L., Yang, D., Liu, H., Shi, Y., & Lu, Y. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.1019590 · Cited by 17
“, 2005), and is an agonist of N-methyl-D-aspartate (NMDA) receptors and a neuroexcitatory toxin found mainly in the forebrain (Schwarcz et al., 2012).”
BackgroundSelf-citation
The Kynurenine Pathway in Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis of Blood Concentrations of Tryptophan and Its Catabolites
Cavaleri, D., Crocamo, C., Morello, P., Bartoli, F., & Carrà, G. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13020583 · Cited by 17
“TRYCATs are produced through the kynurenine pathway (KP), the main route for the catabolism of TRP [14–17].”
BackgroundInfluential
Mass spectrometry for biomarkers, disease mechanisms, and drug development in cerebrospinal fluid metabolomics
Xu, D., Dai, X., Zhang, L., Cai, Y., Chen, K., Ji, W., Dong, L., Shen, L., Yang, J., Zhao, J., et al. (2024) · TrAC Trends in Analytical Chemistry · doi:10.1016/j.trac.2024.117626 · Cited by 17
Host interleukin 6 production regulates inflammation but not tryptophan metabolism in the brain during murine GVHD
Belle, L., Zhou, V., Stuhr, K. L., Beatka, M. J., Siebers, E. M., Knight, J. M., Lawlor, M. W., Weaver, C. T., Hashizume, M., Hillard, C. J., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.93726 · Cited by 17
LPS-induced cortical kynurenic acid and neurogranin-NFAT signaling is associated with deficits in stimulus processing during Pavlovian conditioning
Oliveros, A., Wininger, K. M., Sens, J. P., Larsson, M. K., Liu, X. C., Choi, S., Faka, A., Schwieler, L., Engberg, G., Erhardt, S., et al. (2017) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2017.09.010 · Cited by 18
“KYNA blocks the glycine site of the NMDAR as well as the cholinergic α7 nicotinic receptor (Hilmas et al., 2001; Schwarcz et al., 2012).”
Background
Memantine Is Protective against Cytotoxicity Caused by Lead and Quinolinic Acid in Cultured Rat Embryonic Hippocampal Cells
Rahman, A., Al-Qenaie, S., Rao, M. S. R., Khan, K. M., & Guillemin, G. J. (2019) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.8b00421 · Cited by 17
Toxoplasma gondiiinfection and risk of attention-deficit hyperactivity disorder: a systematic review and meta-analysis
Nayeri, T., Sarvi, S., Moosazadeh, M., Hosseininejad, Z., Amouei, A., & Daryani, A. (2020) · Pathogens and Global Health · doi:10.1080/20477724.2020.1738153 · Cited by 16
“Products of tryptophan catabolism play an important role in the increase of oxidative stress and apoptosis in the brain [64].”
Background
S-Allylcysteine Protects Against Excitotoxic Damage in Rat Cortical Slices Via Reduction of Oxidative Damage, Activation of Nrf2/ARE Binding, and BDNF Preservation
Reyes-Soto, C. Y., Rangel‐López, E., Galván‐Arzate, S., Colín-González, A. L., Silva‐Palacios, A., Zazueta, C., Pedraza‐Chaverrí, J., Carreto, R. J. R., Chavarría, A., Túnez, I., et al. (2020) · Neurotoxicity Research · doi:10.1007/s12640-020-00260-7 · Cited by 17
Morphological and biochemical repercussions of Toxoplasma gondii infection in a 3D human brain neurospheres model
Leite, P. E. C., Portes, J. D. A., Pereira, M. R., Russo, F. B., Martins-Duarte, É. S., Almeida, N., Attias, M., Barrantes, F. J., Beltrão-Braga, P. C. B., & de Souza, W. (2020) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2020.100190 · Cited by 17
“Animal and human in vivo studies suggest that increased levels of kynurenic acid can be related to cognitive deficits observed in schizophrenia spectrum disorders (69).”
Background
Tryptophan Derivatives by Saccharomyces cerevisiae EC1118: Evaluation, Optimization, and Production in a Soybean-Based Medium
Dei, M., Vigentini, I., Vitalini, S., Laganaro, A., Iriti, M., Paroni, R. C., & Foschino, R. C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22010472 · Cited by 17
Experimental diabetes mellitus type 1 increases hippocampal content of kynurenic acid in rats
Chmiel-Perzyńska, I., Perzyński, A., & Urbańska, E. M. (2014) · Pharmacological Reports · doi:10.1016/j.pharep.2014.07.014 · Cited by 17
Evidence for phenotypic plasticity in response to photic cues and the connection with genes of risk in schizophrenia
Miller, C. L. (2013) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2013.00082 · Cited by 17
Luteinizing hormone-follicle stimulating hormone ratio as biological predictor of post-partum depression
Pillai, R. R., Sharon, L., Premkumar, N. R., Kattimani, S., Sagili, H., & Rajendiran, S. (2016) · Comprehensive Psychiatry · doi:10.1016/j.comppsych.2016.09.001 · Cited by 17
Cytoskeleton as a Target of Quinolinic Acid Neurotoxicity: Insight from Animal Models
Pierozan, P., & Pessoa‐Pureur, R. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0654-8 · Cited by 17
Lipopolysaccharide Increases Cortical Kynurenic Acid and Deficits in Reference Memory in Mice
Peyton, L., Oliveros, A., Tufvesson‐Alm, M., Schwieler, L., Starski, P. A., Engberg, G., Erhardt, S., & Choi, D. (2019) · International Journal of Tryptophan Research · doi:10.1177/1178646919891169 · Cited by 17
Effects of kynurenine pathway metabolites on choroid plexus volume, hemodynamic response, and spontaneous neural activity: A new mechanism for disrupted neurovascular communication and impaired cognition in mood disorders
Bravi, B., Verga, C., Palladini, M., Sara, P., Camilla, B., Sut, S., Dall’Acqua, S., Colombo, C., Comai, S., & Benedetti, F. (2025) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2025.01.025 · Cited by 18
Kynurenic Acid and Promotion of Activity-Dependent Synapse Elimination in Schizophrenia
Orhan, F., Malwade, S., Khanlarkhani, N., Gkogka, A., Langeder, A., Jungholm, O., Koskuvi, M., Lehtonen, Š., Schwieler, L., Jardemark, K. E., et al. (2025) · American Journal of Psychiatry · doi:10.1176/appi.ajp.20240048 · Cited by 21
A role for endothelial NMDA receptors in the pathophysiology of schizophrenia
Intson, K., Geissah, S., McCullumsmith, R. E., & Ramsey, A. J. (2020) · Schizophrenia Research · doi:10.1016/j.schres.2020.10.004 · Cited by 16
Kynurenine catabolic enzyme KMO regulates HCC growth
Shi, Z., Gan, G., Gao, X., Chen, F., & Mi, J. (2022) · Clinical and Translational Medicine · doi:10.1002/ctm2.697 · Cited by 16
Is Poor Lithium Response in Individuals with Bipolar Disorder Associated with Increased Degradation of Tryptophan along the Kynurenine Pathway? Results of an Exploratory Study
Fellendorf, F. T., Manchia, M., Squassina, A., Pisanu, C., Dall’Acqua, S., Sut, S., Nasini, S., Congiu, D., Reininghaus, E. Z., Garzilli, M., et al. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11092517 · Cited by 17
“NMDA receptors [4,11,12], and that also induce apoptosis in astrocytes [13].”
Background
Interferon-gamma Mediated Metabolic Pathways in Hospitalized Patients During Acute and Reconvalescent COVID-19
Gietl, M., Burkert, F. R., Seiwald, S., Boehm, A., Hofer, S., Gostner, J. M., Piater, T., Geisler, S., Weiß, G., Löffler‐Ragg, J., et al. (2023) · International Journal of Tryptophan Research · doi:10.1177/11786469231154244 · Cited by 16
The role of NMDA receptors in bipolar disorder: A systematic review
Weiss, F., Caruso, V., Rosa, U. D., Beatino, M. F., Barbuti, M., Nicoletti, F., & Perugi, G. (2023) · Bipolar Disorders · doi:10.1111/bdi.13335 · Cited by 16
Unraveling the link: exploring the causal relationship between diabetes, multiple sclerosis, migraine, and Alzheimer’s disease through Mendelian randomization
Xue, H., Zeng, L., & Liu, S. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1233601 · Cited by 16
“However, the TryptophanKynurenine metabolic pathway was considered to be an important pathway of neuronal damage in neurodegenerative diseases and severe brain injuries (Schwarcz et al., 2012; Battaglia et al., 2023).”
Background
Inhibition of STAT-mediated cytokine responses to chemically-induced colitis prevents inflammation-associated neurobehavioral impairments
Sin, R., Sotogaku, N., Ohnishi, Y. N., Shuto, T., Kuroiwa, M., Kawahara, Y., Sugiyama, K., Murakami, Y., Kanai, M., Funakoshi, H., et al. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.08.019 · Cited by 16
Bridging the Mind and Gut: Uncovering the Intricacies of Neurotransmitters, Neuropeptides, and their Influence on Neuropsychiatric Disorders
Gupta, S., Dinesh, S., & Sharma, S. (2024) · Central Nervous System Agents in Medicinal Chemistry · doi:10.2174/0118715249271548231115071021 · Cited by 18
Dual treatment with kynurenine pathway inhibitors and NAD + precursors synergistically extends life span in Drosophila
Gabrawy, M. M., Westbrook, R., King, A., Khosravian, N., Ochaney, N., deCarvalho, T., Wang, Q., Yu, Y., Huang, Q., Said, A., et al. (2024) · Aging Cell · doi:10.1111/acel.14102 · Cited by 17
“In humans and flies, elevated levels of kynurenines are noted in a number of aging-related diseases, including metabolic syndrome (Matsuoka et al., 2016), neurodegenerative disease (Campesan et al., 2011; Schwarcz et al., 2012), and physical frailty (Westbrook et al., 2020).”
Background
Dysregulated placental expression of kynurenine pathway enzymes is associated with inflammation and depression in pregnancy
Sha, Q., Galvis, M. L. E., Madaj, Z., Keaton, S. A., Smart, L., Edgerly, Y. M., Anis, E., Leach, R., Osborne, L. M., Achtyes, E. D., et al. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.03.042 · Cited by 18
“Inflammation increases the production of down-stream neuroactive metabolites, some of which affect glutamate neurotransmission and are implicated in depression (Schwarcz et al., 2012).”
Dysregulation of the Kynurenine Pathway in Relapsing Remitting Multiple Sclerosis and Its Correlations With Progressive Neurodegeneration
Pires, A. S., Krishnamurthy, S., Sharma, S., Chow, S., Klistorner, S., Guillemin, G. J., Klistorner, A. I., You, Y., & Heng, B. (2025) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000200372 · Cited by 15
Kynurenic acid, an aryl hydrocarbon receptor ligand, is elevated in serum of Zucker fatty rats.
Oxenkrug, G. F., Cornicelli, J. A., van der Hart, M., Roeser, J., & D, P. S. M. (2016) · PubMed · Cited by 16
Toxic Synergism Between Quinolinic Acid and Glutaric Acid in Neuronal Cells Is Mediated by Oxidative Stress: Insights to a New Toxic Model
Pierozan, P., Colín-González, A. L., Biasibetti, H., da Silva, J. C., Wyse, Â. T. D. S., Wajner, M., & Santamarı́a, A. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0761-6 · Cited by 16
“acid (2,3-pyridine-dicarboxylic acid or QUIN), is necessary to adequate brain functioning when synthesized at normal levels [11, 12]; however, when produced in excess, it plays a toxic role, participating in neurological disorders cours ing with exci totoxic i ty, such as Parkinson’s and Huntington’s diseases, as well…”
Background
The role of kynurenine pathway and kynurenic aminotransferase alleles in postpartum depression following cesarean section in Chinese women
Quan, C., Wang, S., Duan, K., Ma, J., Yu, H., Yang, M., Hu, N., Long, G., Zeng, G., & Huang, Z. (2020) · Brain and Behavior · doi:10.1002/brb3.1566 · Cited by 16
Repeated administration of LPS exaggerates amphetamine-induced locomotor response and causes learning deficits in mice
Tufvesson‐Alm, M., Imbeault, S., Liu, X.-C., Zheng, Y., Faka, A., Choi, D., Schwieler, L., Engberg, G., & Erhardt, S. (2020) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2020.577401 · Cited by 14
Inhibition of tryptophan 2,3-dioxygenase impairs DNA damage tolerance and repair in glioma cells
Reed, M. R., Maddukuri, L., Ketkar, A. D., Byrum, S. D., Zafar, M. K., Bostian, A. C. L., Tackett, A. J., & Eoff, R. L. (2021) · NAR Cancer · doi:10.1093/narcan/zcab014 · Cited by 16
“This is higher than physiological concentrations of KYN found in the brain, which have been estimated to lie in the nano- to low micromolar range (22).”
The Kynurenine Pathway Metabolites in Cord Blood Positively Correlate With Early Childhood Adiposity
Tan, K. M. L., Tint, M. T., Narasimhan, K., Michael, N., Sadananthan, S. A., Velan, S. S., Fortier, M. V., Yap, F. K. P., Tan, K. H., Gluckman, P. D., et al. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac078 · Cited by 15
The prevalence and the effect of interferon -γ in the comorbidity of rheumatoid arthritis and depression
Ren, H., Lin, F., Wu, L., Tan, L., Lu, L., Xie, X., Zhang, Y., Bao, Y., Ma, Y., Huang, X., et al. (2022) · Behavioural Brain Research · doi:10.1016/j.bbr.2022.114237 · Cited by 16
2-Aminonicotinic Acid 1-Oxides Are Chemically Stable Inhibitors of Quinolinic Acid Synthesis in the Mammalian Brain: A Step toward New Antiexcitotoxic Agents
Vallerini, G. P., Amori, L., Beato, C., Tararina, M. A., Wang, X., Schwarcz, R. M., & Costantino, G. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm401249c · Cited by 16
Self-citation
Novel Kynurenic Acid Analogues in the Treatment of Migraine and Neurodegenerative Disorders: Preclinical Studies and Pharmaceutical Design
Tajti, J., Majláth, Z., Szok, D., Csáti, A., Toldi, J., Fülöp, F., & Vécsei, L. (2015) · Current Pharmaceutical Design · doi:10.2174/1381612821666150105163055 · Cited by 16
Cannabinoids: Glutamatergic Transmission and Kynurenines
Colín-González, A. L., Aguilera, G., & Santamarı́a, A. (2016) · Advances in neurobiology · doi:10.1007/978-3-319-28383-8_10 · Cited by 16
The kynurenine pathway: Towards metabolic equilibrium
Clarke, G. A., Stone, T. W., & Schwarcz, R. M. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.08.029 · Cited by 16
Self-citation
Diflunisal Derivatives as Modulators of ACMS Decarboxylase Targeting the Tryptophan–Kynurenine Pathway
Yang, Y., Borel, T. J., de Azambuja, F., Johnson, D. K., Sorrentino, J. P., Udokwu, C., Davis, I., Liu, A., & Altman, R. A. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01762 · Cited by 15
GRK3 deficiency elicits brain immune activation and psychosis
Sellgren, C., Imbeault, S., Larsson, M., Oliveros, A., Nilsson, I. A. K., Codeluppi, S., Orhan, F., Bhat, M., Tufvesson-Alm, M., Gracias, J., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01106-0 · Cited by 14
“In line with this, brain KYNA is also mainly produced in astrocytes [55].”
Background
The kynurenine pathway in schizophrenia and other mental disorders: Insight from meta-analyses on the peripheral blood levels of tryptophan and related metabolites
Bartoli, F., Cioni, R. M., Callovini, T., Cavaleri, D., Crocamo, C., & Carrà, G. (2021) · Schizophrenia Research · doi:10.1016/j.schres.2021.04.008 · Cited by 15
Differential pulse voltammetric quantitation of kynurenic acid in human plasma using carbon-paste electrode modified with metal-organic frameworks
Bornaei, M., Khajehsharifi, H., Shahrokhian, S., Sheydaei, O., & Zarnegarian, A. (2022) · Materials Chemistry and Physics · doi:10.1016/j.matchemphys.2022.127016 · Cited by 15
The Association Between Neutrophil-Lymphocyte Ratio and Variability with New-Onset Dementia: A Population-Based Cohort Study
Chou, O., Zhou, J.-D., Li, L., Chan, J., Satti, D., Chou, V., Wong, W., Lee, S.-R., Cheung, B., Tse, G., et al. (2023) · Journal of Alzheimer's Disease · doi:10.3233/jad-220111 · Cited by 13
“Furthermore, inﬂammation may also alter the kynurenine pathway, resulting in neurodegeneration [12].”
Kynurenic acid: translational perspectives of a therapeutically targetable gliotransmitter
Pocivavsek, A., & Erhardt, S. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-023-01681-6 · Cited by 15
Causal association between kynurenine and depression investigated using two-sample mendelian randomization
Zong, L., Ge, M., Wang, J., Kuang, D., Wei, H., Wang, Z., Hu, Z., Zhao, C., Jin, Q., Chen, M., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-52442-4 · Cited by 19
“These studies align with our findings, which demonstrate an increase in KYN levels in individuals with depression 9,11,22–25 .”
Result
Kynurenine Metabolites in CSF and Plasma in Healthy Males
Orhan, F., Schwieler, L., Engberg, G., & Samuelsson, M. (2024) · International Journal of Tryptophan Research · doi:10.1177/11786469241245323 · Cited by 17
Alzheimer’s disease-specific transcriptomic and epigenomic changes in the tryptophan catabolic pathway
Choe, K., Ali, M., Lardenoije, R., Riemens, R. J. M., Pishva, E., Bickel, H., Weyerer, S. B., Hoffmann, P., Pentzek, M., Riedel-Heller, S. G., et al. (2024) · Alzheimer s Research & Therapy · doi:10.1186/s13195-024-01623-4 · Cited by 15
The involvement of the microbiota-gut-brain axis in the pathophysiology of mood disorders and therapeutic implications
Barbosa, I. G., de Miranda, A. S., Berk, M., & Teixeira, A. L. (2024) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2024.2438646 · Cited by 16
“Disruption of tryptophan metabolism with consequent reduction of 5-HT levels and activation of the kynurenine pathway has been implicated in the pathophysiology of depression [56–58].”
Pharmacotherapy of schizophrenia: toward a metabolomic-based approach
Tayeb, H. O., Murad, H. A. S., Rafeeq, M. M., & Tarazi, F. I. (2018) · CNS Spectrums · doi:10.1017/s1092852918000962 · Cited by 15
Elevated peripheral kynurenine/tryptophan ratio predicts poor short-term auditory memory in panic disorder patients
Quagliato, L. A., Freire, R. C. R., & Nardi, A. E. (2019) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2019.03.027 · Cited by 15
An electrochemical chiral sensor based on electrochemically modified electrode for the enantioselective discrimination of D-/L-tryptophan
Erbilen, N., Zor, E., Saf, A. Ö., Akgemci, E. G., & Bingöl, H. (2019) · Journal of Solid State Electrochemistry · doi:10.1007/s10008-019-04370-x · Cited by 15
Characterizing serum amino acids in schizophrenic patients: Correlations with gut microbes
Ma, Q., Gao, F., Zhou, L., Fan, Y., Zhao, B., Xi, W., Wang, C., Zhu, F., Ma, X., Wang, W., et al. (2022) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2022.07.006 · Cited by 15
Development of LC/MS/MS, High-Throughput Enzymatic and Cellular Assays for the Characterization of Compounds That Inhibit Kynurenine Monooxygenase (KMO)
Winkler, D. F. H., Beconi, M. G., Toledo, L. M., Prime, M. E., Ebneth, A., Dominguez, C., & Muñoz-Sanjuán, I. (2013) · SLAS DISCOVERY · doi:10.1177/1087057113489731 · Cited by 15
A 2-Substituted 8-Hydroxyquinoline Stimulates Neural Stem Cell Proliferation by Modulating ROS Signalling
Haigh, C. L., Tumpach, C., Collins, S. J., & Drew, S. C. (2016) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-016-0747-4 · Cited by 16
Benserazide, an Inhibitor of Peripheral Kynurenine Metabolism, Attenuates Olanzapine-Induced Weight Gain, Insulin Resistance, and Dyslipidemia in C57Bl/6j Mice
Oxenkrug, G. F., & D, P. S. M. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-01763-x · Cited by 15
Discovery of Kynurenines Containing Oligopeptides as Potent Opioid Receptor Agonists
Szűcs, E., Stefanucci, A., Dimmito, M. P., Zádor, F., Pieretti, S., Zengin, G., Vécsei, L., Benyhe, S., Nalli, M., & Mollica, A. (2020) · Biomolecules · doi:10.3390/biom10020284 · Cited by 15
“Kyn is able to penetrate the central nervous system (CNS) by transport across the blood–brain barrier (BBB), but it is also produced locally [6].”
Background
Synthesis and Preclinical Evaluation of 6-[18F]Fluorine-α-methyl- l -tryptophan, a Novel PET Tracer for Measuring Tryptophan Uptake
Красикова, Р. Н., Kondrashov, M. V., Avagliano, C., Petukhov, M., Vázquez‐Romero, A., Revunov, E., Johnström, P., Tari, L., Tóth, M., Häggkvist, J., et al. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00135 · Cited by 15
Blunt renal trauma: renal preservation through careful staging and selective surgery.
Nguyen, H. T., & Carroll, P. R. (1995) · PubMed · Cited by 15
Correction: Brain structural abnormalities in obesity: relation to age, genetic risk, and common psychiatric disorders
Opel, N., Thalamuthu, A., Milaneschi, Y., Grotegerd, D., Flint, C., Leenings, R., Goltermann, J., Richter, M. F., Hahn, T., Woditsch, G., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01191-1 · Cited by 14
From orphan to oncogene: The role of GPR35 in cancer and immune modulation
Takkar, S., Sharma, G., Kaushal, J., Abdullah, K. M., Batra, S. K., & Siddiqui, J. A. (2024) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2024.03.004 · Cited by 14
The role of the neuroinflammation and stressors in premenstrual syndrome/premenstrual dysphoric disorder: a review
Cheng, M. T., Jiang, Z., Yang, J., Sun, X., Song, N., Du, C., Luo, Z.-L., & Zhang, Z. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1561848 · Cited by 19
Production, Mechanisms, and Therapeutic Strategies of Tryptophan Metabolites in CNS Diseases
Shi, C., Dong, J., Hui, X., Xu, Z., Zhao, Z., & Dong, L. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05538-5 · Cited by 19
“Dysregulation of the 5-HT pathway and the KP has been implicated in various neuropsychiatric disorders, including AD, MDD, HD, PD, and SCZ [155].”
The role of tryptophan metabolic pathway in children with attention deficit hyperactivity disorder with and without comorbid oppositional defiant disorder and conduct disorder
Sağlam, E., Bi̇lgi̇ç, A., Abuşoğlu, S., Ünlü, A., & Sivrikaya, A. (2021) · Psychiatry Research · doi:10.1016/j.psychres.2021.113770 · Cited by 14
Endocrine disrupting chemicals (EDCs) and placental function: Impact on fetal brain development
Marinello, W. P., & Patisaul, H. B. (2021) · Advances in pharmacology · doi:10.1016/bs.apha.2021.04.003 · Cited by 17
Blockade of KAT II Facilitates LTP in Kynurenine 3-Monooxygenase Depleted Mice
Imbeault, S., Olivé, M. G., Jungholm, O., Erhardt, S., Wigström, H., Engberg, G., & Jardemark, K. E. (2021) · International Journal of Tryptophan Research · doi:10.1177/11786469211041368 · Cited by 14
Breath and plasma metabolomics to assess inflammation in acute stroke
Ahmed, W., White, I. R., Wilkinson, M., Johnson, C. F., Rattray, N. J. W., Kishore, A. K., Goodacre, R., Smith, C. J., & Fowler, S. J. (2021) · Scientific Reports · doi:10.1038/s41598-021-01268-5 · Cited by 14
Brain Kynurenine Pathway and Functional Outcome of Rats Resuscitated From Cardiac Arrest
Lucchetti, J., Fumagalli, F., Olivari, D., Affatato, R., Fracasso, C., Giorgio, D. D., Perego, C., Motta, F., Passoni, A., Staszewsky, L., et al. (2021) · Journal of the American Heart Association : Cardiovascular and Cerebrovascular Disease · doi:10.1161/jaha.121.021071 · Cited by 12
The effect of inflammation, SARS-CoV-2 infection, age and mental health on serotonin, and kynurenine and catecholamine pathway metabolites
Hüfner, K., Vedova, S., Tymoszuk, P., Nelles, P., Bruckner, T., Deisenhammer, E., Egeter, J., Gálffy, M., Giesinger, J. M., Lehmann, J., et al. (2023) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2023.106334 · Cited by 14
Relationship of tryptophan metabolites with the type and severity of multiple sclerosis
IŞIK, Ş. M., Onmaz, D. E., Ekmekci, A. H., Öztürk, Ş., Ünlü, A., & Abuşoğlu, S. (2023) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2023.104898 · Cited by 14
The Preventive Effect of Melatonin on Radiation-Induced Oral Mucositis
Tokuyama-Toda, R., Umeki, H., Okubo, M., Terada-Ito, C., Yudo, T., Ide, S., Tadokoro, S., Shimozuma, M., & Satomura, K. (2023) · Cells · doi:10.3390/cells12172178 · Cited by 14
Promising new pharmacological targets for depression: The search for efficacy
Tsugiyama, L. E., de Moraes, R. C. M., Moraes, Y. A. C., & de Oliveira, J. F. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103804 · Cited by 14
Decreased Plasma Levels of Kynurenine and Kynurenic Acid in Previously Treated and First-Episode Antipsychotic-Naive Schizophrenia Patients
Marković, M., Petronijević, N., Stašević, M., Karličić, I. S., Velimirović, M., Stojković, T., Ristić, S., Stojković, M., Milic, N. M., & Nikolić, T. (2023) · Cells · doi:10.3390/cells12242814 · Cited by 11
“Degradation of TRP (for a detailed overview of KP see [10]) by its oxidation to N-formyl kynurenine is dominantly mediated by one of three enzymes—indolamine 2,3-dioxigenase 1 (IDO1), in-dolamine 2,3-dioxigenase 2 (IDO2) or tryptophan 2,3-dioxigenase (TDO2).”
BackgroundInfluential
The Janus-Faced Nature of Ido1 in Infectious Diseases: Challenges and Therapeutic Opportunities
Greco, F. A., Coletti, A., Camaioni, E., Carotti, A., Marinozzi, M., Gioiello, A., & Macchiarulo, A. (2015) · Future Medicinal Chemistry · doi:10.4155/fmc.15.165 · Cited by 14
Mitohormesis; Potential implications in neurodegenerative diseases
Gohel, D., & Singh, R. K. (2020) · Mitochondrion · doi:10.1016/j.mito.2020.11.011 · Cited by 14
Hydrocortisone Affects Fatigue and Physical Functioning Through Metabolism of Tryptophan: A Randomized Controlled Trial
Sorgdrager, F. J. H., Buning, J. W., Bos, E. H., van Beek, A. P., & Kema, I. P. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-00582 · Cited by 15
Anandamide Reduces the Toxic Synergism Exerted by Quinolinic Acid and Glutaric Acid in Rat Brain Neuronal Cells
Kotlar, I., Rangel‐López, E., Colonnello, A., Aguilera, G., Serratos, I. N., Galván‐Arzate, S., Pedraza‐Chaverrí, J., Túnez, I., Wajner, M., & Santamarı́a, A. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2019.01.014 · Cited by 14
Acute liver failure increases kynurenic acid production in rat brain via changes in tryptophan metabolism in the periphery
Sekine, A., & Fukuwatari, T. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.02.004 · Cited by 14
A wide‐targeted urinary and serum metabolomics strategy reveals the effective substance of the Wu‐tou decoction
Cheng, X., Xu, T., Pi, Z., Liu, S., Song, F., & Liu, Z. (2019) · Journal of Separation Science · doi:10.1002/jssc.201900678 · Cited by 14
Influence of combined functional resistance and endurance exercise over 12 weeks on matrix metalloproteinase-2 serum concentration in persons with relapsing-remitting multiple sclerosis – a community-based randomized controlled trial
Proschinger, S., Joisten, N., Rademacher, A., Schlagheck, M. L., Walzik, D., Metcalfe, A. J., Oberste, M., Warnke, C., Bloch, W., Schenk, A., et al. (2019) · BMC Neurology · doi:10.1186/s12883-019-1544-7 · Cited by 14
The utilization of small non‐mammals in traumatic brain injury research: A systematic review
Zulazmi, N. A., Arulsamy, A., Ali, I. Y., Abidin, S. A. Z., Othman, I., & Shaikh, M. F. (2021) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13590 · Cited by 13
New Approaches to Profile the Microbiome for Treatment of Neurodegenerative Disease
Elmaleh, D. R., Downey, M. A., Kundakovic, L., Wilkinson, J. E., Neeman, Z., & Segal, E. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210198 · Cited by 14
“QuinolinicacidisanNMDAglutamatereceptor agonist with high selectivity for the NR2B subunit (GRIN2B) in the forebrain, and high concentrations areassociatedwithneuronexcitotoxicityandmayini-tiatedisruptionofneuronalcytoskeletonhomeostatic mechanisms[104,105].”
Metabolic Syndrome and Schizophrenia: Adding a Piece to the Interplay Between the Kynurenine Pathway and Inflammation
Sapienza, J., Agostoni, G., Repaci, F., Spangaro, M., Comai, S., & Bosia, M. (2025) · Metabolites · doi:10.3390/metabo15030176 · Cited by 17
“As an antagonist at the glycine-binding site of NMDARs, KYNA reduces excitotox-icity but exacerbates glutamatergic hypofunction—a key feature of cognitive deficits in schizophrenia [21,118].”
The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a systematic review and meta-analysis of cerebrospinal fluid studies
Inam, M. E., Fernandes, B. S., Salagre, E., Grande, I., Vieta, E., Quevedo, J., & Zhao, Z. (2023) · Brazilian Journal of Psychiatry · doi:10.47626/1516-4446-2022-2973 · Cited by 15

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Kynurenines in the mammalian brain: when physiology meets pathology

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks