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
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Background
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The gut-brain axis in ischemic stroke: its relevance in pathology and as a therapeutic target
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“The kynurenine pathway accounts for more than 90% of tryptophan metabolism and is implicated in a number of neurodegenerative diseases [68] and acute brain disorders.”
Background
Behavioral sequelae of astrocyte dysfunction: focus on animal models of schizophrenia
Xia, M., Abazyan, S., Jouroukhin, Y., & Pletnikov, M. V. (2014) · Schizophrenia Research · doi:10.1016/j.schres.2014.10.044 · Cited by 46
A Critical Review of Pro-Cognitive Drug Targets in Psychosis: Convergence on Myelination and Inflammation
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The causative role and therapeutic potential of the kynurenine pathway in neurodegenerative disease
Amaral, M., Outeiro, T. F., Scrutton, N. S., & Giorgini, F. (2013) · Journal of Molecular Medicine · doi:10.1007/s00109-013-1046-9 · Cited by 46
Multifunctional Analogs of Kynurenic Acid for the Treatment of Alzheimer’s Disease: Synthesis, Pharmacology, and Molecular Modeling Studies
Deora, G. S., Kantham, S., Chan, S., Dighe, S. N., Veliyath, S. K., McColl, G., Parat, M., McGeary, R. P., & Ross, B. P. (2017) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.7b00229 · Cited by 46
Sex Differences in Hippocampal Memory and Kynurenic Acid Formation Following Acute Sleep Deprivation in Rats
Baratta, A. M., Buck, S. A., Buchla, A. D., Fabian, C. B., Chen, S., Mong, J. A., & Pocivavsek, A. (2018) · Scientific Reports · doi:10.1038/s41598-018-25288-w · Cited by 46
First molecular modeling report on novel arylpyrimidine kynurenine monooxygenase inhibitors through multi-QSAR analysis against Huntington’s disease: A proposal to chemists!
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Alternative functions of the brain transsulfuration pathway represent an underappreciated aspect of brain redox biochemistry with significant potential for therapeutic engagement
Hensley, K., & Denton, T. T. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.10.581 · Cited by 46
Behavioral disturbances in adult mice following neonatal virus infection or kynurenine treatment – Role of brain kynurenic acid
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Targeting metabotropic glutamate receptors for the treatment of neuroinflammation
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“Notably, the synthesis of 3-hydroxykynurenine and its downstream metabolites occurs in microglia [76], but whether xanthurenic acid influences microglial function by activating mGlu2 or mGlu3 receptors remains to be determined.”
The Janus faces of 3-hydroxykynurenine: Dual redox modulatory activity and lack of neurotoxicity in the rat striatum
Colín-González, A. L., Maya-López, M., Pedraza‐Chaverrí, J., Ali, S. F., Chavarría, A., & Santamarı́a, A. (2014) · Brain Research · doi:10.1016/j.brainres.2014.09.034 · Cited by 46
Unveiling the role of gut-brain axis in regulating neurodegenerative diseases: A comprehensive review
Yadav, H., Jaldhi, Bhardwaj, R., Anamika, A., Bakshi, A., Gupta, S., & Maurya, S. K. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.122022 · Cited by 47
Tryptophan Metabolism Disorder-Triggered Diseases, Mechanisms, and Therapeutic Strategies: A Scientometric Review
Chen, X., Xu, D. W., Yu, J., Song, X., Li, X., & Cui, Y. (2024) · Nutrients · doi:10.3390/nu16193380 · Cited by 48
“At the same time, continuous stimulation of NMDA receptors by QA can damage corresponding neuronal cells, leading to depression [111].”
Background
Inhibition of kynurenine aminotransferase II reduces activity of midbrain dopamine neurons
Linderholm, K. R., Tufvesson‐Alm, M., Larsson, M. K., Olsson, S. K., Goiny, M., Hajós, M., Erhardt, S., & Engberg, G. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.10.028 · Cited by 44
Metabolomic profiles in individuals with negative affectivity and social inhibition: A population-based study of Type D personality
Altmaier, E., Emeny, R. T., Krumsiek, J., Lacruz, M. E., Lukaschek, K., Häfner, S., Kastenmüller, G., Römisch‐Margl, W., Prehn, C. P., Mohney, R. P., et al. (2012) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2012.11.014 · Cited by 43
Vasorelaxing Action of the Kynurenine Metabolite, Xanthurenic Acid: The Missing Link in Endotoxin-Induced Hypotension?
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Tryptophan metabolic profile in term and preterm breast milk: implications for health
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“petitive large amino acid transporters, while KynA, 3-hydroxykynurenine and quinolinic acid cross the blood–brain barrier at relatively low rates((7,20,46)).”
Influential
Simultaneous determination of tryptophan, kynurenine, kynurenic acid and two monoamines in rat plasma by HPLC-ECD/DAD
Du, T., Cui, T., Qiu, H., Wang, N., Huang, D. Y., & Jiang, X. (2018) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2018.05.032 · Cited by 44
Targeted Treatment of Individuals With Psychosis Carrying a Copy Number Variant Containing a Genomic Triplication of the Glycine Decarboxylase Gene
Bodkin, J. A., Coleman, M. J., Godfrey, L., Carvalho, C. M. B., Morgan, C. J., Suckow, R. F., Anderson, T., Öngür, D., Kaufman, M. J., Lewandowski, K. E., et al. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2019.04.031 · Cited by 44
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Neural Regulatory Pathways of Feeding and Fat in Caenorhabditis elegans
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Quinolinic Acid: Neurotoxin or Oxidative Stress Modulator?
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The Opposite Effects of Kynurenic Acid and Different Kynurenic Acid Analogs on Tumor Necrosis Factor-α (TNF-α) Production and Tumor Necrosis Factor-Stimulated Gene-6 (TSG-6) Expression
Mándi, Y., Endrész, V., Mosolygó, T., Burián, K., Lantos, I., Fülöp, F., Szatmári, I., Lőrinczi, B., Balog, A., & Vécsei, L. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01406 · Cited by 46
Sex- and suicide-specific alterations in the kynurenine pathway in the anterior cingulate cortex in major depression
Brown, S. J., Christofides, K., Weissleder, C., Huang, X.-F., Shannon Weickert, C., Lim, C. K., & Newell, K. A. (2024) · Neuropsychopharmacology · doi:10.1038/s41386-023-01736-8 · Cited by 44
“Lastly, our investigation of the enzymes of the KP was limited to gene expression and it is unclear if these changes would be re ﬂ ected at the protein level.”
Background
Therapeutic insights elaborating the potential of retinoids in Alzheimer’s disease
Behl, T., Kaur, D., Sehgal, A., Singla, R. K., Makeen, H. A., Albratty, M., Alhazmi, H. A., Meraya, A. M., & BUNGAU, S. G. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.976799 · Cited by 43
“, 2011) culminating in a microglial-mediated rise in the neurotoxic NMDA-receptor agonist quinolinic acid (Schwarcz et al., 2012).”
Background
Discovering the Potential Mechanisms of Medicinal Mushrooms Antidepressant Activity: A Review
Lazur, J., Hnatyk, K., Kała, K., Sułkowska‐Ziaja, K., & Muszyńska, B. (2023) · Antioxidants · doi:10.3390/antiox12030623 · Cited by 44
“An increase in the level of pro-inflammatory cytokines, such as TNF-α, is one of the causes of the activation of the kynurenic pathway in microglia and the production of neurotoxic compounds, hydroxykynurenine and quinolinic acid [81].”
Background
The effect of transient increases in kynurenic acid and quinolinic acid levels early in life on behavior in adulthood: Implications for schizophrenia
Iaccarino, H. F., Suckow, R. F., Xie, S., & Bucci, D. J. (2013) · Schizophrenia Research · doi:10.1016/j.schres.2013.09.004 · Cited by 44
Tryptophan-Kynurenine Metabolism and Insulin Resistance in Hepatitis C Patients
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Lead Discovery for Human Kynurenine 3-Monooxygenase by High-Throughput RapidFire Mass Spectrometry
Lowe, D. M., Gee, M., Haslam, C. P., Leavens, B. J., Christodoulou, E., Hissey, P., Hardwicke, P. I., Argyrou, A., Webster, S. P., Mole, D. J., et al. (2013) · SLAS DISCOVERY · doi:10.1177/1087057113518069 · Cited by 42
Mood symptoms correlate with kynurenine pathway metabolites following sports-related concussion
Singh, R. P., Savitz, J. B., Teague, T. K., Polanski, D. W., Mayer, A. R., Bellgowan, P. S. F., & Meier, T. B. (2015) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2015-311369 · Cited by 42
Target-based metabolomics for the quantitative measurement of 37 pathway metabolites in rat brain and serum using hydrophilic interaction ultra-high-performance liquid chromatography–tandem mass spectrometry
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Mastocytosis in adulthood and neuropsychiatric disorders
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Inhibition of the kynurenine pathway protects against reactive microglial‐associated reductions in the complexity of primary cortical neurons
O'Farrell, K., Fagan, E., Connor, T., & Harkin, A. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.07.008 · Cited by 38
Aromatic amino acid aminotransferases in plants
Wang, M., & Maeda, H. A. (2017) · Phytochemistry Reviews · doi:10.1007/s11101-017-9520-6 · Cited by 42
“Kynurenine is an intermediate of Trp catabolism towards the generation of neuroactive compounds, kynurenate, 3-hydroxykynurenine, and quinolinate, in the mammalian brain (Schwarcz et al. 2012).”
Background
Elevated Levels of Peripheral Kynurenine Decrease Bone Strength in Rats with Chronic Kidney Disease
Kałaska, B., Pawlak, K., Domaniewski, T., Oksztulska-Kolanek, E., Znorko, B., Roszczenko, A., Rogalska, J., Brzoska, M. M., Lipowicz, P., Doroszko, M., et al. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00836 · Cited by 42
Kynurenic Acid Protects against Thioacetamide-Induced Liver Injury in Rats
Marciniak, S., Wnorowski, A., Smolińska, K., Walczyna, B., Turski, W. A., Kocki, T., Paluszkiewicz, P., & Parada-Turska, J. (2018) · Analytical Cellular Pathology · doi:10.1155/2018/1270483 · Cited by 44
“anticonvulsant, anti-inflammatory, and antioxidant qualities are thoroughly documented [12, 13].”
Background
Metabolic dysfunctions in the kynurenine pathway, noradrenergic and purine metabolism in schizophrenia and bipolar disorders
Steen, N. E., Dieset, I., Hope, S., Vedal, T. S. J., Smeland, O. B., Matson, W. R., Kaddurah‐Daouk, R., Agartz, I., Melle, I. S., Djurovic, S., et al. (2019) · Psychological Medicine · doi:10.1017/s0033291719000400 · Cited by 43
“In the case of the kynurenine pathway, peripheral kynurenine and probably 3OHKY readily crosses the blood-brain barrier and influence the central kynurenine pathway metabolism (Fukui et al., 1991; Schwarcz et al., 2012; Hestad et al., 2017), indicating the utility of blood sampling, especially as the method enables a…”
BackgroundMethod
A Novel, Robust Method for Quantification of Multiple Kynurenine Pathway Metabolites in the Cerebrospinal Fluid
Schwieler, L., Trepci, A., Krzyżanowski, S., Hermansson, S., Granqvist, M., Piehl, F., Venckūnas, T., Brazaitis, M., Kamandulis, S., Lindqvist, D., et al. (2020) · Bioanalysis · doi:10.4155/bio-2019-0303 · Cited by 43
An emerging role for microglia in stress‐effects on memory
Sanguino‐Gómez, J., Buurstede, J. C., Abiega, O., Fitzsimons, C. P., Lucassen, P. J., Eggen, B. J. L., Lesuis, S. L., Meijer, O. C., & Krugers, H. J. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.15188 · Cited by 43
“Kynurenine is further metabolized to, among others, quinolinic acid (Schwarcz et al., 2012).”
Background
Directly and Indirectly Targeting the Glycine Modulatory Site to Modulate NMDA Receptor Function to Address Unmet Medical Needs of Patients With Schizophrenia
Pei, J.-C., Luo, D.-Z., Gau, S.-S., Chang, C., & Lai, W. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.742058 · Cited by 48
Meningeal dendritic cells drive neuropathic pain through elevation of the kynurenine metabolic pathway in mice
Maganin, A. G. M., de Souza, G. R., Fonseca, M. M., Lopes, A. H., Guimarães, R. M., Dagostin, A., Cecílio, N. T., Mendes, A. S., Gonçalves, W. A., Silva, C. E. A., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci153805 · Cited by 48
“Elevated levels of kynurenine metabolites in the CNS, especially 3-Hk and QA, might cause neuronal dysfunction and damage, processes that are dependent on an increase in oxidative stress and glutamatergic N-methyl-D-aspartate (NMDA) receptor activation, respectively (16, 17).”
BackgroundInfluential

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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