Characterisation of kynurenine pathway metabolism in human astrocytes and implications in neuropathogenesis
Open accessAbstract
The role of astrocytes in the production of the neurotoxin quinolinic acid (QUIN) and other products of the kynurenine pathway (KP) is controversial. Using cytokine-stimulated human astrocytes, we assayed key enzymes and products of the KP. We found that astrocytes lack kynurenine-hydroxylase so that large amounts of kynurenine (KYN) and kynurenic acid (KYNA) were produced, while minor amounts of QUIN were synthesised that were completely degraded. We then showed that kynurenine added to macrophages led to significant production of QUIN. These results suggest that astrocytes alone are neuroprotective by minimising QUIN production and maximising synthesis of KYNA. However, it is likely that, in the presence of macrophages and/or microglia, astrocytes are neurotoxic by producing large concentrations of KYN that can be metabolised by neighbouring monocytic cells to QUIN.
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In the brain, KYN is metabolized by microglia to the neurotoxic metabolite QUIN and by astrocytes to the beneficial metabolite kynurenic acid; thus QUIN is increased and KynA is decreased in MDD patients' brain.
“In brain, KYN is metabolized by microglia to the neurotoxic metabolite QUIN and by astrocytes to the beneficial metabolite kynurenic acid (KynA), thus, QUIN is increased and KynA is decreased in MDD patients’ brain. 141 , 254 , 255”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [255]
The Discussion (page unavailable) says astrocytes produce KYNA and may supply KYN for QUIN synthesis by activated microglia; the paper directly demonstrates QUIN production from KYN in macrophages. It does not examine MDD patients’ brains or establish that QUIN is increased and KynA decreased in them. (LLM, conf=0.90)
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References 10 · Cited by 108
Research works printed but not linked: 3
- Guillemin G, Boussin F, Croitoru J, Le Grand R, Dormont D. Obtention and characterization of astrocytes and microglia from adult monkey brains. J Neurosci Res 1997; 49: 576-591.
- Kerr SJ et al. Kynurenine pathway inhibition reduces toxicity of HIV-infected macrophages. Neurology 1997; 49: 1671-1681.
- Brew BJ, Wesselingh SL, Gonzales M, Heyes MP, Price RW. How HIV leads to neurological disease. Med J Aust 1996; 164: 233-234.
- Authors
- Guillemin, G. J., Smith, D. G., Kerr, S. J., Smythe, G. A., Kapoor, V., Armati, P. J., & Brew, B. J.
- Affiliations
- St Vincent's Hospital Sydney (AU)
- UNSW Sydney (AU)
- The University of Sydney (AU)
- Venue
- Redox Report
- Publisher
- Informa UK Limited
- Published
- 2000-04
- Volume
- 5
- Issue
- 2-3
- Pages
- 108-111
- ISSN
- 1351-0002 (ISSN-L)
- 1743-2928
- OpenAlex
- W2043077656
- Cited by
- 108
- References
- 10
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 7 · 2023: 3 · 2022: 7 · 2021: 5 · 2020: 3 · 2019: 2 · 2018: 2 · 2017: 6 · 2016: 7 · 2015: 6 · 2014: 4 · 2013: 7 · 2012: 6
- FWCI
- 1.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Redox Report (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- Sidaction
- Institut National de la Santé et de la Recherche Médicale
- National Health and Medical Research Council
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- kynurenine pathway, astrocytes, quinolinic acid, kynurenic acid, kynurenine, kynurenine hydroxylase, neurotoxicity, neuroprotection, macrophages, microglia, cytokine induction, neuropathogenesis
- MeSH terms
- Astrocytes, Cells, Cultured, Fetus, Humans, Interferon-gamma, Interleukin-1, Kynurenic Acid, Kynurenine, Models, Biological, Neurotoxins, Tumor Necrosis Factor-alpha, Interleukin-6, Granulocyte-Macrophage Colony-Stimulating Factor, Quinolinic Acid
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