Cited by 138Tryptophan and brain disordersAmino Acid Enzymes and MetabolismTreatment of Major Depression

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Tryptophan Metabolism in Central Nervous System Diseases: Pathophysiology and Potential Therapeutic Strategies

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Huang, Yinrou, Zhao, Mengke, Chen, Xuemei, Zhang, Ruoyu, Le, Anh, Hong, Michael, Zhang, Yufei, Jia, Lin, Zang, Weidong, Jiang, Chao, Wang, Junmin, Fan, Xiaochong, Wang, Jian·2023·Aging and disease

DOI 10.14336/ad.2022.0916PMC PMC10187711

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Abstract

The metabolism of L-tryptophan (TRP) regulates homeostasis, immunity, and neuronal function. Altered TRP metabolism has been implicated in the pathophysiology of various diseases of the central nervous system. TRP is metabolized through two main pathways, the kynurenine pathway and the methoxyindole pathway. First, TRP is metabolized to kynurenine, then kynurenic acid, quinolinic acid, anthranilic acid, 3-hydroxykynurenine, and finally 3-hydroxyanthranilic acid along the kynurenine pathway. Second, TRP is metabolized to serotonin and melatonin along the methoxyindole pathway. In this review, we summarize the biological properties of key metabolites and their pathogenic functions in 12 disorders of the central nervous system: schizophrenia, bipolar disorder, major depressive disorder, spinal cord injury, traumatic brain injury, ischemic stroke, intracerebral hemorrhage, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Furthermore, we summarize preclinical and clinical studies, mainly since 2015, that investigated the metabolic pathway of TRP, focusing on changes in biomarkers of these neurologic disorders, their pathogenic implications, and potential therapeutic strategies targeting this metabolic pathway. This critical, comprehensive, and up-to-date review helps identify promising directions for future preclinical, clinical, and translational research on neuropsychiatric disorders.

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Figure 1. Tryptophan metabolism by the kynurenine and methoxyindole pathways. Kynurenine is a central KP metabolite capable of degradation through three specific pathways, shown in (1), (2) and (3) in the schematic diagram, to generate different neuroactive metabolites. Abbreviations: TRP, tryptophan; IDO, indoleamine-2,3-dioxygenase; TDO, tryptophan-2,3-dioxygenase; KAT, kynurenine aminotransferase I-III; AA, anthranilic acid; 3-HK, 3-hydroxykynurenine; 3-HAA, 3-hydroxyanthrenillc acid; KMO, kynurenine 3-monooxygenase; HAAO, 3-hydroxyanthranilate 3,4-dioxygenase; KP, kynurenine pathway; KYNA, kynurenic acid; PA, picolinic acid; QUINA, quinolinic acid; TPH, tryptophan hydroxylase; CA, cinnabarinic acid; XA, xanthurenic acid; NAD+, nicotinamide adenine dinucleotide; 5-HT, 5-hydroxytryptophan; TPH, tryptophan hydroxylase.CC BY · PubMed Central

Figure 2. The main branches of the kynurenine pathway. TRP, L-KYN, and 3-HK can penetrate the BBB. Thus, they are converted to different intermediates in the extracellular space of brain tissue. TRP is converted to L-KYN by IDO1 in macrophages. L-KYN is converted to KYNA in astrocytes. 3-HK is converted to QUINA by HAAO in microglia. In diseases other than SCZ, KYNA is neuroprotective, as it can remove ROS and inhibit NMDARs, α7nAch, and AMPARs. QUIN is neurotoxic, as it can increase ROS formation, increase glutamate production, and activate NMDARs. Abbreviations: TRP, tryptophan; 3-HK, 3-hydroxykynurenine; HAAO, 3-hydroxyanthranilate 3,4-dioxygenase; α7nAChR: α7 nicotinic acetylcholine receptor; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor; BBB: blood-brain barrier; IDO, indoleamine-2,3-dioxygenase; KAT, kynurenine aminotransferases I-III; KMO, kynurenine 3-monooxygenase; KYNA, kynurenic acid; L-KYN, L-kynurenine; NMDAR: N-methyl-D-aspartic acid receptor; TRP, tryptophan; QUINA, quinolinic acid; SCZ, schizophrenia; ROS, reactive oxygen speciesCC BY · PubMed Central

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Authors: Huang, Y., Zhao, M., Chen, X., Zhang, R., Le, A., Hong, M., Zhang, Y., Jia, L., Zang, W., Jiang, C., Wang, J., Fan, X., & Wang, J.
Affiliations: First Affiliated Hospital of Zhengzhou University (CN)
Zhengzhou University (CN)
Washington University in St. Louis (US)
Sinai Hospital (US)
University of Washington (US)
Fifth Affiliated Hospital of Zhengzhou University (CN)
Corresponding author: Wang, Junmin
Fan, Xiaochong
Wang, Jian
ORCID: Zhao, Mengke
Chen, Xuemei
Zhang, Ruoyu
Le, Anh
Hong, Michael
Zhang, Yufei
Zang, Weidong
Jiang, Chao
Wang, Junmin
Fan, Xiaochong
Wang, Jian
Venue: Aging and disease
Publisher: Aging and Disease
Published: 2023
Volume: 14
Issue: 3
Pages: 858
ISSN: 2152-5250 (ISSN-L)
DOI: 10.14336/ad.2022.0916
PMC: PMC10187711
OpenAlex: W4312580438
Cited by: 138
References: 198
Citations by year: 2026: 45 · 2025: 55 · 2024: 36 · 2023: 2
FWCI: 1.76
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
Locations: Aging and Disease (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: Zhengzhou University
Topics: Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Keywords: tryptophan metabolism, kynurenine pathway, central nervous system disorders, schizophrenia, bipolar disorder, major depressive disorder, spinal cord injury, traumatic brain injury, ischemic stroke, intracerebral hemorrhage, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, kynurenic acid, quinolinic acid, serotonin, melatonin, biomarkers, treatment options

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Tryptophan Metabolism in Central Nervous System Diseases: Pathophysiology and Potential Therapeutic Strategies

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