ArticleProceedings of the National Academy of Sciences of the United States of America2016
Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 87 papers.
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Who cites it
87 citing papers in PubMed, 152 citations in OpenAlex.
- Significance of NAD anabolism profiles in neurological diseases.Metabolic brain disease · 2026Review
- Tryptophan metabolism in glaucomatous optic neuropathy: from metabolic dysregulation to therapeutic opportunities.Journal of translational medicine · 2026Review
- Molecular mechanisms and therapeutic potential of tryptophan metabolism in gut-brain signaling transduction: a narrative review.Journal of neuroinflammation · 2026Review
- IDO family: the metabolic crossroads connecting immunity, nerves and tumors.Journal of translational medicine · 2026Review
- Microglia-derived metabolites as novel signaling molecules: regulating neural circuit function, behavior, and their role in psychiatric disorders.Frontiers in cellular neuroscience · 2026Review
- Histone deacetylase SIRT6 regulates tryptophan catabolism and prevents metabolite imbalance associated with neurodegeneration.Nature communications · 2025Article
- Article
- Hippocampal GPR35 Participates in the Pathogenesis of Cognitive Deficits and Emotional Alterations Induced by AβMolecular neurobiology · 2025Article
- Kynurenine pathway: a possible new mechanism for exercise in the prevention and treatment of Alzheimer's disease.Frontiers in aging neuroscience · 2025Review
- Exploring the Neuroprotective Potential of Polyphenolic Compounds in Mitigating Quinolinic Acid-Induced Neurotoxicity in Alzheimer's Disease.Current Alzheimer research · 2025Article
- Oat Beta-Glucan as a Metabolic Regulator in Early Stage of Colorectal Cancer-A Model Study on Azoxymethane-Treated Rats.International journal of molecular sciences · 2024Article
- A Review on the Role and Function of Cinnabarinic Acid, a "Forgotten" Metabolite of the Kynurenine Pathway.Cells · 2024Review
- Nutrient Metabolites Associated With Low D3Cr Muscle Mass, Strength, and Physical Performance in Older Men.The journals of gerontology. Series A, Biological sciences and medical sciences · 2024Article
- Gut-brain axis and neurodegeneration: mechanisms and therapeutic potentials.Frontiers in neuroscience · 2024Review
- A review of the pharmacological action and mechanism of natural plant polysaccharides in depression.Frontiers in pharmacology · 2024Review
- Kynurenine pathway and its role in neurologic, psychiatric, and inflammatory bowel diseases.Molecular biology reports · 2023Review
- Microbiota-gut-brain axis mechanisms in the complex network of bipolar disorders: potential clinical implications and translational opportunities.Molecular psychiatry · 2023Review
- Brain Kynurenine Pathway Metabolite Levels May Reflect Extent of Neuroinflammation in ALS, FTD and Early Onset AD.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Kynurenic acid blunts A1 astrocyte activation against neurodegeneration in HIV-associated neurocognitive disorders.Journal of neuroinflammation · 2023Article
- The Involvement of Kynurenine Pathway in Neurodegenerative Diseases.Current neuropharmacology · 2023Article
27 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
Metabolites of the kynurenine pathway (KP) of tryptophan (TRP) degradation have been closely linked to the pathogenesis of several neurodegenerative disorders. Recent work has highlighted the therapeutic potential of inhibiting two critical regulatory enzymes in this pathway-kynurenine-3-monooxygenase (KMO) and tryptophan-2,3-dioxygenase (TDO). Much evidence indicates that the efficacy of KMO inhibition arises from normalizing an imbalance between neurotoxic [3-hydroxykynurenine (3-HK); quinolinic acid (QUIN)] and neuroprotective [kynurenic acid (KYNA)] KP metabolites. However, it is not clear if TDO inhibition is protective via a similar mechanism or if this is instead due to increased levels of TRP-the substrate of TDO. Here, we find that increased levels of KYNA relative to 3-HK are likely central to the protection conferred by TDO inhibition in a fruit fly model of Huntington's disease and that TRP treatment strongly reduces neurodegeneration by shifting KP flux toward KYNA synthesis. In fly models of Alzheimer's and Parkinson's disease, we provide genetic evidence that inhibition of TDO or KMO improves locomotor performance and ameliorates shortened life span, as well as reducing neurodegeneration in Alzheimer's model flies. Critically, we find that treatment with a chemical TDO inhibitor is robustly protective in these models. Consequently, our work strongly supports targeting of the KP as a potential treatment strategy for several major neurodegenerative disorders and suggests that alterations in the levels of neuroactive KP metabolites could underlie several therapeutic benefits.
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