ArticleThe FEBS journal2021
Pharmacological validation of TDO as a target for Parkinson's disease.
Article in The FEBS journal, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 28 citations in OpenAlex.
- Cellular and systemic modifiers of alpha-synuclein proteostasis.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2026Review
- IDO family: the metabolic crossroads connecting immunity, nerves and tumors.Journal of translational medicine · 2026Review
- Elevated brain manganese induces motor disease by upregulating the kynurenine pathway of tryptophan metabolism.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Kynurenine Pathway Dysregulation in Parkinson's Disease: Insights for Disease Modulation and Therapy.International journal of tryptophan research : IJTR · 2025Review
- Secondary Sphere Lewis Acid Activated Heme Superoxo Adducts Mimic Crucial Non-Covalent Interactions in IDO/TDO Heme Dioxygenases.Chemistry (Weinheim an der Bergstrasse, Germany) · 2024Article
- Revolutionizing our understanding of Parkinson's disease: Dr. Heinz Reichmann's pioneering research and future research direction.Journal of neural transmission (Vienna, Austria : 1996) · 2024Review
- Prebiotic diet normalizes aberrant immune and behavioral phenotypes in a mouse model of autism spectrum disorder.Acta pharmacologica Sinica · 2024Article
- From the Gut to the Brain: The Role of Enteric Glial Cells and Their Involvement in the Pathogenesis of Parkinson's Disease.International journal of molecular sciences · 2024Review
- Bidirectional communication of the gut-brain axis: new findings in Parkinson's disease and inflammatory bowel disease.Frontiers in neurology · 2024Review
- Cortisol as a Target for Treating Mental Disorders: A Promising Avenue for Therapy.Mini reviews in medicinal chemistry · 2024Review
- Targeting amino acid-metabolizing enzymes for cancer immunotherapy.Frontiers in immunology · 2024Review
- Research progress on the kynurenine pathway in the prevention and treatment of Parkinson's disease.Journal of enzyme inhibition and medicinal chemistry · 2023Review
- Tumor-associated nonmyelinating Schwann cell-expressedScience advances · 2023Article
- Therapeutic Approaches to Non-Motor Symptoms of Parkinson's Disease: A Current Update on Preclinical Evidence.Current neuropharmacology · 2023Article
- The Impact of Gut Microbiota-Derived Metabolites in Autism Spectrum Disorders.International journal of molecular sciences · 2021Review
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Authors and funding
18 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Parkinson's disease patients suffer from both motor and nonmotor impairments. There is currently no cure for Parkinson's disease, and the most commonly used treatment, levodopa, only functions as a temporary relief of motor symptoms. Inhibition of the expression of the L-tryptophan-catabolizing enzyme tryptophan 2,3-dioxygenase (TDO) has been shown to inhibit aging-related α-synuclein toxicity in Caenorhabditis elegans. To evaluate TDO inhibition as a potential therapeutic strategy for Parkinson's disease, a brain-penetrable, small molecule TDO inhibitor was developed, referred to as NTRC 3531-0. This compound potently inhibits human and mouse TDO in biochemical and cell-based assays and is selective over IDO1, an evolutionary unrelated enzyme that catalyzes the same reaction. In mice, NTRC 3531-0 increased plasma and brain L-tryptophan levels after oral administration, demonstrating inhibition of TDO activity in vivo. The effect on Parkinson's disease symptoms was evaluated in a rotenone-induced Parkinson's disease mouse model. A structurally dissimilar TDO inhibitor, LM10, was evaluated in parallel. Both inhibitors had beneficial effects on rotenone-induced motor and cognitive dysfunction as well as rotenone-induced dopaminergic cell loss and neuroinflammation in the substantia nigra. Moreover, both inhibitors improved intestinal transit and enhanced colon length, which indicates a reduction of the rotenone-induced intestinal dysfunction. Consistent with this, mice treated with TDO inhibitor showed decreased expression of rotenone-induced glial fibrillary acidic protein, which is a marker of enteric glial cells, and decreased α-synuclein accumulation in the enteric plexus. Our data support TDO inhibition as a potential therapeutic strategy to decrease motor, cognitive, and gastrointestinal symptoms in Parkinson's disease.
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