The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.
Kynurenine 3-Monooxygenase Inhibition in Blood Ameliorates Neurodegeneration
Open accessAbstract
SUMMARY Metabolites in the kynurenine pathway of tryptophan degradation are thought to play an important role in neurodegenerative disorders such as Alzheimer’s disease and Huntington’s disease. Metabolites that cause glutamate receptor-mediated excitotoxicity and free radical formation are elevated in the blood and vulnerable brain regions in these diseases, while levels of the neuroprotective metabolite kynurenic acid are often decreased. Here we describe the synthesis and characterization of JM6, a novel small-molecule pro-drug inhibitor of kynurenine 3-monooxygenase (KMO). JM6 raises kynurenic acid and reduces extracellular glutamate in the brain after chronic oral administration by inhibiting KMO in blood. In a transgenic mouse model of Alzheimer’s disease, JM6 prevented spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extended life span, prevented synaptic loss, and decreased microglial activation in a mouse model of Huntington’s disease. These findings support a critical link between blood cells and neurodegeneration that is mediated by KMO and the kynurenine pathway.
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Scherzinger, E., Lurz, R., Turmaine, M., Mangiarini, L., Hollenbach, B., Hasenbank, R., Bates, G. P., Davies, S. W., Lehrach, H., & Wanker, E. E. (1997) · Cell · doi:10.1016/s0092-8674(00)80514-0 · Cited by 1,291 · cited 2×
“R6/2 mice also display neuronal inclusion bodies (Scherzinger et al., 1997), a pathological hallmark of HD and other polyglutamine diseases (DiFiglia et al.”
Deficient glutamate tranport is associated with neurodegeneration in Alzheimer's disease
Masliah, E., Hansen, L., Alford, M., Deteresa, R., & Mallory, M. (1996) · Annals of Neurology · doi:10.1002/ana.410400512 · Cited by 476
Yamamoto, M., Kiyota, T., Horiba, M., Buescher, J. L., Walsh, S. M., Gendelman, H. E., & Ikezu, T. (2007) · The American Journal of Pathology · doi:10.2353/ajpath.2007.060378 · Cited by 367
Cited by
Bates, G. P., Dorsey, R., Gusella, J. F., Hayden, M. R., Kay, C., Leavitt, B. R., Nance, M., Ross, C. A., Scahill, R. I., Wetzel, R., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.5 · Cited by 1,641
Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets
Gao, C., Jiang, J., Tan, Y., & Chen, S. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01588-0 · Cited by 1,616
Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond
Platten, M., Nollen, E. A. A., Röhrig, U. F., Fallarino, F., & Opitz, C. A. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0016-5 · Cited by 1,586
Kynurenines in the mammalian brain: when physiology meets pathology
Schwarcz, R., Bruno, J. P., Muchowski, P. J., & Wu, H.-Q. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3257 · Cited by 1,530
Self-citationNAD+ in Brain Aging and Neurodegenerative Disorders
Lautrup, S., Sinclair, D. A., Mattson, M. P., & Fang, E. F. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.09.001 · Cited by 790
Metadata
- Authors
- Zwilling, D., Huang, S.-Y., Sathyasaikumar, K. V., Notarangelo, F. M., Guidetti, P., Wu, H.-Q., Lee, J., Truong, J., Andrews-Zwilling, Y., Hsieh, E. W., Louie, J. Y., Wu, T., Scearce-Levie, K., Patrick, C., Adame, A., Giorgini, F., Moussaoui, S., Laue, G., Rassoulpour, A., Flik, G., Huang, Y., Muchowski, J. M., Masliah, E., Schwarcz, R., & Muchowski, P. J.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2011-06
- Volume
- 145
- Issue
- 6
- Pages
- 863-874
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W1990286385
- Cited by
- 515
- References
- 3
- FWCI
- 9.79
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Zwilling, D., Huang, S.-Y., Sathyasaikumar, K. V., Notarangelo, F. M., Guidetti, P., Wu, H.-Q., Lee, J., Truong, J., Andrews-Zwilling, Y., Hsieh, E. W., Louie, J. Y., Wu, T., Scearce-Levie, K., Patrick, C., Adame, A., Giorgini, F., Moussaoui, S., Laue, G., Rassoulpour, A., . . . Muchowski, P. J. (2011). Kynurenine 3-Monooxygenase Inhibition in Blood Ameliorates Neurodegeneration. Cell. https://doi.org/10.1016/j.cell.2011.05.020
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
