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Title: Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration.
Authors: Zwilling, D
Huang, SY
Sathyasaikumar, KV
Notarangelo, FM
Guidetti, P
Wu, HQ
Lee, J
Truong, J
Andrews-Zwilling, Y
Hsieh, EW
Louie, JY
Wu, T
Scearce-Levie, K
Patrick, C
Adame, A
Giorgini, Flaviano
Moussaoui, S
Laue, G
Rassoulpour, A
Flik, G
Huang, Y
Muchowski, JM
Masliah, E
Schwarcz, R
Muchowski, PJ
First Published: 10-Jun-2011
Citation: CELL, 2011, 145 (6), pp. 863-874
Abstract: Metabolites in the kynurenine pathway, generated by tryptophan degradation, are thought to play an important role in neurodegenerative disorders, including Alzheimer's and Huntington's diseases. In these disorders, glutamate receptor-mediated excitotoxicity and free radical formation have been correlated with decreased levels of the neuroprotective metabolite kynurenic acid. Here, we describe the synthesis and characterization of JM6, a small-molecule prodrug inhibitor of kynurenine 3-monooxygenase (KMO). Chronic oral administration of JM6 inhibits KMO in the blood, increasing kynurenic acid levels and reducing extracellular glutamate in the brain. In a transgenic mouse model of Alzheimer's disease, JM6 prevents spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extends life span, prevents synaptic loss, and decreases microglial activation in a mouse model of Huntington's disease. These findings support a critical link between tryptophan metabolism in the blood and neurodegeneration, and they provide a foundation for treatment of neurodegenerative diseases.
DOI Link: 10.1016/j.cell.2011.05.020
eISSN: 1097-4172
Type: Journal Article
Appears in Collections:Published Articles, Dept. of Genetics

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