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Kynurenine 3-monooxygenase Inhibition in Blood Ameliorates Neurodegeneration

Kynurenine 3-monooxygenase Inhibition in Blood Ameliorates Neurodegeneration

Daniel Zwilling, Shao-Yi Huang, Korrapati V Sathyasaikumar, Francesca M Notarangelo, Paolo Guidetti, Hui-Qiu Wu, Jason Lee, Jennifer Truong, Yaisa Andrews-Zwilling, Eric W Hsieh, Jamie Y Louie, Tiffany Wu, etc.

Cell. 2011 Jun 10;145(6):863-74.

PMID: 21640374

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1008119832	JM6		1008119-83-2	Price

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