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Cell. 2011 Jun 10;145(6):863-74. doi: 10.1016/j.cell.2011.05.020.

Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration.

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  • 1Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA.

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.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
21640374
[PubMed - indexed for MEDLINE]
PMCID:
PMC3118409
Free PMC Article
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