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Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration.

Daniel D Zwilling, Shao-Yi SY Huang, Korrapati V KV Sathyasaikumar, Francesca M FM Notarangelo, Paolo P Guidetti, Hui-Qiu HQ Wu, Jason J Lee, Jennifer J Truong, Yaisa Y Andrews-Zwilling, Eric W EW Hsieh, Jamie Y JY Louie, Tiffany T Wu, Kimberly K Scearce-Levie, Christina C Patrick, Anthony A Adame, Flaviano F Giorgini, Saliha S Moussaoui, Grit G Laue, Arash A Rassoulpour, Gunnar G Flik, Yadong Y Huang, Joseph M JM Muchowski, Eliezer E Masliah, Robert R Schwarcz, and Paul J PJ Muchowski

Cell 145(6):863-74 (2011) PMID 21640374 PMCID PMC3118409

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 Ltd. All rights reserved.

DOI: 10.1016/j.cell.2011.05.020
Version: za2963e q8za3 q8zb8 q8zc1 q8zd3 q8zef q8zfa q8zg3
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