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Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration |
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| Authors: | Zwilling Daniel Huang Shao-Yi Sathyasaikumar Korrapati V Notarangelo Francesca M Guidetti Paolo Wu Hui-Qiu Lee Jason Truong Jennifer Andrews-Zwilling Yaisa Hsieh Eric W Louie Jamie Y Wu Tiffany Scearce-Levie Kimberly Patrick Christina Adame Anthony Giorgini Flaviano Moussaoui Saliha Laue Grit Rassoulpour Arash Flik Gunnar Huang Yadong Muchowski Joseph M Masliah Eliezer Schwarcz Robert Muchowski Paul J |
| Affiliation: | 1 Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA 2 Department of Biochemistry and Biophysics and Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA 3 Taube-Koret Center for Huntington's Disease Research and The Hellman Family Foundation Program in Alzheimer's Disease Research, San Francisco, CA 94158, USA 4 Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD 21228, USA 5 Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA 6 Department of Genetics, University of Leicester, Leicester LE1 7RH, UK 7 Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland 8 Brains On-Line BV, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands |
| 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. |
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