Kynurenine 3-monoxygenase in blood ameloriates neurodegeneration
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Zwilling, Daniel, Huang, Shao-Yi, Guidetti, Paolo, Lee, Jason, Truong, Jennifer, Andrews-Zwilling, Yaisa, Hsieh, Eric, Louie, Jamie, Wu, Tiffany, Scearce-Levie, Kimberly, Wu, Hui-Qiu, Patrick, Christina, Adame, Anthony, Giorgini, Flaviano, Moussaoui, Saliha, Laue, Grit, Rassoulpour, Arash, Huang, Yadong, Muchowski, Joseph M, Masliah, Eliezer, Schwarcz, Robert and Muchowski, Paul J (2011) Kynurenine 3-monoxygenase in blood ameloriates neurodegeneration. Cell, 145 (6). pp. 863-874. ISSN 0092-8674
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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| Additional Information: | JM6 is patented by Dr Paul J. Muchowski et al. (Gladstone Institute of Neurological Disease, University of California, San Francisco, California, 94158, USA). Data generated in different academic laboratories (see below list of authors) Novartis contribution : limited to some support on pharmacokinetics and some pharmacodynamics data. No metabolism studies and no contribution in full profiling of JM6 compound (eg in relation to pro-drug claims). The academic authors remain responsible of their conclusion Authors of the paper: Daniel Zwilling1,*, Shao-Yi Huang1,2,*, Paolo Guidetti3, Jason Lee1, Jennifer Truong1, Yaisa Andrews-Zwilling1, Eric Hsieh1, Jamie Louie1, Tiffany Wu1, Kimberly Scearce-Levie1, Hui-Qiu Wu2, Christina Patrick3, Anthony Adame3, Flaviano Giorgini4, Saliha Moussaoui5, Grit Laue5, Arash Rassoulpour6, Yadong Huang1, Joseph M. Muchowski1, Eliezer Masliah3, Robert Schwarcz3 & Paul J. Muchowski1,2,7** 1Gladstone Institute of Neurological Disease, University of California, San Francisco, California, 94158, USA 2Taube-Koret Center for Huntington’s Disease Research, San Francisco, California, 94158, USA 3Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland 21228, USA 3Department of Neurosciences, University of California, San Diego, La Jolla, California, 92093, USA 4Department of Genetics, University of Leicester, Leicester LE1 7RH, UK 5Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland 6Brains On-Line BV, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands 7Department of Biochemistry and Biophysics, and Department of Neurology, University of California, San Francisco, California, 94158 |
| Keywords: | kynurenine 3-monooxygenase (KMO), tryptophan degradation, excitotoxicity, neurodegeneration, KMO inhibitor JM6, Huntington's disease, Alzheimer's disease |
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| Date Deposited: | 13 Oct 2015 13:15 |
| Last Modified: | 13 Oct 2015 13:15 |
| URI: | https://oak.novartis.com/id/eprint/4049 |