Kynurenine 3-Monooxygenase Inhibition in Blood Ameliorates Neurodegeneration | Zendy

Daniel Zwilling | Zendy; Shao-Yi Huang | Zendy; Korrapati V. Sathyasaikumar | Zendy; Francesca M. Notarangelo | Zendy; Paolo Guidetti | Zendy; HuiQiu Wu | Zendy; Jason H. Lee | Zendy; Jennifer K. Truong | Zendy; Yaisa AndrewsZwilling | Zendy; Eric Hsieh | Zendy; Jamie Louie | Zendy; Tiffany Wu | Zendy; Kimberly ScearceLevie | Zendy; Christina Patrick | Zendy; Anthony Adame | Zendy; Flaviano Giorgini | Zendy; Saliha Moussaoui | Zendy; Grit Laue | Zendy; Arash Rassoulpour | Zendy; Gunnar Flik | Zendy; Yadong Huang | Zendy; Joseph M. Muchowski | Zendy; Eliezer Masliah | Zendy; Robert Schwarcz | Zendy; Paul J. Muchowski | Zendy

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Kynurenine 3-Monooxygenase Inhibition in Blood Ameliorates Neurodegeneration

Author(s) -

Daniel Zwilling,

Shao-Yi Huang,

Korrapati V. Sathyasaikumar,

Francesca M. Notarangelo,

Paolo Guidetti,

HuiQiu Wu,

Jason H. Lee,

Jennifer K. Truong,

Yaisa AndrewsZwilling,

Eric Hsieh,

Jamie Louie,

Tiffany Wu,

Kimberly ScearceLevie,

Christina Patrick,

Anthony Adame,

Flaviano Giorgini,

Saliha Moussaoui,

Grit Laue,

Arash Rassoulpour,

Gunnar Flik,

Yadong Huang,

Joseph M. Muchowski,

Eliezer Masliah,

Robert Schwarcz,

Paul J. Muchowski

Publication year - 2011

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2011.05.020

Subject(s) - kynurenic acid , kynurenine , quinolinic acid , neuroprotection , neurodegeneration , kynurenine pathway , biology , excitotoxicity , indoleamine 2,3 dioxygenase , glutamate receptor , pharmacology , microdialysis , neuroscience , biochemistry , extracellular , medicine , receptor , tryptophan , disease , amino acid

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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