title: Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration.
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.
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zwilling
authors.forename: Shao-Yi
authors.initials: SY
authors.lastname: Huang
authors.forename: Korrapati V
authors.initials: KV
authors.lastname: Sathyasaikumar
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Notarangelo
authors.forename: Paolo
authors.initials: P
authors.lastname: Guidetti
authors.forename: Hui-Qiu
authors.initials: HQ
authors.lastname: Wu
authors.forename: Jason
authors.initials: J
authors.lastname: Lee
authors.forename: Jennifer
authors.initials: J
authors.lastname: Truong
authors.forename: Yaisa
authors.initials: Y
authors.lastname: Andrews-Zwilling
authors.forename: Eric W
authors.initials: EW
authors.lastname: Hsieh
authors.forename: Jamie Y
authors.initials: JY
authors.lastname: Louie
authors.forename: Tiffany
authors.initials: T
authors.lastname: Wu
authors.forename: Kimberly
authors.initials: K
authors.lastname: Scearce-Levie
authors.forename: Christina
authors.initials: C
authors.lastname: Patrick
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Flaviano
authors.initials: F
authors.lastname: Giorgini
authors.forename: Saliha
authors.initials: S
authors.lastname: Moussaoui
authors.forename: Grit
authors.initials: G
authors.lastname: Laue
authors.forename: Arash
authors.initials: A
authors.lastname: Rassoulpour
authors.forename: Gunnar
authors.initials: G
authors.lastname: Flik
authors.forename: Yadong
authors.initials: Y
authors.lastname: Huang
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Muchowski
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarcz
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Muchowski
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D001923:Brain Chemistry; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy*; D007736:Kynurenic Acid / Q000032:analysis* / Q000097:blood; D050601:Kynurenine 3-Monooxygenase / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D013844:Thiazoles / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: C560311:2-(3,4-dimethoxybenzenesulfonylamino)-4-(3-nitrophenyl)-5-(piperidin-1-yl)methylthiazole; C110196:Ro 61-8048; D013449:Sulfonamides; D013844:Thiazoles; D050601:Kynurenine 3-Monooxygenase; D007736:Kynurenic Acid