Kynurenine 3-Monooxygenase Inhibition in Blood Ameliorates Neurodegeneration

被引：441

作者：

Zwilling, Daniel ^{[1
]}

Huang, Shao-Yi ^{[1
,4
,5
]}

Sathyasaikumar, Korrapati V. ^{[6
]}

Notarangelo, Francesca M. ^{[6
]}

Guidetti, Paolo ^{[6
]}

Wu, Hui-Qiu ^{[6
]}

Lee, Jason ^{[1
]}

Truong, Jennifer ^{[1
]}

Andrews-Zwilling, Yaisa ^{[1
]}

Hsieh, Eric W. ^{[1
]}

Louie, Jamie Y. ^{[1
]}

Wu, Tiffany ^{[1
]}

Scearce-Levie, Kimberly ^{[1
]}

Patrick, Christina ^{[7
]}

Adame, Anthony ^{[7
]}

Giorgini, Flaviano ^{[8
]}

Moussaoui, Saliha ^{[9
]}

Laue, Grit ^{[9
]}

Rassoulpour, Arash ^{[10
]}

Flik, Gunnar ^{[10
]}

Huang, Yadong ^{[1
]}

Muchowski, Joseph M. ^{[1
]}

Masliah, Eliezer ^{[7
]}

Schwarcz, Robert ^{[6
]}

Muchowski, Paul J. ^{[1
,2
,3
,4
,5
]}

机构：

[1] Univ Calif San Francisco, Gladstone Inst Neurol Dis, San Francisco, CA 94158 USA

[2] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA

[3] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA

[4] Taube Koret Ctr Huntingtons Dis Res, San Francisco, CA 94158 USA

[5] Hellman Family Fdn Program Alzheimers Dis Res, San Francisco, CA 94158 USA

[6] Univ Maryland, Maryland Psychiat Res Ctr, Sch Med, Baltimore, MD 21228 USA

[7] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

[8] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England

[9] Novartis Inst BioMed Res, CH-4002 Basel, Switzerland

[10] Brains On Line BV, NL-9713 AV Groningen, Netherlands

来源：

CELL | 2011年 / 145卷 / 06期

基金：

美国国家卫生研究院;

关键词：

QUINOLINIC ACID; MOUSE MODEL; TRYPTOPHAN-METABOLISM; ALZHEIMERS-DISEASE; GLUTAMATE UPTAKE; PATHWAY; EXPRESSION; AMINOTRANSFERASE; NEUROTOXICITY; INFLAMMATION;

D O I：

10.1016/j.cell.2011.05.020

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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 smallmolecule 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.

引用

页码：863 / 874

页数：12

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