Author/Authors :
Daniel Zwilling، نويسنده , , Shao-Yi Huang، نويسنده , , Korrapati V. Sathyasaikumar، نويسنده , , Francesca M. Notarangelo، نويسنده , , Paolo Guidetti، نويسنده , , Hui-Qiu Wu، نويسنده , , Jason Lee، نويسنده , , Jennifer Truong، نويسنده , , Yaisa Andrews-Zwilling، نويسنده , , Eric W. Hsieh، نويسنده , , Jamie Y. Louie، نويسنده , , Tiffany Wu، نويسنده , , Kimberly Scearce-Levie، نويسنده , , Christina Patrick، نويسنده , , Anthony Adame، نويسنده , , Flaviano Giorgini، نويسنده , , Saliha Moussaoui، نويسنده , , Grit Laue، نويسنده , , Arash Rassoulpour، نويسنده , , Gunnar Flik، نويسنده , , et al.، نويسنده ,
Abstract :
Metabolites in the kynurenine pathway, generated by tryptophan degradation, are thought to play an important role in neurodegenerative disorders, including Alzheimerʹs and Huntingtonʹs 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 Alzheimerʹs 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 Huntingtonʹs 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.
