Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration

Metabolites of the kynurenine pathway, produced through tryptophan degradation, are increasingly recognized for their role in neurodegenerative diseases such as Alzheimer’s and Huntington’s. In these conditions, reduced levels of kynurenic acid—a neuroprotective metabolite—have been associated with glutamate receptor-mediated excitotoxicity and oxidative stress. In this study, we report the synthesis and characterization of JM6, a small-molecule prodrug that inhibits kynurenine 3-monooxygenase (KMO). Chronic oral administration of JM6 effectively inhibits peripheral KMO activity, resulting in elevated kynurenic acid levels and reduced extracellular glutamate in the brain. In a transgenic mouse model of Alzheimer’s disease, JM6 prevents spatial memory impairments, anxiety-like behavior, and synaptic degeneration. In a Huntington’s disease mouse model, JM6 extends lifespan, preserves synaptic integrity, and reduces microglial activation. These results highlight the therapeutic potential of targeting peripheral tryptophan metabolism to modulate central nervous system pathology and support JM6 Ro 61-8048 as a promising candidate for treating neurodegenerative disorders.