Kynurenine 3-Monooxygenase Inhibition in Blood Ameliorates Neurodegeneration

Abstract

SUMMARY Metabolites in the kynurenine pathway of tryptophan degradation are thought to play an important role in neurodegenerative disorders such as Alzheimer’s disease and Huntington’s disease. Metabolites that cause glutamate receptor-mediated excitotoxicity and free radical formation are elevated in the blood and vulnerable brain regions in these diseases, while levels of the neuroprotective metabolite kynurenic acid are often decreased. Here we describe the synthesis and characterization of JM6, a novel small-molecule pro-drug inhibitor of kynurenine 3-monooxygenase (KMO). JM6 raises kynurenic acid and reduces extracellular glutamate in the brain after chronic oral administration by inhibiting KMO in blood. In a transgenic mouse model of Alzheimer’s disease, JM6 prevented spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extended life span, prevented synaptic loss, and decreased microglial activation in a mouse model of Huntington’s disease. These findings support a critical link between blood cells and neurodegeneration that is mediated by KMO and the kynurenine pathway.

Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity

“…Kynurenine enzymes are being pursued as clinical targets for neurodegenerative and inflammatory disease, with at least two studies reporting that pharmacological inhibitors improve cognition (Pocivavsek et al ., 2011; Zwilling et al ., 2011). Mechanistic differences between branches of the kynurenine pathway are directly relevant to age‐associated disease in humans, where the dominant pathway branch varies by cell and tissue type (Schwarcz et al ., 2012).…”

A Small-Molecule Screen Identifiesl-Kynurenine as a Competitive Inhibitor of TAA1/TAR Activity in Ethylene-Directed Auxin Biosynthesis and Root Growth inArabidopsis

“…Kyn, KYNA (one branch of Kyn metabolism), 3-hydroxykynurenine, and quinolinic acid (another branch of Kyn metabolism) are all neuroactive compounds that play important roles in neurodegenerative disorders, including Alzheimer's and Huntington's diseases (Schwarcz et al, 1983;Foster et al, 1984;Sas et al, 2007). Recently, the augmentation of the KYNA-to-3-hydroxykynurenine ratio by genetic or pharmacological approaches was shown to have potential therapeutic benefits in both fly and mouse Huntington's disease models (Campesan et al, 2011;Zwilling et al, 2011). However, it has been reported that most core enzymes in Kyn metabolism could not be found in the Arabidopsis genome (Katoh and Hashimoto, 2004).…”

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

“…Microglia produce quinolinic acid (QA), a selective NMDAR agonist and a metabolite of the tryptophan degradation pathway, that elicits symptoms reminiscent of HD when injected into the striatum, and symptoms similar to AD when injected into the nucleus basalis of rodents 35 . A recent study furthermore demonstrates that inhibiting kynurenine 3-monooxygenase, an enzyme in the pathway generating QA, can ameliorate excitotoxicity and disease phenotypes in mouse models of both AD and HD 35 .…”

“…Alterations in microglial tryptophan metabolism, leading to increased release of neurotoxic metabolites 5,14,35 Neurotrophic factor related abnormalities…”