Metabolites of kynurenine pathway (KP) are implicated in the pathophysiology of neurodegenerative disorders including Huntington’s disease (HD). Enzyme Kynurenine 3-monooxygenase (KMO) plays an important role in the KP since its inhibition leads to the increase of neuroactive metabolite kynurenine (KYN) and kynurenic acid (KYNA) and decreases levels of the presumed neurotoxic metabolites 3-hydoxykynurenine (3-HK) and quinolinic acid (QA) in the brain. Inhibition of KMO leads to the increase of kynurenine (KYN) in the blood and peripheral tissues. KYN crosses the BBB and is consequently converted to the KYNA by the enzyme kynurenine aminotransferase (KAT II) in brain astrocytes. Recently, it was demonstrated that peripheral inhibition of KMO with small molecule1or KYNA up-regulation by means of KYNA analogue2,3modulate synaptic plasticity and have neuroprotective and anti-inflammatory role in the Huntington’s disease models. The mechanism how KMO inhibition achieves these effects, i.e. relative contribution and importance of KP metabolites KYN and KYNA in modulation of synaptic plasticity has not yet been elucidated. As a part of our drug development program, CHDI has developed a series of potent KMO inhibitors including the lead KMO inhibitor CHDI-340246, which are promising tools to analyse the consequences of KMO inhibition in animal HD models as well in HD patients through experimental medicine. This talk will describe the CHDI efforts to understand the effects of KMO inhibition in HD rodent models and normal nonhuman primates as well as other experiments towards the translational medicine of KMO inhibitors.
References 1Zwilling et al. Cel2011;145:1–12
2Zadori et al. J. Neural Transm118
3Vecsei et al. Nature Rev Drug Discovery2013;12:64–82
- Kynurenine pathway
- KMO inhibition
- Huntington’s disease
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