..inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites, 2019, Zhang et al

Andy · Jan 13, 2020

In animal models.
Full title - A brain-permeable inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites

Dysregulation of the kynurenine pathway (KP) leads to imbalances in neuroactive metabolites associated with the pathogenesis of several neurodegenerative disorders, including Huntington’s disease (HD). Inhibition of the enzyme kynurenine 3-monooxygenase (KMO) in the KP normalises these metabolic imbalances and ameliorates neurodegeneration and related phenotypes in several neurodegenerative disease models. KMO is thus a promising candidate drug target for these disorders, but known inhibitors are not brain permeable. Here, 19 new KMO inhibitors have been identified. One of these (1) is neuroprotective in a Drosophila HD model but is minimally brain penetrant in mice. The prodrug variant (1b) crosses the blood–brain barrier, releases 1 in the brain, thereby lowering levels of 3-hydroxykynurenine, a toxic KP metabolite linked to neurodegeneration. Prodrug 1b will advance development of targeted therapies against multiple neurodegenerative and neuroinflammatory diseases in which KP likely plays a role, including HD, Alzheimer’s disease, and Parkinson’s disease.
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Open access, https://www.nature.com/articles/s42003-019-0520-5

mariovitali · Jan 13, 2020

This i believe is one of the most relevant parts to ME (hypothesis) :

Indeed, studies indicate that KP metabolite imbalances leading to elevated levels of the free-radical generator 3-hydroxykynurenine (3-HK) and the excitotoxin quinolinic acid (QUIN) relative to the neuroprotective metabolite kynurenic acid (KYNA) (Fig. 1) contribute to pathogenesis8. Upregulation of the central neurotoxic branch of the KP is linked to expression of proinflammatory cytokines during inflammation, which increases expression of KMO and indoleamine-2, 3-dioxygenase 19
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rvallee · Jan 13, 2020

I can't make sense of it all but there seems to be a lot of research on the kynurenine pathway, it just keeps popping up. Hopefully this becomes relevant to us, if the findings hold up.

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..inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites, 2019, Zhang et al

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..inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites, 2019, Zhang et al

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