Editors' ChoiceDrug Discovery

Protecting the Protector

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Science Translational Medicine  15 Jun 2011:
Vol. 3, Issue 87, pp. 87ec89
DOI: 10.1126/scitranslmed.3002751

Neurodegenerative disorders such as Alzheimer’s disease and Huntington’s disease are caused by the progressive deterioration and loss of neurons in the brain resulting in a broad swath of cognitive and motor disabilities. There is an urgent need for disease-modifying therapies that can halt or even reverse neuronal loss in these diseases. Zwilling et al. now show that targeting the enzyme kynurenine 3-monooxygenase (KMO) in blood with a small-molecule drug ameliorates symptoms in animal models of Alzheimer’s and Huntington’s disease.

KMO acts at a key branching point in the kynurenine metabolic pathway involved in tryptophan degradation. Inhibition of KMO boosts production of a neuroprotective metabolite called kynurenic acid (KYNA). A decrease in KYNA has been associated with glutamate receptor–mediated excitotoxicity and free radical formation, which are damaging to neurons.

Using the KMO inhibitor Ro61-8048 as a guide, the investigators developed a small-molecule “prodrug” called JM6. This slow-release compound has improved metabolic stability and can be given orally, unlike Ro61-8048. The researchers demonstrated that administration of JM6 to wild-type mice inhibited KMO in blood, resulting in higher concentrations of KYNA in serum and brain and a reduction in extracellular glutamate (an excitatory neurotransmitter) in brain. In a mouse model of Huntington’s disease, mice usually die by 15 weeks of age. However, when these animals were dosed orally with JM6 their survival was extended by 40%, and they exhibited improved motor coordination and lost fewer neuronal synapses. Additionally, in a transgenic mouse model of Alzheimer's disease JM6 ameliorated spatial memory deficits, anxiety-related behaviors, and the decrease in synapses that is associated with memory loss.

The most surprising finding, however, was that JM6 does not cross the blood-brain barrier and therefore cannot act directly on the brain. Rather, the neuroprotective effects of JM6 stem from inhibition of KMO in the peripheral circulation. The protective increase in KYNA concentrations and reduction in extracellular glutamate in the brain that help to preserve neuronal function pinpoint a new therapeutic pathway for treating neurodegeneration. The authors present clear pharmacological evidence that inhibition of KMO is protective in animal models of Alzheimer’s and Huntington’s disease. Targeting this enzyme and the kynurenine pathway may ultimately lead to new therapies to alter the course of these devastating neurodegenerative disorders.

D. Zwilling et al., Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell 145, 863–874 (2011). [Abstract]

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