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Novel 'prodrug' alleviates symptoms in Huntington's and Alzheimer's mice
Date:6/2/2011

A study in a special early online publication of Cell, a Cell Press publication, reveals a promising new slow-release compound that protects mice against the neurodegenerative effects of both Huntington's and Alzheimer's disease. The 'prodrug' known only as JM6 works through a pathway involved in the breakdown of the amino acid tryptophan.

Surprisingly, JM6 delivers those benefits even though it doesn't cross the blood-brain barrier and therefore cannot act directly on the brain.

"Most would have assumed that the drug would have to enter the brain to have an effect," said Paul Muchowski of the University of California, San Francisco. He says the new study may therefore pave the way to new strategies for the treatment of brain diseases more broadly.

The kynurenine pathway is a major route of tryptophan breakdown. Scientists had suspected the pathway to play a role in neurodegeneration since the late 1970s, Muchowski said. Metabolites of the pathway can lead to excessive stimulation of neurons, causing damage and even death of the cells.

Muchowski's team started with a compound earlier designed to target an enzyme called kynurenine 3-monooxygenase or KMO.When KMO is inhibited, it shunts the kynurenine pathway in a direction that increases production of a neuroprotective compound known as kynurenic acid (KYNA). KYNA levels are known to decline in Huntington's and Alzheimer's brains.

But the researchers found that the starting compound (Ro 61-8048) was unstable and degraded quickly. Fortunately for Muchowski, his recently retired father Joseph Muchowski is a synthetic chemist with experience in drug development. He enlisted him in generating a slow-release prodrug version of the KMO inhibitor, which they call JM6.

They first treated mice with Huntington's disease with JM6. Chronic delivery of JM6 inhibited KMO in the animals' blood, increasing kynurenic acid levels and reducing extracellular levels of t
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Contact: Elisabeth Lyons
elyons@cell.com
617-386-2121
Cell Press
Source:Eurekalert

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