The main drug used by millions of people with Parkinson’s disease could be made more effective and have its side effects limited, new research into gut bacteria and enzymes suggests.
Levodopa is used to treat many of the symptoms experienced by the 10 million people with Parkinson’s. The drug works by passing the blood-brain barrier and releasing dopamine in the brain.
But some of the drug is converted to dopamine before it gets there, which can cause adverse side effects and limit the drug’s effectiveness. A particular problem is that the drug is broken down by enzymes in the gut and blood vessels. For this reason, people with Parkinson’s usually take levodopa in combination with another drug, carbidopa, that inhibits the break down.
Researchers have been working to see how much of a role our microbiome could be playing in the varying responses people experience with levodopa.
Caught in the act
Now a US team has identified the enzymes and organisms in the gut that are responsible for breaking down the drug. “The specific advance is really understanding which specific gut bacteria and enzymes have the potential to metabolise levodopa,” says Emily Balskus at Harvard University.
The team also found a way that could allow more of the drug to make it to the brain. It came in the shape of a small molecule, alpha-fluoromethyltyrosine (AFMT), which in tests in mice showed was able to block the pathway through which the enzymes break down the drug.
“This opens up the door to the possibility of developing a new class of therapeutics to improve patient response to levodopa – that would be drugs targeting gut microbe metabolism in addition to targeting host metabolism,” says Balskus.
In practice, this would mean people with Parkinson’s might take a third drug along with levodopa and carbidopa. But she cautions her work is a proof of concept. “We are a long way from actually developing such a drug.” The research builds on finding published in Nature Communications earlier this year.
Maria Dominguez-Bello at Rutgers University in New Jersey says showing the degradation in the gut of levodopa is of “great clinical importance” and points to the potential to improve treatment for Parkinson’s. One concern, she says, will be whether the third drug has physiological impacts of its own.
David Dexter of the charity Parkinson’s UK says such an approach could reduce the side effects some people with the disease experience. “It has the potential to be impactful. It just needs further research.”
Journal reference: Science, DOI: 10.1126/science.aau6323
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