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Oren Levy, M.D., Ph.D.
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Manolo Carta, Ph.D.
Could it be that the involuntary writhing movements experienced by many people as Parkinson’s disease (PD) progresses are caused by serotonin neurons?
During his time as a Parkinson’s Disease Foundation (PDF) research fellow in 2007, Manolo Carta, Ph.D., of Cagliari University in Italy, found evidence to support this theory. In collaboration with Anders Björklund, M.D., at Lund University in Sweden (also previously supported by PDF), Dr. Carta used funding from PDF to investigate the role of serotonin neurons, and how they may be manipulated to prevent or suppress dyskinesias.
Dyskinesias can occur in the later stages of Parkinson’s and are caused by levodopa (Sinemet®). Dr. Carta suggests that it is serotonin neurons — not the dopamine neurons normally implicated in Parkinson’s — that work with levodopa to cause dyskinesias.
It is known that when a person takes levodopa, dopamine neurons in the brain convert the medication into dopamine. The extra dopamine helps to ease the symptoms of Parkinson’s. The dopamine neurons have a “feedback control mechanism” that ensures they release just the right amount.
But as Parkinson’s progresses, and more levodopa is required, serotonin neurons also pitch in to convert levodopa to dopamine. Unlike dopamine neurons, however, serotonin neurons cannot regulate the release of dopamine. They sometimes release excessive levels, causing dyskinesias.
Dr. Carta and Dr. Björklund theorized that if scientists could find a way to suppress this overproduction, they might be able to stop the dyskinesias.
They tested a combination of two serotonin agonists — both designed to stop serotonin neurons from producing dopamine — at very low doses in animal models. They found that this combination was effective in preventing too much dopamine from being released and — when administered from the very first dose of levodopa — were also effective in stopping the cellular changes that lead to dyskinesias.
These findings led Dr. Carta to develop a compound that would imitate these effects and work in humans.
The compound is in an early stage clinical trial, where it is being evaluated for efficacy and safety. The first round of results is expected later this year. If successful, one possible outcome would be the development of a drug that would offer the anti-parkinsonian benefits of levodopa but suppress the dyskinetic side effects.
Dr. Carta’s work has added valuable insight into the mechanisms behind dyskinesias. Certainly any new knowledge about this common medication side effect is welcome by the Parkinson’s community. Dr. Carta noted, "PDF's early support first allowed us to explore the potential of this idea, which in turn enabled its progression to a clinical trial. We look forward to reporting results to the community as they are released."
Dr. Carta is assistant professor at the University of Cagliari in Italy, and still actively collaborates with Dr. Björklund. Dr. Carta was funded through the Research Fellowships Program. In FY2012, PDF is supporting five research fellowships with total funding of $250,000.