In an international study, Northwestern Medicine scientists and colleagues have identified a novel strategy for reducing the side effects of uncontrolled movement caused by the drug levodopa, commonly used to treat the stiffness, tremors and poor muscle control of Parkinson’s disease. These unwanted movements caused by levodopa significantly diminish the quality of life for Parkinson’s disease patients. A team lead by D. James Surmeier, PhD, chair and Nathan Smith Davis Professor of Physiology found neurons in the brain responsible for the side effects have a distinctive surface receptor that normally helps balance the effects of levodopa treatment. When mouse or primate models of Parkinson’s disease were given a compound that boosts functioning of this receptor, the uncontrolled motor side effects of levodopa treatment were dramatically reduced.
In the study, the team of researchers discovered that the brain neurons responsible for levodopa’s side effects have a unique surface receptor that should normally help balance the effects of the drug. When mice and monkeys with Parkinson-like diseases were given a new compound that boosted the function of the receptor, there was a sharp drop in uncontrolled movement caused by levodopa, Surmeier’s team said. Dr. Nora Chan directs the movement disorders program at Winthrop-University Hospital in Mineola, N.Y. She said that, as it stands now, “There is no consistently effective way to treat dyskinesias pharmacologically without compromising patients’ motor function.”She called the new study “promising.” However, success in animal studies doesn’t always pan out in patients, so the compound’s “application in humans still needs to be examined,” Chan said.
Although this new compound, an M4 muscarinic receptor positive allosteric modulator is not currently approved for human use, it is in development with the goal of clinical trials, a phase I trial possibly starting by 2017. “There has been an international effort to find a drug that can be combined with levodopa to reduce the uncontrolled movement,” Surmeier said. “If clinical trials confirm our preliminary findings, the eventual drug developed could make a significant improvement in the quality of life for people with Parkinson’s disease.” Surmeier’s effort was built upon previous work of his lab and other research exploring the striatum, a part of the brain circuitry targeted by levodopa and thought to drive dyskinesia. At doses of levodopa treatment that produce dyskinesia, part of the striatal network becomes abnormally re-wired.
They found a protein in one type of these striatal neurons that could counter-balance the effects of levodopa without diminishing its positive effect on movement. By using a novel class of drug, one that augments the normal function of the receptor, scientists could boost function of this ‘balancing’ M4 muscarinic receptor. This novel compound or drug lead was developed by the group of Jeffrey Conn at Vanderbilt University in Nashville, Tennessee. While all of the studies in Surmeier’s lab and that of his collaborator Angela Cenci Nilsson, MD, PhD, of Lund University in Sweden, were conducted in mice, scientists wanted to make sure they were relevant to humans. To test the effects in non-human primates, Erwan Bezard, PhD, and his group in Bordeaux, France, gave a variant of the compound tested in mice to Parkinsonian primates. As in the mice, the novel compound significantly reduced dyskinesia induced by levodopa treatment without compromising its symptomatic benefit.
Parkinson’s is the second most common neurodegenerative disease in the U.S., affecting more than a million people, a number expected to double by 2030. In its early stages, the primary symptom of the disease, difficulty moving can be effectively treated by levodopa. But as the disease progresses, the dose of levodopa required to alleviate symptoms rises and side effects begin to appear. The most prominent of these is uncontrolled movement or dyskinesia. There are no treatment strategies that can help other than neurosurgery.
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