Scientists have identified a new strategy to attenuate one of the side effects — uncontrolled movement — caused by levodopa, the most effective treatment in the management of Parkinson’s disease symptoms. The study, entitled “M4 Muscarinic Receptor Signaling Ameliorates Striatal Plasticity Deficits in Models of L-DOPA-Induced Dyskinesia,” was published in Neuron.
Levodopa, converted in the brain to dopamine, is one of the main drug therapies used in the management of such PD symptoms as stiffness, tremors, and inadequate muscle control. However, long-term usage can cause a series of side effects that strongly affect patients’ quality of life, especially dyskinesia, or the involuntary and erratic movement of muscles in the face, arms and legs.
To find a possible treatment for this unwanted effect, a team of scientists led by Professor D. James Surmeier, chair of physiology at Northwestern University Feinberg School of Medicine, investigated the specific brain region targeted by the drug, an area named the striatum, which is thought to be involved in the development of dyskinesia. Researchers found that neurons responsible for the side effect have a receptor, the M4 muscarinic receptor, that helps to balance the drug treatment. As levodopa doses increase with the progression of the disease, however, imbalances and dyskinesia result. Importantly, the team identified a protein that was able to counter this effect by boosting the receptor’s function. In addition to mice models of PD, researchers also tested a variant of the compound in diseased primates, observing the same dyskinesia reduction without compromising levodopa’s beneficial effects.
The compound, an M4 muscarinic receptor positive allosteric modulator, is currently in development and a Phase I trial is expected to being in 2017. “There has been an international effort to find a drug that can be combined with levodopa to reduce the uncontrolled movement. 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,” Dr. Surmeier said in a press release.