Long-term treatment for Parkinson’s disease often brings with it a bothersome side effect: involuntary and erratic movements that significantly affect patients’ quality of life. These motor complications, known as levodopa (L-DOPA)-induced dyskinesia, have been a persistent challenge in managing Parkinson’s disease. However, recent research has shed light on a possible solution that could alleviate these debilitating effects, offering renewed hope for those suffering from this chronic disease.
Researchers have made significant progress in addressing motor complications associated with long-term treatment of Parkinson’s disease (PD). Led by Professor Heinz Steiner, Dr Feras Altwal, Connor Moon and Professor Anthony West from Rosalind Franklin University of Medicine and Science, they explored the effects of the multimodal serotonergic agent vilazodone on L-DOPA-induced gene regulation in striatal projection neurons and its potential to mitigate dyskinesia in an animal model of PD. Their findings were published in the journal Cells.
Parkinson's disease, a neurodegenerative disorder characterized by the loss of dopamine-producing neurons, is often treated with L-DOPA. While L-DOPA remains the gold standard, long-term use of L-DOPA can lead to L-DOPA-induced dyskinesia, a condition characterized by involuntary and erratic movements. Dyskinesia significantly impairs the quality of life of PD patients by complicating the therapeutic benefits of L-DOPA.
The research team investigated vilazodone, a drug approved by the US Food and Drug Administration for its antidepressant properties, which combines the effects of selective serotonin reuptake inhibitors (SSRIs) with partial agonist activity at the 5-HT1A receptor. Their study was based on a well-established animal model of PD, in which rats were subjected to unilateral dopamine depletion using 6-hydroxydopamine (6-OHDA). Rats were then treated with L-DOPA alone or in combination with vilazodone for three weeks.
“Our most important finding is that vilazodone effectively suppresses the development of L-DOPA-induced dyskinesia without interfering with the beneficial motor effects of L-DOPA,” said Professor Steiner. The researchers found that L-DOPA treatment significantly increased the expression of certain genes, such as dynorphin, 5-HT1B, and zif268 mRNA, in the striatum ipsilateral to the lesion. Coadministration of vilazodone inhibited these neuronal effects, suggesting a specific mechanism by which vilazodone mitigates dyskinesia.
The findings also highlighted that vilazodone's influence was specific to the direct pathway of the dopamine-deficient striatum, as it did not affect enkephalin expression in the indirect pathway or gene expression in the intact striatum. This specificity could be crucial for developing complementary therapies that offer symptomatic relief without compromising the efficacy of the primary treatment.
Professor Steiner said: “These results position vilazodone as a potential adjunctive drug for the treatment of L-DOPA-induced motor side effects in Parkinson’s disease. The drug’s ability to modulate the serotonin and dopamine systems could pave the way for new treatment strategies.”
In summary, the study by Professor Steiner and colleagues demonstrates that vilazodone can effectively reduce L-DOPA-induced dyskinesia, a common and debilitating side effect of PD therapy, without impairing the therapeutic efficacy of L-DOPA. These promising results suggest that vilazodone, already approved as an antidepressant, could be repurposed to improve the quality of life of PD patients undergoing L-DOPA treatment. Future research will focus on validating these findings in clinical trials exploring the long-term benefits of vilazodone as part of PD management.
Journal reference
Altwal F., Moon C., West AR, Steiner H. “The multimodal serotonergic agent vilazodone inhibits L-DOPA-induced gene regulation in striatal projection neurons and associated dyskinesia in an animal model of Parkinson’s disease.” Cells. 2020. DOI: https://doi.org/10.3390/cells9102265
About the Author
Dr. Heinz Steiner is a Professor of Cellular and Molecular Pharmacology at the Chicago Medical School, Rosalind Franklin University of Medicine and Science, and a Principal Investigator at the Stanson Toshok Center for Brain Function and Repair at Rosalind Franklin University. Dr. Steiner received his MS in Biology from the Swiss Federal Institute of Technology (ETH) in Zurich, Switzerland, and his PhD in Physiological Psychology from the University of Dusseldorf, Germany. After postdoctoral work at the National Institute of Mental Health, Bethesda, he was a Research Assistant Professor in the Department of Anatomy and Neurobiology at the University of Tennessee, College of Medicine and the Neuroscience Center in Memphis. He joined the faculty of the Department of Cellular and Molecular Pharmacology at the Chicago Medical School in 2000, and served as chair of the department from 2011 to 2022. Dr. Steiner’s research focuses on the functional organization of the basal ganglia and related brain systems, especially the role of the neurotransmitters dopamine and serotonin in regulating interactions between the basal ganglia and the cortex. A major focus of his work is to understand how dopaminergic and serotonergic drug treatments produce changes in the genetic regulation of the basal ganglia and the consequences for drug addiction and other brain disorders. Dr. Steiner is senior editor of the Handbook of Basal Ganglia Structure and Function and co-editor of Elsevier’s Handbook of Behavioral Neuroscience series.
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