for treating levodopa-induced dyskinesias in parkinson’s disease
Parkinson’s disease is the second most common neurodegenerative disease. It is a neurological disorder whose prevalence increases with age. With the average age of the population rising in many countries of the world, including the U.S., there is an urgent need to develop safe and effective treatments. While the cause of Parkinson’s disease remains unknown, the symptoms associated with the disease are due to a loss of a specific subset of neurons in the brain that synthesize and secrete a neurotransmitter called dopamine. The most effective therapy for treating Parkinson’s disease involves administration of dopamine to make up for the loss of the cells that normally make dopamine in the brain. Unfortunately, about 60-80% of the patients treated with exogenous dopamine eventually develop severe movement disorders that are collectively called dyskinesias. The biological reason for the development of dyskinesias remains unclear. Currently, there are no pharmacotherapeutic means to effectively treat drug-induced dyskinesias in Parkinson’s disease.
The molecular mechanisms underlying the development of levodopa-induced dyskinesia (LID) in Parkinson’s disease (PD) are not well understood. Studies have shown that expression of a number of genes are altered in dyskinetic animals. In particular, in both rodents and primates, studies have reported a specific increase in the D3 dopamine receptor expression in the basal ganglia of dyskinetic animals. The functional consequence of the increased D3 receptor expression, in areas that normally express the D2 dopamine receptor, is unknown. We have shown that the D3 dopamine receptor, but not the D2 dopamine receptor, exhibits tolerance and slow response termination (SRT) properties. The tolerance property of the D3 receptor describes the progressive decrease in receptor signaling function upon repeated stimulation by classical agonists, including dopamine. The SRT property describes the prolongation of time taken to terminate the signaling function of the D3 receptor, after removal of the agonist. Differences in the properties of D2 and D3 receptors give rise to a differential modulation of neuronal firing.
Based on these results, we have proposed a hypothesis that in LID the alterations of D2/D3 receptor expression ratio leads to aberrant expression of D3 receptor tolerance and SRT properties, which could result in aberrant modulation of neuronal firing in the basal ganglia of the dyskinetic animals and contribute to the development of dyskinesia symptoms. Thus, if D3 receptor tolerance and SRT properties could be abolished, then the modulation of neuronal firing by the over-expressed D3 receptor in the basal ganglia of dyskinetic animals would be similar to the natively expressed D2 receptors and potentially prevent the expression of dyskinesia. The hypothesis predicts that if the D3 dopamine receptor properties associated with dyskinesia could be selectively abolished using synthetic drugs, one could potentially cure dyskinesia associated with Parkinson’s disease treatment.
To test the hypothesis, we first screened a library of D3 receptor agonists and identified a compound that was a full agonist at D3 receptor but lacked the tolerance and SRT properties. Using electrophysiological and biochemical functional assays in a heterologous expression model, we demonstrated that the newly identified D3 agonist showed no evidence of tolerance and SRT. The new D3 receptor agonist essentially converted the D3 receptor to a functional equivalent of the D2 dopamine receptor. With the help of Dr. Steven Zalcman in the Department of Psychiatry at UMDNJ-New Jersey Medical School, we next compared the effect of this novel D3 receptor agonist to classical D3 receptor agonists (which elicit tolerance and SRT) in mice locomotor behavior assays. These experiments showed that the novel D3 agonist induced different locomotor behavior compared to traditional tolerance and SRT-inducing D3 receptor agonists. Finally, to directly test our hypothesis, we evaluated the effect of the novel D3 receptor agonist in a rodent PD model that can be induced to exhibit dyskinesia following chronic levodopa treatment. The preliminary results supported our hypothesis that the novel D3 receptor agonist significantly attenuated dyskinesia in the rodent PD model.
To discover novel D3 agonists as potential clinical treatments for
dyskinesia, we employed computational tools to screen extensive chemical databases to identify additional lead compounds that are structurally analogous to the original D3 agonist. The goal is to identify and characterize several lead candidates that can be tested for function, safety and efficacy. The long-term goal of this collaborative effort is to validate these novel drug candidates in the clinical setting to treat the negative symptoms associated with dopamine replacement therapy in Parkinson’s disease. If the attractive side-effects profile of this new D3 agonist is validated, we anticipate pursuing further preclinical and clinical studies aimed at FDA approval and
eventual marketing of this novel prospective drug candidate.
Eldo Kuzhikandathil earned his PhD from the University of Delaware in molecular biology and received postdoctoral training in neurobiology at the University of North Carolina at Chapel Hill. He joined the Department of Pharmacology & Physiology at UMDNJ-New Jersey Medical School in 2000, and is currently an assistant professor there.
William J. Welsh holds the appointment of Norman H. Edelman Chair in Bioinformatics & Molecular Design, and professor in the Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School (RWJMS). Dr. Welsh serves as director of the Informatics Institute of UMDNJ. Concurrently, he serves as director of the EPA-supported Environmental Bioinformatics & Computational Toxicology Center (ebCTC). Dr. Welsh received his PhD from the University of Pennsylvania and postdoctoral training at the University of Cincinnati (OH) and the National Institutes of Health in Bethesda, MD. He joined the RWJMS faculty in 2001.
Sandhya Kortagere earned her PhD from the National Institute of Mental Health & Neurosciences in India and did her postdoctoral training at Mount Sinai School of Medicine and Weill Cornell Medical College. She was a research teaching specialist at RWJMS from 2005 to 2008 and is currently an assistant professor at Drexel University College of Medicine.