"[This] is an opportunity to test potential disease-modifying therapies."
Kateri Spinelli, Ph.D.
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Anthony R. West, Ph.D.
Anthony R. West,
Scientists have long recognized that people with Parkinson’s disease (PD) lack a crucial chemical messenger in their brains, called dopamine. It turns out dopamine may be the first leg in a complex chemical message relay that controls the body’s movement.
In 2004 and 2005, Anthony R. West, Ph.D., Associate Professor in the Department of Neuroscience at the Rosalind Franklin University of Medicine and Science (RFUMS), investigated this chemical relay with funding from PDF’s International Research Grants Program.
Dr. West notes that because dopamine plays an important role in beginning the relay, it can slow or disrupt the relay when its levels are insufficient. This is what happens in Parkinson’s. He says that the results from his studies suggest a new approach to Parkinson’s therapy — involving a neurotransmitter called nitric oxide — that targets another step in this relay.
How does the relay work? First, cells in the brain’s substantia nigra release dopamine into the area of the brain called the striatum, long known as a key control center for the initiation of movement. Dopamine targets two major types of cells in the striatum called projection neurons and interneurons. Although the interneurons are few in number, they hold powerful influence over the projection neurons by sending a second leg of relay signals, including nitric oxide, to these cells. In the third stage of the neurotransmitter race, these projection neurons release signaling molecules related to the body’s movement in downstream brain centers.
Early in his research, Dr. West discovered that the neurotransmitter nitric oxide excites the projection neurons by stimulating the production of “messenger molecules” called cyclic nucleotides. In PD, this excitement is thought to be too strong, which leads to disruptions in movement, such as akinesia.
More than 10 years ago, Dr. West was unraveling this chemical circuit in the brains of normal rats. Grants from PDF allowed him to expand his research to an animal model that mimics aspects of Parkinson’s. “The funding from PDF allowed us to get into the Parkinson’s field — it had a major impact on the direction of my research,” says Dr. West. “With the Parkinson’s animal models, we could test some of our hypotheses generated from studies in normal rats.”
To expand his studies to Parkinson’s, Dr. West teamed up with colleague Kuei Tseng, M.D., Ph.D., who works with a mouse model of Parkinson’s. Their work showed that reducing cyclic nucleotides in the striatum also reduced the abnormal excitation of the projection neurons. Many scientists have studied such nerve signaling using slices of brain in a glass dish. Dr. West and Dr. Tseng instead developed methods that allowed them to look at these signaling processes in the intact brain, and determine how nerve cells respond to changing levels of cyclic nucleotides.
“Those are promising approaches that PDF helped us to develop and apply to Parkinsonian models” says Dr. West. Data collected from these studies helped Dr. West secure further funding from the National Institute of Neurological Disorders and Stroke.
Dr. West’s basic studies point to a new therapeutic approach to Parkinson’s: finding ways to lessen the excitatory impact of cyclic nucleotides. He has already tested one compound that does this, ODQ, in rat and mouse models. He has found that the drug significantly improved measures of “stepping behavior” used to assess akinesia, that is, trouble with initiating movement.
“We don’t know yet whether the drug tested in animals is safe for human use,” says Dr. West, “but we think that the general approach of manipulating this pathway has great potential as a therapy for Parkinson’s.”
The bottom line is this: the investment that PDF made almost a decade ago in a young scientist’s risk-taking research not only helped launch a laboratory devoted to basic PD science, but also may pay off in the form of a new PD treatment.
Dr. West’s research was funded through the International Research Grants Program. In FY2012, PDF is supporting the program with $825,000.