Senyei-Supported Study Leads to Progress in Parkinson’s Disease Treatment
In 2006, the newly established Drew Senyei, MD, Translational Research Awards supported four projects. The awards were made possible by a $1 million gift from Dr. Senyei, a 1979 medical school alumnus and Northwestern University Board of Trustees member, and exemplify Northwestern University’s commitment to “bench to bedside” research. One of the Senyei-awarded research studies is already offering hope for patients with Parkinson’s disease.
D. James Surmeier, PhD, Nathan Smith Davis Professor and chair of the Department of Physiology, Feinberg School of Medicine, is the principal investigator of a study exploring the use of a drug that may slow, and even halt, the progression of Parkinson’s disease. This movement disorder affects one million Americans. The drug, isradipine, rejuvenates aging dopamine cells, whose death in the brain causes symptoms that include rigidity, tremor, weakness, and loss of balance.
It has long been known that the symptoms of Parkinson’s disease result from the progressive death of neurons supplying the neurotransmitter dopamine. Dr. Surmeier and his team sought to understand why dopaminergic neurons, but not cortical pyramidal cells or other brain neurons, die. To do so, they looked at their electrical activity and re-discovered that dopaminergic neurons are calcium-dependent pacemakers. Pacemakers are cells that don’t need synaptic input to initiate action potential. “Cardiac cells are pacemakers,” Dr. Surmeier explains. “For example, your heart beats on its own without any external pacing.”
As sometimes happens in science, a fortunate series of events combined and provided new insight about these cells. Dr. Surmeier’s lab team obtained mice in which the gene coding for the calcium channel driving dopaminergic neuron pacemaking had been deleted. But the mice looked perfectly normal. Further recording showed that the dopaminergic cells in these animals were pacemaking in a normal way, indicating that the calcium channel was not absolutely necessary. “That observation led to experiments that showed that reliance on calcium ion channels was developmentally regulated,” Dr. Surmeier says. “Younger neurons used sodium ion channels. As they grew older, they relied more and more on calcium. That pointed us toward a potential therapy. We wondered, if we could block the calcium channel pharmacologically, would the dopaminergic neurons revert to their juvenile phenotype? Sure enough, that’s what they did.”
The calcium channels used in dopaminergic neurons are members of the L-type channel class, and dihydropyridine drugs that block these channels are commonly used to treat hypertension. Dr. Surmeier used one of these drugs, isradipine, and in both in vitro and in vivo experiments it caused dopaminergic neurons to revert to sodium channel pacemaking. “This made them resistant to the three toxins used to induce Parkinsonism in animal models,” he explains.
Dr. Surmeier notes that since isradipine has been used safely in humans for decades, it made sense to translate this discovery into clinical practice. He turned to Senyei award co-investigators, John Kessler, MD, Ken and Ruth Davee Professor of Stem Cell Biology and chair, Ken and Ruth Davee Department of Neurology and Neurological Sciences, and Tanya Simuni, MD, associate professor of neurology in the Department. They have initiated a clinical trial with early-stage Parkinson’s disease patients to determine whether they tolerate isradipine treatment and, with safety data from this trial, will apply to the National Institutes of Health to fund a larger study. Another member of the Senyei award research team, Richard B. Silverman, PhD, John Evans Professor of Chemistry, Weinberg College of Arts and Sciences, and member of the Center for Drug Discovery and Chemical Biology, has joined with Dr. Surmeier in screening compounds to identity a more selective antagonist for the brain channel.
“This work is an excellent example of how our scientists and clinicians are working together to maximize the impact of translational research,” says Jonathan Leis, PhD, professor of microbiology-immunology and senior associate dean for research. “We believe a drug like isradipine has the potential to slow or stop the progression of Parkinson’s symptoms,” says Dr. Surmeier. “If given early enough, it might even prevent the development of this disease.”
Written by: Gina Pryma