 | | | (Reprinted with permission from the Fall 2007 issue of Ward Rounds, the quarterly magazine of Northwestern University's Feinberg School of Medicine, article written by Michael Nyquist) For more than 50 years, scientists have known that the symptoms of Parkinson’s disease, a movement disorder, result from the progressive death of neurons supplying the neurotransmitter dopamine. No one knows why dopaminergic neurons die. “Why dopamine neurons and not cortical pyramidal cells or some other type of neuron in the brain?” asks D. James Surmeier, PhD, Nathan Smith Davis Professor and chair of physiology. “We wanted to understand what was different about them at the basic physiological level that might give us a clue about their vulnerability.” Much of the research on the etiology of Parkinson’s disease has focused on dopamine itself or environmental toxins such as pesticides. Dr. Surmeier and his lab team essentially went back to the drawing board. “Through electrophysiological recordings of dopaminergic neurons, we rediscovered that they are calcium-dependent pacemakers,” says Dr. Surmeier. “Pacemakers are cells that don’t need synaptic input to initiate action potentials, like cardiac cells. Your heart beats on its own without any external pacing.” Many different types of pacemaking cells exist in the brain, especially in the basal ganglia, a part of the brain controlled by dopamine. But nearly all of the other known pacemakers rely on sodium ion channels for their activity. “As often happens in science, a fortunate series of events came together that provided a new insight,” says Dr. Surmeier. His lab team obtained mice in which the gene coding for the calcium channel driving dopaminergic neuron pacemaking had been deleted. Surprisingly, these mice looked perfectly normal. They recorded the electrical activity of the dopaminergic cells from those animals. “The cells were pacemaking along in a perfectly normal way, which told us that the calcium channel was not absolutely necessary,” Dr. Surmeier says. “Some type of plasticity enabled these cells to function in the absence of that channel.” That observation led to a series of experiments showing the reliance on calcium ion channels was developmentally regulated. “The younger neurons used sodium ion channels,” continues Dr. Surmeier. “As they grew older, they relied more and more on calcium. That pointed us toward a potential therapy. If we blocked that calcium channel pharmacologically, would the dopaminergic neurons revert to the juvenile phenotype? Sure enough, that’s what they did.” The calcium channels used in dopaminergic neurons are members of the L-type channel class that are prominent in the cardiovascular system. Dihydropyridine drugs that block L-type channels are commonly used to treat hypertension because they cause vascular smooth muscle to relax. Dr. Surmeier used a member of this drug class, isradipine, to block the L-type channels in dopaminergic neurons. In both in vitro and in vivo experiments, dopaminergic neurons were forced to switch back to sodium ion channel pacemaking. “From a physiological standpoint, that was just fascinating,” enthuses Dr. Surmeier. “No other examples of that type of plasticity exist in the literature, at least to my knowledge. More important from a clinical perspective was that when dopaminergic neurons reverted to the juvenile form of pacemaking, they became resistant to the three toxins used to induce Parkinsonism in animal models.”  | Rejuvenating neurons
Electrophysiological recordings of single dopaminergic neurons (above) in Dr. James Surmeier’s lab provide evidence suggesting isradipine, a calcium channel blocker commonly prescribed for hypertension, could potentially “rejuvenate” these neurons in Parkinson’s disease. |
The shift to calcium-dependent pacemaking may elevate the stress level of dopaminergic neurons just enough to make them vulnerable to genetic mutations or environmental toxins that in and of themselves don’t cause neuronal death. Since isradipine has been used safely in humans for decades, Dr. Surmeier went to his clinical coinvestigators on the Senyei grant, John A. Kessler, MD, Ken and Ruth Davee Professor of Stem Cell Biology and chair of neurology, and Tanya Simuni, MD, associate professor of neurology and director of the Parkinson’s Disease and Movement Disorders Center at the Feinberg School, to attempt to translate this discovery into clinical practice. They initiated a small Northwestern Medical Faculty Foundation–supported clinical trial with early stage Parkinson’s patients to determine whether they tolerate isradipine treatment as well as the general population. With safety data from this trial, they plan to apply to the NIH to fund a larger neuroprotection trial, enrolling at least 100 early-stage Parkinson’s patients.
“In the early stage of Parkinson’s disease, most symptoms are managed reasonably well pharmacologically with either L-dopa or direct-acting dopamine agonists,” says Dr. Surmeier. “These therapies are generally good for 5–10 years. But as the disease progresses, you have to keep escalating the dose as neurons continue to die. At the highest doses, side effects such as dyskinesias begin to occur. Isradipine could extend the window of effectiveness for those treatments by rejuvenating the remaining dopaminergic neurons.” Doubling or tripling the therapeutic window would be a tremendous advance in clinical treatment for Parkinson’s patients. If given early enough, it’s possible a drug like isradipine could even prevent the development of Parkinson’s disease within a normal lifespan. Since isradipine targets both the brain and cardiovascular L-type calcium channels, Dr. Surmeier and co-investigator Richard B. Silverman, PhD, John Evans Professor of Chemistry in the Weinberg College of Arts and Sciences and a member of the Center for Drug Discovery and Chemical Biology, are screening compounds to identify a more selective antagonist for the brain channel. Such a molecule likely would be patentable and attractive commercially. Isradipine has been off-patent for decades, so no pharmaceutical company has exclusive rights to it. “The sequence of events that brought us this far is a beautiful example of bench-to-bedside research,” states Dr. Surmeier. “This type of grant connects experimentalists like me with clinicians such as Dr. Kessler and Dr. Simuni to bridge that gap.” | |
