New research offers the promise of treatments for the one million Americans affected by Parkinson's disease, the second most common degenerative nerve disorder (after Alzheimer's) in the U.S.
A team at Northwestern University's Feinberg School of Medicine in Chicago reports that isradipine (brand name DynaCirc), a drug currently prescribed to reduce high blood pressure, may block the death of neurons in patients with advanced cases of Parkinson's and may also be able to prevent the development of the disease.
In a separate but related study, scientists this week also announced that they successfully reversed Parkinson-like symptoms in several monkeys by transplanting human neural stem cells into their brains.
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The symptoms of Parkinson's—which is characterized by stiffness and can lead to a loss of motor and speech function—are triggered by the progressive death of neurons in a midbrain region called the substantia nigra that produce the neurotransmitter dopamine (implicated in the pleasure and reward systems as well as in the maintenance of proper movement control). These nerve cells send dopamine to the striatum, another midbrain structure, which regulates the planning of movement. Without such dopamine signaling, the striatum cannot properly execute a motion.
The Northwestern team, led by physiologist James Surmeier, reports in the online edition of Nature that the dopamine neurons, which are targeted by Parkinson's, are constantly at work—like a pacemaker—sending the striatum nonstop, electrical pulses. (Neurons generate these signals by passing charged ions across their membranes.) Most of these so-called "pacemaking neurons" utilize charged sodium ions to create their electrical impulses.
According to Surmeier, when young, the dopamine-producing neurons in the substantia nigra appear to rely on sodium for signaling, as well. But, for some unknown reason, they come to rely more on calcium channels as they mature. Calcium, however, puts a strain on cells—it is known to hinder protein-folding and metabolism when it accumulates—disrupting normal cellular function. The researchers hypothesize that, in the case of Parkinson's, these calcium ions are not properly sequestered or ferried out of the substantia nigra neurons, making those cells possibly more vulnerable to toxins.
Since calcium channels are only found in heart and brain tissue, the researchers sought a drug approved to block these pathways. They settled on isradipine. "If our hypothesis is correct that Parkinson's is really a calcium-regulation disorder," Surmeier says, "then stopping that process … should stop the progression of the disease.''
Researchers observed a 50 percent loss of cells when they injected normal mice with an agent that selectively kills dopamine neurons of the substantia nigra (to emulate Parkinson's) semiweekly for five weeks. Initially, the mice given isradipine showed very little activity in these dopamine neurons (because their calcium intake had been frozen). But within hours, their dying neurons appeared healthy again, because they reverted to using sodium to transmit signals in lieu of the blocked calcium.
"If you were to take the drug prophylactically, you may never get Parkinson's disease," says Surmeier. He says his team is so confident with its results that it plans to petition the Food and Drug Administration this fall to test isradipine's effectiveness in human Parkinson's patients, because the drug has already been approved for human use.
If All Else Fails
A second research team injected human neural stem cells into the substantia nigras of 27 African green monkeys in which it had induced Parkinson's symptoms (including difficulty eating, tremors and stiffness).
"The potential advantage of stem cells," says Eugene Redmond, a professor of neurosurgery at the Yale University School of Medicine and the lead author of that study, "is that they still have the potential to migrate and position themselves in appropriate places depending on what signals are there [in the brain]."
Redmond and colleagues report in Proceedings of the National Academy of Sciences USA that only some of the stem cells implanted in the monkey's brains went on to replace the lost dopamine neurons. They noticed, however, that other brain cells, which had shrunken in size as a result of their lost neighbors, seemed to normalize. They also saw vast improvement in the monkeys' symptoms during four months of study.
Comparing his study to Surmeier's, Redmond noted: "One is an approach to try to minimize disease progression or maybe even get some recovery, the other is more aimed at the other end, after (dopamine-producing] cells are already dead."
He cautions, however, that there is a lot more work to be done to assess the effectiveness of transplants. Most notably: he plans to review long-term results to check potential side effects, such as dyskinesia (repeating, involuntary motions), which is commonly observed in patients on L-dopa, a Parkinson's drug that is converted to dopamine in the brain.