from:Scientific American, June 12, 2007

note: "Surmeier 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. "

Blood Pressure Drug, Stem Cell Transplant Seen as Possible New 
Parkinson's Treatments

Researchers report they alleviated the debilitating effects of the 
neurodegenerative disease in mice and monkeysNew 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. 
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 
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. 
 
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