June 17, 2007 by mike.

by Sea Stachura, Minnesota Public Radio

St. Paul, Minn. — Dr. Demetrius Maraganore did what most disease researchers do when they’re searching for genetic links in a disease: he took it one gene at a time. But no matter what gene he looked at, his findings weren’t that conclusive.

“If I told you your risk for Parkinson’s disease was 4 percent instead of 2 percent, that wouldn’t motivate you to change your behaviors very much,” according to Maraganore.

He had found one gene that made a person about 2 percent more likely to get Parkinson’s. Maraganore wondered, “why that gene?” If that gene mutates, why does that make a person more likely to get Parkinson’s? This gene is actually a chemical that helps create neurological connections. Those make the brain function.

“That isn’t a random process,” he points out. “This wiring is very detailed. And as it turns out, there are chemicals that guide this wiring process during brain development.”

The gene Maraganore found is part of a series of genes that make up what’s called the axon guidance pathway, or the wiring pathway. Maraganore looked at the group collectively when there were multiple gene mutations or mistakes. Bingo.

“The findings were stunning. We found that common variations in axon guidance pathway genes — or brain wiring genes — resulted in a 90-times increase risk for Parkinson’s disease,” he says.

Maraganore says these results, statistically speaking, are conclusive, but he’ll do further research on global populations.

Gene mutation is known for causing disease, but that doesn’t mean Parkinson’s is hereditary. Until now, researchers have looked at pesticide exposure, for example, as a possible environmental cause of the disease. But Maraganore says researchers should look at fetal development. He says brain wiring takes place in-utero. He wonders if maternal health factors might affect that wiring.

“If your mother was exposed to pesticides or not while she was pregnant with you, if your mother had an infection when you she was pregnant with you, if your mother smoked or drank coffee, how might those factors similarly alter the mapping of the brain and how might that also contribute to Parkinson’s disease?” Maraganore says.

Maraganore says these findings may be useful in looking at other conditions like schizophrenia, Alzheimer’s and dyslexia.

He says this finding ccould be used on middle- age men and women today. He’s developing a clinical blood test that would determine whether a person is genetically predisposed to the disease, and to what severity.

“We’re right there,” he says. “The patents have been filed. We’re in the process of doing the fine finishing to show that this is really a useful test for patients and clinics worldwide.”

Maraganore says he is working with a team on a drug treatment for the disease if the genetic tests are positive. He says that treatment is about five years away.

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June 15, 2007 by mike.

http://nationmultimedia.com:80/world…ewsid=30036474

PARIS - A drug tested on lab mice slows and may even halt the progress of Parkinson’s, offering the brightest pharmacological hope in decades of rolling back this tragic disease, US researchers report on Sunday.

Isradipine, already licensed for treatment for high blood pressure, rejuvenated ageing dopamine cells, the brain cells whose death causes Parkinson’s, they say.

The outcome among mice was so promising that the team now plan on conducting trials on human volunteers.

“Our hope is that this drug will protect dopamine neurons, so that if you began taking it early enough, you won’t get Parkinson’s disease, even if you were at risk,” said lead researcher James Surmeier, professor of physiology at Northwestern University in Chicago.

“It would be like taking a baby aspirin every day to protect your heart.”

Parkinson’s is an incurable, degenerative disease of the central nervous system that causes uncontrollable shaking, along with impaired speech and movement. In approximately one third of cases it also results in dementia.

Estimates of its prevalence vary between 0.1 and 0.3 per cent of the population, meaning that approximately one in 500 people contract the disease.

The cause is a loss of dopamine, a chemical messenger that helps direct movement. The substance is provided in a part of the brain called the substantia nigra.

Most pacemaking neurons use sodium ions to produce a regular electrical signal.

But the new research unexpectedly found that dopamine cells, when they reached adulthood, start to depend more and more on calcium ions.

This discovery is important, because calcium ions are far more troublesome to control than their placid sodium counterparts: the cell uses up lots of energy, either to round up and sequester the calcium or pump it out.

As a result, the dopamine cells become stressed on reaching their calcium-addicted adulthood and die prematurely.

Surmeier’s hunch was to try isradipine, a well-tolerated hypertension and stroke drug commercialised under the name of DynaCirc, which blocks the channels in the cell surface that admit calcium.

Tested on lab-dish cells and then on mice which had been genetically engineered to have Parkinson’s, the team found that within a few hours of being exposed to the drug, the neurons reverted to their youth-like state, of using sodium.

This lowered the cells’ stress level, making them less vulnerable to the toxins, still poorly understood, that kills them.

“They start acting like they’re youngsters again,” Northwestern quoted Surmeier as saying.

The study is published online on Sunday by Nature, the British science journal.

So far the work has only been carried out on animals, and more needs to be done to assess the drug’s effect on humans.

But Surmeier voiced cautious hopes it could be the first treatment to prevent or slow the progression of this devastating disease.

The mainstay treatment for Parkinson’s is L-DOPA, a drug that the brain converts into dopamine.

At first, L-DOPA has a seemingly miraculous effective on symptoms. The problem, though, is that it becomes less and less effective as time wears on and the disease progresses. That forces doctors to raise the dose of this drug, which induces unwanted side-effects, including spastic, jerky movements.

So, if isradipine can slow the death of dopamine neurons, the L-DOPA “honeymoon” could be significantly extended.

“If we could double or triple the therapeutic window for L-DOPA, it would be a huge advance,” said Surmeier. “There has not been a major advance in the pharmacological management of Parkinson’s in 30 years.”

Agence France-Presse

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June 15, 2007 by mike.

Science Daily — Northwestern University researchers have discovered a drug that slows — and may even halt — the progression of Parkinson’s disease. The drug rejuvenates aging dopamine cells, whose death in the brain causes the symptoms of this devastating and widespread disease.

D. James Surmeier, the Nathan Smith Davis Professor and chair of physiology at Northwestern University’s Feinberg School of Medicine, and his team of researchers have found that isradipine, a drug widely used for hypertension and stroke, restores stressed-out dopamine neurons to their vigorous younger selves. The study is described in a feature article in the international journal Nature, which will be published on-line June 10.

Dopamine is a critical chemical messenger in the brain that affects a person’s ability to direct his movements. In Parkinson’s disease, the neurons that release dopamine die, causing movement to become more and more difficult.

Ultimately, a person loses the ability to walk, talk or pick up a glass of water. The illness is the second most common neurodegenenerative disease in the country, affecting about 1 million people. The incidence of Parkinson’s disease increases with age, soaring after age 60.

“Our hope is that this drug will protect dopamine neurons, so that if you began taking it early enough, you won’t get Parkinson’s disease, even if you were at risk. ” said Surmeier, who heads the Morris K. Udall Center of Excellence for Parkinson’s Disease Research at Northwestern. “It would be like taking a baby aspirin everyday to protect your heart.”

Isradipine may also significantly benefit people who already have Parkinson’s disease. In animal models of the disease, Surmeier’s team found the drug protected dopamine neurons from toxins that would normally kill them by restoring the neurons to a younger state in which they are less vulnerable.

The principal therapy for Parkinson’s disease patients currently is L-DOPA, which is converted in the brain to dopamine. Although L-DOPA relieves many symptoms of the disease in its early stages, the drug becomes less effective over time. As the disease progresses, higher doses of L-DOPA are required to help patients, leading to unwanted side-effects that include involuntary movements. The hope is that by slowing the death of dopamine neurons, isradipine could significantly extend the time in which L-DOPA works effectively.

“If we could double or triple the therapeutic window for L-DOPA, it would be a huge advance,” Surmeier said.

The work by Surmeier’s group is particularly exciting because nothing is known to prevent or slow the progression of Parkinson’s disease.

“There has not been a major advance in the pharmacological management of Parkinson’s disease for 30 years,” Surmeier said.

Surmeier, who has researched Parkinson’s disease for 20 years, had long been frustrated because it wasn’t known how or why dopamine cells die in the disease. “It didn’t seem like we were making much progress in spite of intense study on several fronts,” he said.

Because he’s a physiologist, Surmeier decided to investigate whether the electrical activity of dopamine neurons might provide a clue to their vulnerability. All neurons in the brain use electrical signals to do their job, much like digital computers.

First, Surmeier observed that dopamine neurons are non-stop workers called pacemakers. They generate regular electrical signals seven days a week, 24 hours a day, just like pacemaker cells in the heart. This was already known. But then he probed more deeply and discovered something very strange about these dopamine neurons.

Most pacemaking neurons use sodium ions (like those found in table salt) to produce electrical signals. But Surmeier found that adult dopamine neurons use calcium instead.

Sodium is a mild mannered ion that does its job without causing a whit of trouble to the cell. Calcium ions, however, are wild and rambunctious. Remember when Marlon Brando rode into town with his motorcycle gang in “The Wild One”" Those guys were like calcium ions.

“The reliance upon calcium was a red flag to us,” Surmeier said. Calcium ions need to be chaperoned by the cell almost as soon as they enter to keep them from causing trouble, he noted. The cell has to sequester them or keep pumping them out. This takes a lot of energy.

“It’s a little like having a room full of two year olds you have to watch like a hawk so they don’t get into trouble,” Surmeier said. “That’s really going to stress you.” With three boys under age eleven, he can relate to the stressed dopamine neuron.

Surmeier theorized that the non-stop stress on the dopamine neurons explains why they are more vulnerable to toxins and die at a more rapid rate as we age.

But these findings still didn’t offer him a new therapy.

Then, serendipity struck when he was working on a different problem. He discovered that young dopamine neurons and adult ones have an entirely different way of operating.

When the neurons are young, Surmeier found they actually use sodium ions to do their work. But as the neurons age, they become more and more dependent on the troublesome calcium and stop using sodium. This calcium dependence — and the stress it causes the neurons –is what makes them more vulnerable to death.

What would happen, Surmeier wondered, if he simply blocked the calcium’s route into the adult neuron cells?  Would the neurons revert to their youthful behavior and start using sodium again?

“The cells had put away their old childhood tools in the closet. The question was if we stopped them from behaving like adults would they go into the closet and get them out again”" Surmeier asked. “Sure enough, they did.”

When he gave the mice isradipine, it blocked the calcium from entering the dopamine neuron. At first, the dopamine neurons became silent. But within a few hours, they had reverted to their childhood ways, once again using sodium to get their work done.

“This lowers the cells’ stress level and makes them much more resistant to any other insult that’s going to come along down the road. They start acting like they’re youngsters again,” Surmeier said.

The next step will be launching a clinical study.

“This animal study suggests that calcium channel blockers, drugs currently used to reduce blood pressure, might someday be used to slow the steady progression of Parkinson’s disease,” said Walter J. Koroshetz, M.D., deputy director of the NINDS.

Note: This story has been adapted from a news release issued by Northwestern University.

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June 15, 2007 by mike.

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June 8, 2007 by mike.

Parkinson’s is a debilitating disease that affects a person’s movement, strength, and balance, and in many ways is still a mystery to doctors and scientists. One thing that is becoming more clear, however, is that regular physical exercise seems to help slow the progression of the symptoms and delay the effects of the disease. And now a certified trainer, David Zid, and a doctor afflicted with Parkinson’s himself, Thomas H. Mallory M.D., have collaborated to create a fitness regimen specifically designed for Parkinson’s patients.

The fitness plan is available in the book “Delay the Disease: Exercise and Parkinson’s Disease,” and part of the proceeds from the sale of the book will go to support the research, development and treatment of Parkinson’s.

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June 8, 2007 by mike.

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