[willone]

Drug slows and may halt Parkinson's disease
CHICAGO -- 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.
Source:
http://www.eurekalert.org/pub_releas...-nfd060707.php

[Sasha]

Does anyone happen to be taking a calcium channel blocker for any reason? This research strikes me as potentially very important - I guess I figure that, for most of us already reading this forum, our best chance comes from the fortuitous discovery of some off-label use of an established drug.

As a former psychiatric social worker, I saw siezure medications become great tamers of anxiety - and a blood pressure medication turned out to be an outstanding treatment for performance anxiety.

Novel approaches developed from scratch are just going to take too long. My MDS tells me that there is nothing much in the pipeline - or nothing to hold my breath for. (but then, he isn't a real upbeat guy!)

I'm betting on either off-label or some of the combinations the White Rats have been so valiantly experiementing with...maybe only because I'm toooo chicken for brain surgery - I had to drill some skulls and place some electrodes in white rat - and cat - brains zillions of years ago as a psychology student. So scary, I lived in terror or catching the dura mater and scrambling some poor cat's brain...even dissected a human brain once, an experience that filled me with awe- - - guess I never expected to become so preoccupied with the functioning or lack of in my own brain...sorry to rattle on so. Bye.

[indigogo]

James Surmeier is first rate! He has appeared at a number of PAN forums to present his research - he has stated in the past that he was looking at a "heart" medication currently on the market that he thought would be effective - this is the first time he is actually mentioning the drug. I guess this would suggest his findings have only continued to buttress his theory.

Potentially good news for us!

He's presenting at the PDF symposium in NYC in October. This guy is so fun to listen to - he loves what he does and his enthusiasm translates well - even when talking about the most complex and untranslatable details of his science. I'm glad he's on our side!

[Slumpy]

Sasha,
I just started taking this drug on Saturday for moderately high BP. My primary care doc and I decided it was time to treat my BP even though it hasn't really reached the level where they normally start treatment. When I asked him if he normally prescribed a calcium channel blocker, he said no. So I showed him the article on Isradipine (brand name: DynaCirc) and requested that we try it and MAYBE kill two birds with one drug. He agreed and I starting taking DynaCirc 5 MG X 1 on Saturday afternoon.

Obviously way too early to provide any conclusion on whether it will help but I saw a conclusion on the "Ask the Doctor" forum for a PWP who had been taking 5 MG x 2 for a month and had seen very positive results.

Slumpy

[jeanb]

The link below is another thread on Isradipine.

http://neurotalk.psychcentral.com/sh...ght=isradipine

I have been taking it for about 4 months now - no cure yet for me yet. But I do seem to have less neuropathic pain in my feet. I plan to stay on isradipine for a full year to give this a chance to work. (I'm taking 25mg 2X day -- maybe that's too low?)

I'll see my neurologist in a couple of weeks and plan to talk to her about it.

[Ronhutton]

Jeanb,
You are right, the dosage is all important. In

http://www.aboutxinjiang.com/Science...nt_1977627.htm
it says,
"The research team by James Surmeier implanted a time-release capsule of the drug beneath the skin of mice that had just reached adulthood. This implant released a daily dose of isradipine that, if scaled up for humans, would correspond to roughly 10 times the dose for a person with hypertension, but less than the amount given to treat stroke."

It looks as if you need a much higher dose to see an effect on your PD.

Actually, the British PDS (Parkinson's Disease Society) have asked me to write an article for their magazine, after I alerted them to the link with hypertension drugs.
The other hypertension drugs are:
Ramipril
Burinex
Hydrazoline
Captoprill,
Tetrazosin.
I am investigating the effect of these drugs on the BBB, and am corresponding with a professor who specialises in the role of the BBB in MS.
I have personally met two people who were diagnosed with PD up to 20 years ago, and have never needed any PD medication. One has taken Ramipril for many years for hypertension, and the other has taken Burinex for years.
Ron

[jeanb]

Ron,

I had unsuccessfully searched for a recomended dose. I've got an appointment with my neurologist in 2 weeks. So I'll see if she'll increase the dose then. I'm going to ask her to increase it - at least double . Even so it will still be lower than recommended in the article - but it might make a difference to me.

I'll let you know what happens.

thanks,

[Sasha]

Slumpy, JeanB - please keep us posted on how it's going. My internist found this study very interesting - if only I had high blood pressure instead of high cholesterol! - Is this really supposed to reverse the disease or merely slow, hopefully halt, the progression? Did sound like it reversed things for the rats with that cellular calcium to sodium switch. Wow.

[Perryc]

Ron et al,

What would you say to a person like me whose blood pressure is 100/60 about taking high does of calcium channel blockers. Is there a risk of hypo-tension?

Along the same vein, I have been a research participant in studies done at NIH by Dr. David Goldstein which were the first to demonstrate effects of PD outside the brain and striatum. He did PET scans of the heart and discovered that Orthod-static hypotention is highly correlated with 'denervation' of the heart muscle, and those with the most denervation (black PET scan) suffered the greatest problems (dizziness when standing up). My PET scan was perfect in 4 tests over 5 years (no hypotention), so contrary to some beliefs, I do have a heart, but I gave my brain to science.

More preventive cardiology is the finding reported in the newspapers this week (Washington Post) that zocor, a statin drug used to treat high cholesterol, seems to prevent progression in Alzheimers and PD, but other statins (lipidor, mevacor, etc) do not have this effect. My primary doctor is swithching me to zocor from mevacor (both are available as generics), saying that it shouldn't do any harm.

The human body is very complex.

Perry

[jeanb]

I met with my neurologist yesterday, and we agreed to double my dose of isradipine from 2.5mg 2x/day to 5mg 2x/day.

I'm doing fine on it - no adverse reactions. And I'd started taking 5mg 2x/day about 2 weeks before my appointment so I could let her know how I felt on the increased dose. My BP is still fine. She said she'd had other patients ask about starting on it, but they had low BP already, so she couldn't prescribe it for them. Since I DO have hypertension, it isn't a problem.

Who would have imagined that having hypertension would be a good thing? Anyway, I'm going to stay at this dose for the next 5 months and see how I do. After that I will probably double the dose again.

She did say I seemed better now that I had when she last saw me - it's been quite a while - nearly a year. So it may be isradipine, or increased exercise, or both. (I never seem to change only one thing at a time.)