June 10, 2007
Isradipine Might Slow Or Stop Parkinson's Disease
Isradipine might shift dopamine neurons into a state that is less stressful and by doing so slow the progression of Parkinson's.
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.
What would isradipine do for aging minds in general? We all have dopamine neurons. Those neurons age in all of us, albeit at a slower rate than they age in people who have Parkinson's.
Decades of research have not produced a single drug that slows the rate of neuronal cell death in Parkinson's.
“There has not been a major advance in the pharmacological management of Parkinson’s disease for 30 years,” Surmeier said.
Thousands of drugs exist in pharmacies. Why did it take decades before someone tried isradipine? Surmeier made a basic discovery about the behavior of adult dopaminergic neurons: unlike most neurons they use calcium for signaling rather than sodium.
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.
Actually, other types of neurons use calcium as well though in a more limited manner. My knowledge on this is rather dated at this point but calcium fluxes across membranes help initiate waves of depolarization at the dendrite end of neurons when neurotransmitters bind to a dendrite's receptors. But apparently dopamine neurons use calcium more extensively and instead of sodium.
Aged dopamine neurons switch to using calcium instead of sodium (why?) and this calcium has toxic effects on dopamine neurons that probably makes them wear out more rapidly.
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.
So then would long term use of isradipine slow general brain aging?
Surmeier decided to block off calcium channels in dopamine cells by use of isradipine. The result: the dopamine cells switched over to use of less toxic sodium instead.
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.
Hat's off to this scientist and his team. Good job.
Well, I guess it's time to add to the low-dose deprenyl recommendation, a low-dose isradipine recommendation. I too would expect low-dose isradipine to be neuro-protective.
Great little piece of basic research by going back to the basics. Love it.
Makes you wonder how many other similar things may be going on in other cells that we are completely missing...
On great little piece of basic research: Yes, don't you just love it? Make a fundamental discovery on what a system does and, wham, you know how to intervene and you already have a tool that will do the intervention you want. It doesn't get much prettier than that, does it?
Of course, this guy is smart. It is easy to describe after the fact why it makes sense. But he had to have a lot of knowledge and an excellent clear mind to see this.
Isradipine (DynaCirc Novartis) is a calcium channel blocker, most often used for treating hypertension, but also useful for other cardiovascular conditions. The good news is that because it an approved and marketed drug, it may be used to treat other diseases "off label" without going through the full and extraordinarily expensive FDA approval process, which can take years and cost a quarter billion dollars.
Excellent research product. Well done. Hats off!!! Hope many deprived and needy patients would benifit out of this. - Kishore Gowda
Would other calcium channel blockers do the same, or is there something intrinsic about isradipine? In otherwords, might this be a class effect for the dihydropyridine CCB's? And I can't find anywhere what doses are being used. Greater than those for hypertension, I assume.
I would expect this to be something the whole class of calcium channel blockers do. Other calcium channel blockers could certainly get tested the same way Isradipine was tested for this effect.
This drug has been around long enough that it should be easy to see how many people who use it have Parkinsons.
I would like to know how to go about getting this drug prescribed for my 85 year old dad. He is currently taking Permax which is the only drug that helps him have a good quality of life. What is "off label"? Can it be prescribed for his advnced Parkinson's? We know Permax is dangerous...we get it from New Zealand. I have been trying to research any other alternative.
I was already on a Calcium Chanel blocker Norvasc, when I read this article last winter. My Cardiologist switched me onto DynaCircCr 10 mg twice a day in April. I was diagnosed with Parkinsons about two years ago. Right now it seems that I am on a good combination of drugs and exercise (Myo fascial release). I would like to know how much Isradipine is recommended and any follow-ups that are being done!
I recently took a calcium blocker (Renedil) to supplement a beta blocker (Adalat) and what a shock to find all my PD symptoms dissappeared for 4 days. They did come back and my GP took me off the Renedil due to a side effect. After reading this I'm going to push for medication changes.
I would like to know more about CCB's and PD as relates with blood pressure... this is too simple to not try it for myself... Isradipine dosage level understanding is sought also.
I am amazed that the news of this portentious effect is so subdued. Also, why is there such a time lag in reporting...???!!!
Love to have a conversation with Dr James Surmeier at Northwestern University in Illinois or his colleague.
How can I help with study or publicizing...?
HAS THERE BEEN ANY FOLLOW UP IN THE LAST TWO YEARS AND HOW AN I FIND OUT?
My wife's neurologist just mentioned yesterday (Nov. 27, 2010) that isridipine is helpful in an animal model of Parkinson's. He pointed out something that I think will be helpful for many of the people who have posted on this topic: Isridipine readily crosses the blood brain barrier (BBB) - and can thus access the brain dopamine cells - whereas most calcium channel blockers do not readily cross the BBB and would therefore not be helpful in this particular target.
After consulting with my neurologist and family doctor, I dropped one of my hypertension drugs and titrated my isridipine dosage up to 40mg/day after 8 weeks. The 2nd to 9th week was hard as, I assumed, the dopamine cells shutdown. Then on the 10th week, I noticed an improvement in my on/off times. I believe that this treatment is worth trying, but the down weeks are difficult and make you want to give up. My hope is that I will recover some of my lost dopamine production in the next few months. Isridipine is available as a generic and is not too expensive. My mail-order drug supplier only has it available in 5mg capsules so I have to take 8 per day.