During the week of February 11, 2008, news media all over the world reported on a study showing that a widely used, FDA-approved high blood pressure medication — a class of drugs known as calcium channel blockers — seems to reduce the risk of Parkinson’s disease. Independently, D. James Surmeier, PhD, professor and chair of the Department of Physiology at the Feinberg School of Medicine and director of the Morris K. Udall Center of Research Excellence for Parkinson’s Disease of Northwestern University, published work last year showing that one such drug, isradipine, protected dopamine neurons from death in an animal model of Parkinson’s disease. In response, MJFF granted Dr. Surmeier a Rapid Response Innovation Award to investigate the effects of isradipine further to help inform eventual clinical testing. To help people with PD place the excitement around calcium channel blockers in perspective, the Foundation spoke to Dr. Surmeier this week about next steps toward determining the potential of these drugs as a treatment for Parkinson’s disease.

NOTE: The medical information contained in this article is for general information purposes only. The Michael J. Fox Foundation has a policy of refraining from advocating, endorsing or promoting any drug therapy, course of treatment, or specific company or institution. It is crucial that care and treatment decisions related to Parkinson’s disease and any other medical condition be made in consultation with a physician or other qualified medical professional.

MJFF: Calcium channel blockers are already FDA-approved, so we must know a great deal about these drugs. 

DJS: Historically, the main use of calcium channel blockers has been to decrease hypertension (high blood pressure). They do this by stopping calcium from entering muscle cells that make up the walls of the heart and blood vessels. Decreasing calcium entry reduces the strength of heart contractions and relaxes blood vessels, which reduces blood pressure. 

MJFF: How is this related to how these drugs may be protecting dopamine neurons from the cell death seen in Parkinson’s disease?

DJS: Calcium channels are found in many cells of the body, including dopamine neurons — the brain cells that die in Parkinson’s disease. But unlike the vast majority of cells, dopamine neurons rely heavily upon calcium channels to maintain their normal level of activity. We think that the cells’ reliance on calcium to drive this activity creates a lot of ‘wear and tear’ on dopamine neurons — aging them more rapidly than other neurons and making them vulnerable to genetic mutations and other stressors, like environmental toxins.

What is particularly fascinating about dopamine neurons is that early in their life they employ a much less stressful way of generating their activity, one that relies on sodium rather than calcium. We discovered that this juvenile mechanism remains latent in adult dopamine neurons, and can be reactivated when calcium channels are blocked with the drugs used to treat hypertension. When dopamine neurons are forced back to this juvenile method of generating their activity, they became much more resistant to the toxins used to create Parkinsonian symptoms in animal models.

There is also significant interest in calcium channel blockers among the Alzheimer’s disease community, because these drugs also seem to slow cognitive decline in animal models of Alzheimer’s disease. We don’t understand yet precisely how they exert this effect, but it is not entirely unexpected because calcium has been implicated in several forms of neurodegeneration.

MJFF: This all sounds extremely promising, especially because the drug is already FDA-approved. What’s holding up the use of calcium channel blockers as a PD therapy?

DJS: There are several challenges. The principal one at this point is in finding the correct dose to use in people. Isradipine is approved for human use to treat blood pressure, but it is not clear what dose should be used in humans for neuroprotection. Studies funded by MJFF suggest that isradipine, when used in the FDA-approved dose range, is protective in animal models. This conclusion is consistent with the study reported last week showing a decreased incidence of PD in patients treated for high blood pressure with calcium channel blockers. But more work needs to be done.

MJFF: People with PD often have low blood pressure. Is it safe for them to take a medication designed to lower blood pressure further?

DJS: First, many PD patients have high blood pressure and are medicated for it. High blood pressure often comes with age. So it’s not uncommon in itself that someone with PD would be taking a medication designed to lower blood pressure. That said, PD patients often have difficulty regulating their blood pressure. For example, they might feel light-headed or dizzy when they stand up too quickly. In these patients, the effects of isradipine treatment would have to be monitored closely. However, a tolerability study being conducted by a colleague of mine here at Northwestern has not found this be a major issue in early-stage PD patients.

MJFF: In that case, if you are a person living with PD and high blood pressure, should you ask your doctor to prescribe isradipine or another calcium channel blocker right away?

DJS: We are hearing anecdotally that many people with Parkinson’s disease are asking their physicians to be switched to a calcium channel blocker from another class of high blood pressure drug, such as beta blockers. In general this is a perfectly reasonable strategy as long as the physician agrees to it and the patient is carefully monitored.

I would note, however, that more research is needed before calcium channel blockers can be considered a truly safe and effective PD treatment. The study published earlier this month was a retrospective study looking at calcium channel blocker use and occurrence of Parkinson’s disease. A prospective study is critical to knowing whether calcium channel blockers actually prevent or slow PD. 

MJFF: What are the next steps to carry this work forward into clinical trials? 

DJS: Last week my colleague and I met with officials at the National Institute of Neurological Disease and Stroke (NINDS) to discuss a larger-scale tolerability and neuroprotection trial that will help us address the challenges I have mentioned. The formal application to conduct the study will be submitted in June, and we hope the trial can move forward by the end of 2008 in collaboration with the FDA and NINDS. 

MJFF: For people with PD, what’s the bottom-line takeaway? 

DJS: There are good reasons to be hopeful that we will have a treatment in the near term that will slow or stop Parkinson’s disease. Calcium channel blockers, like isradipine, have a long record of safe use in humans, making them very attractive therapeutically. However, there is work left to do. In particular, we need a potent and selective drug to block the calcium channels we think make dopamine neurons vulnerable. With hard work and resources, I’m sure this is possible.