For release: Friday, August 3, 2007
For decades, scientists have tried to learn what causes the death of a select group of nerve cells in the brains of people with Parkinson's disease (PD). New research identifies an unusual mode of activity in these cells that makes them exceptionally vulnerable to toxins and stress and shows that a common drug can protect these neurons in animal models of PD. This work suggests a possible new way to slow or prevent the disease.
The researchers found that the drug tested in this study, a calcium channel blocking drug called isradipine, forces mouse dopamine neurons in a brain region called the substantia nigra to switch to a more youthful way of generating electrical signals. This reduced the neurons' vulnerability to toxins. The study appears in the June 28, 2007, issue of Nature.1
"This animal study offers the hope that specific types of calcium channel blockers, relatives of those currently widely used to reduce blood pressure, might someday slow the steady progression of Parkinson’s disease,” says Walter J. Koroshetz, M.D., deputy director of the National Institute of Neurological Disorders and Stroke (NINDS), which funded this work.
Many, but not all symptoms, in patients with PD occur due to the death of dopamine-producing neurons in the brain's substantia nigra. These neurons are essential for the brain circuits that initiate and control movement. Dysfunction and death of the dopamine neurons is responsible for the tremor, slowness, imbalance, and muscle rigidity that is so prominent in patients with PD. Medications that increase dopamine in the brain can dramatically reduce the symptoms of patients with early stages of PD, but they lose effectiveness in late stages of the disease. Deep brain stimulation has been shown to help some patients with PD in the later stages of illness. However, none of the current treatments has been shown to slow down the progression of the disease or the death of the dopamine neurons.
“There is no widely accepted model of why Parkinson’s disease occurs,” says D. James Surmeier, Ph.D., director of the Morris K. Udall Center of Excellence for Parkinson’s Disease Research at Northwestern University in Chicago, Illinois, who led the new study. “We asked whether there is something different about the dopamine neurons in the brain’s substantia nigra that makes them susceptible to damage.”
Like cells in the heart, dopamine neurons in the substantia nigra work as pacemakers, constantly generating spikes of electrical activity, called action potentials, in order to maintain normal dopamine levels in other parts of the brain. These action potentials are created by ion channels — pores in the cell membrane that control the flow of electrically charged ions in and out of cells.
Most pacemaker neurons use sodium ion channels to generate activity. However, the dopamine neurons that die in PD use calcium channels instead. While sodium entry causes few problems, calcium can be very harmful to cells. To control the damage, cells either pump out excess calcium or continually mop it up. The constant work of controlling the calcium takes a lot of energy, stressing the cell. Dr. Surmeier theorized that this constant stress might make the dopamine neurons more vulnerable to toxins.
The researchers discovered that, in very young mice, dopamine neurons use sodium ions instead of calcium to generate activity. The neurons gradually switch to using calcium as they age. However, dopamine neurons in mice lacking the particular calcium channels used to generate activity continued to spike normally even after the mice grew into adults. This showed that the calcium channels were not essential for the neurons to function.
By using isradipine to block these calcium channels, Dr. Surmeier and his colleagues found that they could force adult neurons to use sodium channels, just like younger neurons. Neurons in mice implanted with pellets that slowly release isradipine became very resistant to toxins, such as the chemical MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine), that normally cause Parkinson’s-like brain damage and symptoms in animals.
“We think the disease results from the interaction between this naturally occurring stress in the dopamine neurons and environmental toxins or genetic mutations that further increase their stress level,” says Dr. Surmeier. Thus, stopping the constant influx of calcium into the neurons may reduce the stress and help protect the cells.
Isradipine and similar drugs are approved for use in people and, at doses needed to reduce blood pressure, they usually cause only minor side effects. However, the dose needed to prevent brain damage is likely to be higher than what is needed to reduce blood pressure. Dr. Surmeier and his colleagues are beginning a small study in people to learn whether higher-than-normal doses of isradipine are safe.
"One critically important issue is whether the doses needed to block calcium channels in the brain would cause dangerous drops in blood pressure, particularly in patients with Parkinson's disease who often have trouble with fainting due to low blood pressure," Dr. Koroshetz says.
Unlike most other calcium channel blockers that are used to treat hypertension, isradipine is very effective at blocking the type of calcium channel expressed by the vulnerable dopamine neurons. This makes it particularly well suited for treating PD.
If isradipine proves safe and effective at reducing neuron damage in people, it might eventually be used to prevent PD in people at risk of the disease, in addition to treating the disease after it begins, Dr. Surmeier suggests.
Dr. Surmeier is now studying isradipine in animal models to learn more about how much of the drug is needed to protect neurons. He also plans to study how the calcium channels in dopamine neurons interact with the genes linked to PD. If all goes well, he hopes to begin a clinical trial to test the effectiveness of isradipine in people with PD.2
Ultimately, researchers may be able to find a drug that works primarily on the type of calcium channel found in the substantia nigra, Dr. Surmeier says. Such a drug would have fewer effects on blood pressure and heart function than current calcium channel blockers.
The Morris K. Udall Parkinson's Disease Research Centers of Excellence program was developed in honor of former Congressman Morris K. Udall, who died in 1998 after a long battle with Parkinson's disease. The 13 Udall Centers focus on scientific research designed to improve the diagnosis and treatment of patients with PD and related neurodegenerative disorders and on research to gain a better understanding of the fundamental causes of the disease.
The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system. The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
-By Natalie Frazin
1 Chan CS, Guzman JN, Ilijic E, Mercer JN, Rick C, Tkatch T, Meredith GE, Surmeier DJ. "'Rejuvenation' protects neurons in mouse models of Parkinson's disease." Nature, June 28, 2007, Vol. 447, pp: 1081-1086.
2 Clinical trial results have been published: Simuni T, Borushko E, Avram MJ, Miskevics S, Martel A, Zadikoff C, Videnovic A, Weaver FM, Williams K, Surmeier DJ. “Tolerability of isradipine in early Parkinson's disease: a pilot dose escalation study.” Movement Disorders (2010), 25(16):2863-6.
Parkinson Study Group. “Phase II safety, tolerability, and dose selection study of isradipine as a potential disease-modifying intervention in early Parkinson's disease (STEADY-PD).” Movement Disorders (2013), 28(13):1823-1831.
Last Modified March 13, 2014