Isradipine, an antihypertensive drug, is emerging as a potential new treatment for Parkinson's disease due to promising results of in vitro tests. Until now, it was unclear whether administering the drug in vivo would yield the same benefits — new research shows that it does.
Previous studies have found that people who took the drug had lower rates of Parkinson's disease, so scientists wanted to examine it closely.
Further tests showed that the drug protects the dopamine-producing neurons that are affected in Parkinson's disease.
Now, a new study shows that treating mice with the drug protects the rodents' dopaminergic neurons as well.
D. James Surmeier, Ph.D., who is the Nathan Smith Davis Professor of Physiology at Northwestern Medicine in Chicago, IL, led the study, and the findings were published in the Journal of Clinical Investigation.
Isradipine affects the neurons' mitochondria
Prof. Surmeier and team administered isradipine to mice for 7–10 days. Then, using a quantitative imaging technique called two-photon laser scanning microscopy, they measured the levels of calcium inside the dopamine-producing neurons.
The tests found that the drug had lowered calcium levels inside these cells. This is important since calcium channels stimulate the mitochondria of dopaminergic neurons, sometimes making these brain cells overly active.
Prof. Surmeier says that this occurs due to the evolutionary role of dopaminergic neurons. These cells are key for activating brain regions responsible for quick motor responses, which is very useful in "fight-or-flight" situations, such as being confronted by a predator.
However, to fulfill this high-energy role, these neurons need to keep their mitochondria working at full capacity at all times. Mitochondria are tiny organelles inside of cells that are responsible for turning fats and nutrients into energy, or the cells' fuel.
Working to such a high capacity at all times is not only no longer necessary in our society, but it can create toxic byproducts. Such toxic compounds ultimately kill neurons, which is what happens in Parkinson's disease.
But in this study, isradipine inhibited calcium channels, which slowed the activity of mitochondria and lowered the production of toxic compounds.
Toward human clinical trials
Also, after treatment with isradipine, the mitochondria of the dopamine-producing neurons had a lower level of oxidative stress than untreated cells.
The scientists also found that high oxidative stress in dopaminergic neurons damaged the cells' mitochondria.
However, treating mice with isradipine lowered this mitochondrial damage. "We diminished the damage being done to mitochondria enough that dopaminergic neurons looked the same as neurons that are not lost in Parkinson's disease," says Prof. Surmeier.
Last but not least, the drug did not induce any side effects, and the rodents continued to behave normally.
The researchers say that the findings reinforce the efforts of a nationwide clinical trial that is now testing isradipine in humans.
The trial, called STEADY-PD, is now in its third phase, and it is being carried out at Northwestern Medicine and 50 other sites in the United States.
Dr. Tanya Simuni, who is the chief of movement disorders in the Ken & Ruth Davee Department of Neurology at Northwestern University, is the primary investigator of this trial. She is hopeful about the results of this study in rodents.
"These data provide additional strong preclinical rationale for the ongoing phase III study of isradipine in human patients [...] We are cautious as so many drugs have failed, but if successful, isradipine will be the first drug to demonstrate the ability to slow progression of Parkinson's disease."
Dr. Tanya Simuni