In an animal model of Parkinson’s, exercise was shown to prevent degeneration of nerve cells that are normally impaired or destroyed by the disease, according to Pitt researchers.
Based on their work, which was presented Oct. 24 at the Annual Meeting of the Society for Neuroscience in San Diego, a small pilot study has been initiated in patients with Parkinson’s to determine whether regular exercise has an impact on the progression of their disease.
In Parkinson’s, cells in the brain that contain dopamine, a neurotransmitter essential for purposeful and facile muscle control, progressively die until only a small percentage remains. Dopamine carries signals from the nerve cells, or neurons, located deep inside the brain in an area called the substantia nigra along nerve fibers that end in the brain’s striatum, an area involved in control of movement. In the absence of dopamine, neurons can’t send the appropriate messages for smooth motor control, resulting in the telltale symptoms of Parkinson’s: uncontrollable tremors, rigidity of limbs, slow movements, and stooped posture.
In one of the studies presented by Annie D. Cohen, a doctoral student in the Department of Neurology and Center for Neuroscience in Pitt’s School of Medicine, researchers examined the brains of rats that had been forced to exercise for seven days before receiving a toxin that normally induces Parkinson’s disease. The scientists found that, compared with animals that had not been exercised, significantly fewer dopamine-containing neurons died in the brains of the exercised rats.
“Whereas a number of explanations could be offered as to why the exercised animals do so well, we have evidence that indicates it’s because exercise stimulates production of key proteins that are important for survival of neurons,” said the study’s senior author, Michael J. Zigmond, a Pitt professor of neurology, neurobiology, and psychiatry, and co-director of the Parkinson’s Disease Center of Excellence in the University’s medical school.
Called neurotrophic factors, these proteins protect neurons and promote their survival. According to the researchers’ studies, one particular neurotrophic factor, glial cell line-derived neurotropic factor, or GDNF, is increased with exercise by 40 percent. “GDNF, and probably other factors as well, may help offset the cell’s vulnerability to the effects of oxidative stress from free radical molecules that are produced by the toxin we use in our rat model,” Zigmond explained.
Parkinson’s is induced by giving animals a substance called 6-hydroxydopamine (6-OHDA). The toxin results in brain pathology that mimics what is seen in human disease—a decrease of dopamine-containing neurons in the substantia nigra and of axon terminals in the striatum, the site where dopamine is usually released.
When delivered to one side of the brain, 6-OHDA causes movement deficits in the limbs on the opposite side. If a cast is placed on the animal’s left forelimb, for example, and 6-OHDA is administered to the left side of the brain, the toxin would normally cause the right forelimb to be impaired. But this is not the case. Earlier studies at the University of Texas in Austin found that by immobilizing the left arm—the good arm—the rat has no choice but to use its right arm and does so without much difficulty.
To determine if forcing exercise of a particular limb could be protective against Parkinson’s, Zigmond’s group performed a study whereby one forelimb was immobilized in a cast for seven days, placing more physical demands on the free forelimb. After the cast was removed, 6-OHDA was administered to the brain on the same side as the limb that had been casted. Researchers observed no deficits in movement with either limb. Most importantly, the limb that had been exercised and should have been affected by the toxin was fine.
In addition, Cohen reported, an analysis of brain tissue 28 days after 6-OHDA injection found that in the animals that were forced to exercise a limb, only 6 percent of dopamine-containing neurons were lost. But in animals given the toxin without prior exercise, these neurons were reduced by 87 percent.
“We looked for certain cell markers to assess to what extent exercise was protective against degeneration, and even at two days after 6-OHDA administration, we saw there to be a protective effect,” Cohen said. “Our data suggest the possibility that exercise can make dopamine neurons resistant to neurotoxins and may therefore be a useful therapy for Parkinson’s disease.”
Zigmond added, “Whether exercise can reduce the risk of Parkinson’s disease or can slow down its progression are intriguing questions. We are certainly encouraged that in our experimental models we can demonstrate that this sort of forced exercise improves motor function and protects the neurons affected by the disease.”
Zigmond’s research was supported by grants from the National Institute of Neurological Disorders and Stroke, the U.S. Army, and the Michael J. Fox Foundation.
In a collaboration with the University of Texas, Zigmond’s team is now looking at more clinically relevant forms of exercise, such as running. “We also plan to look at the effects of housing our rats in an enriched environment,” he said.
As an extension to the animal research, Zigmond has enlisted researchers from Pitt’s School of Health and Rehabilitation Sciences to begin a study whereby patients with Parkinson’s disease are enrolled in a 60-minute exercise program that meets three times a week. The study plans to enroll 20 patients in its initial phase.
