Exercise protects brain cells affected by Parkinson's

In an animal model of Parkinson's, exercise prevents degeneration of nerve cells that are normally impaired or destroyed by the disease, according to University of Pittsburgh researchers.

Based on their work, which was presented today 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 if regular exercise has an impact on the progression of their disease.

Parkinson's disease belongs to a group of conditions called motor system disorders. The four primary symptoms are tremor or trembling in hands, arms, legs, jaw, and face; rigidity or stiffness of the limbs and trunk; bradykinesia or slowness of movement; and postural instability or impaired balance and coordination. As these symptoms become more pronounced, patients may have difficulty walking, talking, or completing other simple tasks.

The disease is both chronic, meaning it persists over a long period of time, and progressive, meaning its symptoms grow worse over time. It is not contagious nor is it usually inherited — that is, it does not pass directly from one family member or generation to the next.

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 at the University of Pittsburgh School of Medicine, the 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. They found that, compared to animals that had not been exercised, significantly fewer dopamine-containing neurons died.

"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, Ph.D., professor of neurology, neurobiology and psychiatry, and co-director of the Parkinson's Disease Center of Excellence at the University of Pittsburgh School of Medicine.

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," Dr. 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 by Timothy Schallert, Ph.D., 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, Dr. 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. The 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, reported Ms. Cohen, an analysis of brain tissue 28 days after 6-OHDA injection found that in the animals that were forced to exercise their 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. 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," noted Ms. Cohen.

"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," added Dr. Zigmond. "In a collaboration with Dr. Shallert's lab at the University of Texas, we are 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."

As an extension to their animal research, Dr. Zigmond has enlisted Anthony DeLitto, Ph.D., P.T., FAPTA, and colleagues from the University of Pittsburgh 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.

In addition to Zigmond, other authors of the abstract presented by Ms. Cohen are Amina El Ayadi, Ph.D., and Amanda Smith, Ph.D., also from the department of neurology at the University of Pittsburgh School of Medicine. Related studies also were presented by Niklas Lindgren, Ph.D., and Eva Lin, Ph.D., both from the department of neurology; and Jane E. Cavanaugh, Ph.D., of the department of pharmacology. Their research was supported by grants from the National Institute of Neurological Disorders and Stroke, the United States Army, and the Michael J. Fox Foundation.