Exercising Limbs Protects Brain Cells Affected By Parkinson's, Study
In Rodents Shows

Contact: Lisa Rossi
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Alan Aldinger
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University of Pittsburgh Medical Center

SAN DIEGO, Oct. 24 – 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.

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.

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SOURCE: EurekAlert, DC
http://www.eurekalert.org/pub_releases/2004-10/uopm-elp101904.php

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