Pesticides May Promote Parkinson's Disease And Exercise May Offer
Protection, According To New Reports

New research into Parkinson's disease is helping scientists better
understand some of the mechanisms of this serious and disabling brain
disorder, which affects about 1 million people in the United States.
Knowledge of the environmental factors and genetics of this illness
has allowed investigators to create models of disease that are being
used to examine potential causes of neuron disease and to test
experimental therapeutics in animals. Some of the research will
eventually lead to the development of more effective treatments of
this human illness.

The second most common neurodegenerative disease (after Alzheimer's
disease), Parkinson's occurs when certain groups of nerve cells are
damaged and destroyed. For example, neurons in the substantia nigra,
an area of the brain that is important for normal voluntary
movements, are invariably damaged. These abnormalities result in a
variety of signs, including tremor, muscle stiffness, and slowness of
movement. People with Parkinson's may also experience depression,
anxiety, dementia, constipation, urinary difficulties, and sleep
disturbances. Symptoms tend to worsen over time.

Researchers at Emory University and the University of Washington have
developed a new nonhuman primate model of this disorder. They have
shown for the first time that chronic exposure to the “organic”
pesticide rotenone can cause Parkinson's-like pathology in monkeys.
This finding builds upon their previous study in which they
demonstrated that rotenone, a commonly used agricultural pesticide
made from the extracts of tropical plants, can reproduce parkinsonian
features in rats.

“Monkeys have a brain structure that is much more similar to humans
than rats,” notes J. Timothy Greenamyre, MD, PhD, of Emory
University. “These studies on monkeys, therefore, support our
previous findings that chronic pesticide exposure may be capable of
causing parkinsonian pathology in humans.” The results also support
epidemiological studies that suggest that chronic exposure to
environmental toxins, such as pesticides, may contribute to the
incidence of Parkinson's in humans.

In this pilot study, two monkeys were treated with rotenone—one at
Greenamyre's laboratory at Emory University and the other at the
University of Washington laboratory of Marjorie Anderson, PhD. The
rotenone was administered subcutaneously to the animals over a period
of 18 months in one case and 19 months in the other before the
Parkinson's-like pathology developed. When the monkeys' brains were
later examined, the scientists found anatomical and biochemical
changes virtually identical to the major abnormalities seen in
Parkinson's disease, including degeneration of the nigrostriatal
dopaminergic pathway and synuclein positive cytoplasmic inclusions in
nerve cells in the substantia nigra.

Although this study does not prove that rotenone causes Parkinson's
disease, it adds to previous questions about the pesticide's safety
and that of similar environmental toxins. “We think this is an
important proof of the concept that what we eat, drink, breathe, or
are otherwise exposed to can predispose us to Parkinson's disease,”
says Greenamyre.

One of the most promising new drugs for the treatment of Parkinson's
disease is rotigotine, which acts as a dopamine agonist (a drug that
tricks certain receptor cells into thinking they have been activated
by dopamine). Unlike other dopamine agonists, rotigotine is delivered
via a once-a-day skin patch, a delivery system that enables blood
levels of the drug to stay consistent throughout the day. Consistency
is vital because too much of the drug can cause uncontrolled
movements, and too little can result in paralysis.

Past studies have suggested that rotigotine may have properties that
not only lessen parkinsonian symptoms, but that also protect nerve
cells in the substantia nigra from degeneration and death. To
investigate these possible protective properties, scientists at
Schwarz BioSciences in Monheim , Germany , tested rotigotine on a
mouse model of Parkinson's disease. Rotigotine was administered to
the mice subcutaneously in three (high, medium, and low) doses. A
“slow release” formulation of the drug was used so the treatment
would mimic the constant, long-lasting properties of the rotigotine
patch used by patients with Parkinson's disease.

“When we examined the brains of the mice after treatment, we found
that rotigotine not only reduced the number of degenerating neurons
in the substantia nigra, but also preserved the density of cellular
connections originating from that area of the brain,” says Dieter
Scheller, PhD. “The effects were significant at the low dose and
became more pronounced as the doses increased.” The study's results
suggest that rotigotine has neuroprotective properties, at least in
the mouse model. Scheller and his colleagues plan to continue their
investigations in other animal species.

Recent experiments suggest that exercise may protect against the loss
of dopamine neurons—and thus help slow or prevent the development of
Parkinson's disease, according to new studies on rats conducted by
researchers at the University of Pittsburgh and the University of
Texas. This research is encouraging news for people with Parkinson's
disease who are looking for safe and effective ways to stem the
progression of the illness.

In past studies, the researchers reported that rats forced to use
limbs that mimicked the effects of Parkinson's could regain motor
skills within a week of physical activity. When scientists later
examined the rats' brains, they found that the rats forced to be
active had lost fewer dopamine neurons than the sedentary rats.

“There was a problem with these studies, however,” says Michael J.
Zigmond, PhD, of the University of Pittsburgh. “The injections of the
neurotoxin used to mimic Parkinson's were made in a way that causes a
very abrupt death of the dopamine nerve cells—a process that doesn't
resemble the slow, progressive nature of Parkinson's disease in
humans.”

So Zigmond and his colleagues re-did the study, this time injecting
the neurotoxin—6-hydroxydopamine (6-OHDA), which selectively targets
dopamine neurons—directly into the corpus straitum, the region of the
brain where dopamine projections normally end. This caused a much
slower and progressive loss of dopamine neurons—a progression that
started in the corpus straitum and then spread back to the substantia
nigra. “We believe that such a pattern of dopamine neuron death comes
closer to the pattern that occurs in Parkinson's disease,” says
Zigmond. “We've also shown that such lesions can be made in mice as
well as in rats.”

In the second study, the rats were again forced to exercise. When all
the animals' brains were analyzed for the presence of dopamine
neurons, those that exercised showed a near-complete blockade of the
toxic effects of 6-OHDA. The exercise had protected their dopamine
neurons from the neurotoxin.

“We have observed comparable effects in mice,” notes Zigmond. “This
opens up the possibility of using genetically modified mice to study
the involvement of specific genes in both the development of the
disease and in the protective effects of physical activity and other
possible therapies.”

At Columbia University, Serge Przedborski, MD, PhD, and his
colleagues have been studying the seemingly critical role that a
protein called cyclooxygenase type-2 ( COX-2) plays in the
progression of Parkinson's disease. Although best known for promoting
arthritis-related inflammation, COX-2 proteins cause inflammation in
damaged tissues throughout the body, including in the brain. Anti-
inflammatory COX-2 inhibitors—now used primarily for the treatment of
arthritis—may, therefore, prove useful in slowing the progression of
Parkinson's disease.

In past studies, the Columbia researchers found that after mice were
injected with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP), which stimulates Parkinson's symptoms by
killing neurons involved in the control of movement, the expression
of COX-2 increased in the mice's midbrain, especially in nerve cells
that use dopamine as their neurotransmitter. Using human postmortem
samples, the researchers also showed that the amount of COX-2 protein
was higher in patients with Parkinson's disease than in those without
the disease.

“These results show that there is a relationship between the disease
and the presence and amounts of this protein in the brain,” says
Przedborski.

Of the different cell death mechanisms that have been identified, one
of particular interest for researchers studying Parkinson's and other
neurodegenerative diseases is programmed (or apoptotic) cell death,
which is known to occur in these diseases. Przedborski and his
colleagues recently investigated whether the COX-2 protein is
involved in the apoptotic death of nerve cells in Parkinson's
disease. Using the MPTP mice model, they induced Parkinson's symptoms
in two groups of mice—those with the COX-2 protein and those without
it. “We found that in the absence of the COX-2 protein, the quantity
of apoptotic cell death induced by MPTP was reduced by 40 percent,”
says Przedborski. “Overall, these findings indicate that in the MPTP
mouse model, the protein COX-2 may play a role in the process that
leads to the death of the cells implicated in the control of movement
by interfering with the programmed cell death process.”

Przedborski intends to confirm this role for the COX-2 protein by
investigating whether the intensity of cell death increases in mice
that possess an excess of COX-2 protein. “Understanding how this
protein interferes with these mechanisms may lead us to discover
drugs that would allow us to control this protein in Parkinson's
disease patients, possibly leading to a reduced severity of the
disease's symptoms,” says Przedborski.

Editor's Note: The original news release can be found here.
http://apu.sfn.org/content/AboutSFN1/NewsReleases/am2004_parkinsons.ht
ml

This story has been adapted from a news release issued by Society For
Neuroscience.

SOURCE: Science Daily (press release)
http://tinyurl.com/3ov3d

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