Pesticides, Exercise, and Parkinsons

[Guest guest]

[This message contains the original ews release, followed by articles

that report on the release. Interestingly, the pesticide link was hard

to find any articles on, (only found a Newsday.com article) but the

protective effect of exercise in Parkinson's was widely reported. -- David]

 

PESTICIDES MAY PROMOTE PARKINSON'S DISEASE AND EXERCISE MAY OFFER

PROTECTION, ACCORDING TO NEW REPORTS

http://apu.sfn.org/content/AboutSFN1/NewsReleases/am2004_parkinsons.html

10/24/2004

 

For more information, please call Dawn McCoy at 202-462-6688.

 

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.

 

==================================================

MONKEY TEST SHOWS LINK

Pesticide and Parkinson's

Brain-damaging effects of rotenone that had been shown in rats are

replicated in simian subjects

 

BY JAMIE TALAN

STAFF WRITER

 

October 26, 2004

 

Two monkeys exposed to a common pesticide for more than a year

developedclassic signs of Parkinson's disease, strong evidence

environmental factors may destroy key brain cells regulating movement,

scientists reported Sunday at the annual meeting of the Society for

Neuroscience, in San Diego.

 

Investigators first discovered the brain-damaging effects of rotenone in

rats but wanted to test whether the widely used agricultural pesticide

also triggered Parkinson's symptoms in an animal closer to

humans. " Monkeys have a brain structure that is much more similar to

humans than rats, " said Dr. J. Timothy Greenamyre of Emory University in

Atlanta. " Chronic pesticide exposure may be capable of causing Parkinson

pathology in humans. "

 

About 500,000 Americans have Parkinson's, with 50,000 new cases

diagnosed every year. Brain damage in an area called the basal ganglia

leads to muscle tremors, rigidity and slowed movements. Over time, it is

crippling. Tissue in this structure and in the neighboring substantia

nigra are rich in dopamine. The disease damages these cells, and

symptoms appear after 80 percent of these cells are lost.

 

Greenamyre's lab treated one monkey with the pesticide daily over an

18-month period and his collaborator, Marjorie Anderson of the

University of Washington, tested another monkey for 19 months. An

examination of the brains found striking similarities to the human

version of the disease: a substantial loss of dopamine-containing cells

in these pathways and sticky inclusions in nerve cells.

 

" We think this is an important proof of the concept that what we eat,

drink, breathe, or are otherwise exposed to can predispose to

Parkinson's, " Greenamyre said.

 

It is not known whether the pesticide, rotenone, triggers brain damage

in humans. The doses used in the monkeys were small. The repeated

chronic administration triggered the disease, Greenamyre said.

 

According to Greenamyre, rotenone inhibits a substance called complex I

that works in cells' energy-producing " factories, " called mitochondria.

If inhibiting complex I can lead to Parkinson's, scientists can try to

figure out ways to stop this process. Complex I has been shown to be

reduced in patients with Parkinson's.

 

Virginia Lee and colleagues at University of Pennsylvania have long

suspected environmental toxins could trigger the death of vulnerable

brain cells. Lee, co-director of Penn's Center for Neurodegenerative

Disease Research, said the formation of oxygen free radicals, molecules

that can accumulate and damage cells through oxidative stress, are at

the heart of the problem in some degenerative brain diseases. Greenamyre

and Lee suspect rotenone's damage to complex I is carried out through

the formation of these oxygen free radicals, which in turn damage key

brain cells. Greenamyre said many pesticides have the same effect on

mitochondria.

 

2004, Newsday, Inc.

=====================================================

Slow Parkinson's With Exercise

http://www.cbsnews.com/stories/2004/10/25/health/webmd/main651214.shtml

 

Oct. 25, 2004

 

(WebMD) Exercise may slow the onset of Parkinson's disease, a new animal

study shows. A pilot study is under way to test this theory in

Parkinson's disease patients.

 

It's a wake-up call for the rest of us to get some regular exercise, the

researchers say.

 

" The concept is emerging that exercise is not only good for the heart

and body weight, but also good for the brain, " senior researcher Michael

J. Zigmond, PhD, co-director of the Center for Neurosciences at the

University of Pittsburgh School of Medicine, tells WebMD.

 

Zigmond heads the team presenting this newest report at the Society for

Neuroscience annual meeting, held in San Diego this week.

 

" Studies show consistently that people who lead active lives — who

exercise and walk every day — are less likely to get Parkinson's

disease, " Zigmond says. " Studies are also under way to identify

individuals with Parkinson's disease, put them on an exercise regimen,

to see if it is preventive. In the next few years, we should have a real

handle on that. "

 

Parkinson's disease is a mystery, its cause unknown but the symptoms

unmistakable. The progression of this brain-wasting disease causes

uncontrollable tremors, rigidity of limbs, slow movements, and stooped

posture. This results from the slow breakdown of nerve cells in the

brain that produce dopamine, a chemical that helps control movement.

 

While some medications or surgery help relieve symptoms, researchers

have searched for ways to prevent the downward spiral of Parkinson's

disease. This newest study offers hope for an extremely doable

alternative, says Zigmond.

 

 

Simulating Parkinson's Disease

 

In their study, the Pittsburgh researchers first put a cast on a lab

rat's forearm and forced the rat to exercise the other " good arm " for

seven days. Researchers then removed the cast, and — to simulate

Parkinson's disease — injected one side of the rat's brain (the same

side as the casted limb) with a toxin that triggers brain cell loss,

mimicking what is seen in Parkinson's disease.

 

The side of the brain that was injected was chosen because it controls

movement in the free limb. By casting the opposite limb, the researchers

were hoping to force exercise in the limb that should have had its

movement destroyed by the brain toxin.

 

Animals that exercised their free limb lost significantly fewer brain

cells that contain dopamine— just 6 percent of these brain cells.

Another group of rats that also received the toxin but were not forced

to exercise lost 87 percent of their brain cells. Parkinson's disease is

caused by the destruction of dopamine-producing brain cells.

 

Two days after the toxin was given, the " exercised " rats still had brain

cells that appeared healthy.

 

Previous research has shown a similar pattern — that people who lead

active lives, who exercise and walk every day, are less likely to get

degenerative brain disorders like Parkinson's disease, Zigmond says.

 

In fact, just last month two studies showed that exercise helps prevent

or delay onset of Alzheimer's disease, which also involves brain cell

death, Zigmond tells WebMD. Those studies showed that " the more active

you are, the older you were when you developed it, and the less severe

it was. "

 

Studies have also shown that exercise stimulates production of key

proteins — specifically a nerve growth factor called GDNF that is

important for survival of brain cells, he explains.

 

" Exercise increases concentrations of growth factors that reduce the

rate at which nerve cells die, " Zigmond explains. " We've known that

these growth factors are very important during a child's early years.

But now we realize that they can become important again in adulthood. "

 

Several small pilot studies are under way involving patients diagnosed

with Parkinson's disease, he says. Researchers plan to enroll 20

patients in a 60-minute exercise program that meets three times a week.

 

Preventing, Slowing Parkinson's Disease May Be Possible

 

Zigmond's study is " exciting, very interesting, " Spyridon

Papapetropoulos, MD, PhD, professor of neurology at the University of

Miami School of Medicine, tells WebMD. " All our efforts up to now have

been in preventing further degeneration of these nerve cells or

restoring brain cells with embryonic stem cells. If exercise can prevent

loss, that's very exciting. "

 

However, he advises against getting overly excited about the research

just yet. " It's too early to know whether this works in humans. By the

time that Parkinson's disease is diagnosed, people have already lost 60

percent to 80 percent of their dopamine-producing neurons. One can

speculate that if it's caught early enough, it's possible to salvage

[brain cells] that have survived. "

 

" It's an intriguing finding. ... We're all looking for interventions to

prevent these degenerative diseases, and this growth factor GDEF has

looked promising, " Burton Scott, MD, professor of neurology at the Duke

University Movement Disorders Center, tells WebMD. " But how to deliver

this growth factor so it works in patients hasn't been determined. So

far, those efforts have been unsuccessful. This study presents another

avenue to explore. "

 

SOURCES: Neuroscience 2004, San Diego, Oct. 23-27, 2004. Michael J.

Zigmond, PhD, co-director, Center for Neurosciences, University of

Pittsburgh School of Medicine. Spyridon Papapetropoulos, MD, PhD,

professor of neurology, University of Miami School of Medicine. Burton

Scott, MD, professor of neurology, Duke University Movement Disorders

Center.

 

By Jeanie Lerche Davis

Reviewed by Brunilda Nazario, MD

© 2004, WebMD Inc. All rights reserved.