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

Date:
November 3, 2004
Source:
Society For Neuroscience
Summary:
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.

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.

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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.


Story Source:

The above story is based on materials provided by Society For Neuroscience. Note: Materials may be edited for content and length.


Cite This Page:

Society For Neuroscience. "Pesticides May Promote Parkinson's Disease And Exercise May Offer Protection, According To New Reports." ScienceDaily. ScienceDaily, 3 November 2004. <www.sciencedaily.com/releases/2004/10/041030133705.htm>.
Society For Neuroscience. (2004, November 3). Pesticides May Promote Parkinson's Disease And Exercise May Offer Protection, According To New Reports. ScienceDaily. Retrieved November 28, 2014 from www.sciencedaily.com/releases/2004/10/041030133705.htm
Society For Neuroscience. "Pesticides May Promote Parkinson's Disease And Exercise May Offer Protection, According To New Reports." ScienceDaily. www.sciencedaily.com/releases/2004/10/041030133705.htm (accessed November 28, 2014).

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