Category: Parkinson’s

Deep brain stimulation, a surgical procedure to suppress faulty nerve signals, allowed 77 percent of patients to stop the medications used to treat their essential tremors within one year following the surgery, University of South Florida researchers report.

"It's a significant finding demonstrating that patients see a lot of symptom improvement with this treatment option," said Andrew Resnick, a research assistant in the USF Health Department of Neurology. Resnick will present results of the limited retrospective study April 12, 2011, at the annual meeting of the American Academy of Neurology in Honolulu, Hawaii.

Essential tremor, which affects the hands, head and voice, is three times more prevalent than Parkinson's disease. The largely hereditary neurological condition can cause uncontrollable shaking that interferes with normal daily activities such as eating, drinking and getting dressed. Tremors can begin in early adulthood and become more severe as a person grows older.

While medications (primidone, propranolol and/or topiramate) help alleviate essential tremors in some patients, over time many patients discontinue the drugs because their effectiveness wanes or the side effects become intolerable, said USF Health neurologist Theresa Zesiewicz, MD, who was the lead author in developing the AAN's first guidelines for treatment of essential tremor. "Essentially, they just give up trying to treat essential tremor."

The USF study reviewed the charts of 31 patients who underwent unilateral deep brain stimulation (DBS) surgery for essential tremor from 2000 to 2010. The therapy uses an implanted device similar to a pacemaker to stimulate a targeted region of the brain with electrical impulses, blocking or correcting abnormal nerve signals that cause the tremors.

At the time of surgery, 20 of the 31 patients had been diagnosed with essential tremor for 10 or more years and 11 had been diagnosed for less than 10 years.

The researchers found that all 13 patients still taking anti-tremor medications at the time of DBS surgery gained effective control of their tremors following the procedure. In fact, symptom improvement was so good that 10 patients in this group (77 percent) stopped the anti-tremor medications within one year of surgery. The remaining three (23 percent) continued to take propranolol, an antihypertensive as well as an anti-tremor drug, only because they still needed it to control blood pressure.

Eighteen of the 31 patients (54 percent) had discontinued anti-tremor medications a year or more before the DBS surgery — 10 because the medications stopped working and eight because of adverse side effects such as nausea, headaches and other flu-like symptoms, drops in blood pressure, cognitive impairment or depression. Most patients in this group had long-standing essential tremor (10 or more years). All these patients also benefitted from the DBS surgery, though some experienced longer symptom improvement than others.

USF Health neurosurgeon Dr. Donald Smith, a pioneer in DBS surgery, has performed more than 200 procedures since the FDA approved the anti-tremor treatment in 1997.

By the time patients reach the point of contemplating surgery, the tremors are usually very debilitating, said Dr. Smith, surgical co-director of the Movement Disorders Clinic in the USF Department of Neurosurgery.

"People may not be able to write, or comb their hair; they can't use tools, can't sew or knit. They have difficult feeding themselves and drinking, so they're often embarrassed to go out to eat." Dr Smith said. "It a rewarding procedure to perform, because most patients come in with high levels of disability and can be turned around quickly. It's a home-run surgery."

A limitation of the USF study was that only unilateral DBS, which treats one side of the brain affecting tremors in the dominant hand, was examined. Bilateral DBS for tremor in both hands is associated with more side effects, Dr. Zesiewicz said, but patients are often satisfied when they regain control in the dominant hand.

Future research should include larger, long-term studies investigating how long the tremor control effects of DBS last, the researchers conclude. For instance, will patients who have undergone the procedure need medication again 10 to 20 years after the surgery, or can physicians alter the intensity of electrical impulses delivered by the DBS device so that the procedure's benefits are sustained?

In addition to Resnick, Dr. Smith and Dr. Zesiewicz, USF Health's Teresita Malapira, Dr. Fernando Vale, Kelly Sullivan (neuroepidemiologist) and Amber Miller, and the University of Florida's Dr. Michael Okun conducted the study.

As Parkinson's Awareness Month gets underway, a Canadian-led international study is providing important new insight into Parkinson's disease and paving the way for new avenues for clinical trials. The study, led by Dr. Michael Schlossmacher in Ottawa, provides the first link between the most common genetic risk factor for Parkinson's and the hallmark accumulation of a protein called alpha-synuclein within the brains of people with Parkinson's.

It is published in the most recent edition of the journal Annals of Neurology.

"This study addresses a major riddle in Parkinson's disease," explains Dr. Schlossmacher, who holds the Canada Research Chair in Parkinson's disease at the Ottawa Hospital Research Institute and the University of Ottawa, and is also an active neurologist at The Ottawa Hospital. "Thanks to pioneering research done by geneticists in the United States and Israel, we've known for six years now that 10-12 per cent of people with Parkinson's have a mutation in one copy of a gene called glucocerebrosidase, or GBA. However, until now we have not understood how these mutations contribute to the disease and how they fit with other pieces of the puzzle, such as the accumulation of alpha-synuclein in the brain."

Alpha-synuclein has been likened to the "bad cholesterol" of Parkinson's because it gradually accumulates in the brain as Parkinson's progresses. Affected brain cells show signs of injury, and when they die, this leads to the tremors, stiffness and slowness that are typically associated with Parkinson's disease.

Using a series of experimental laboratory models, Dr. Schlossmacher and his colleagues have now shown that the GBA mutations found in Parkinson's patients prevent brain cells from efficiently breaking down and removing alpha-synuclein.

"While the GBA mutations don't cause Parkinson's disease on their own, they do significantly increase the risk of developing the disease, probably by making people susceptible to the accumulation of alpha-synuclein," says Dr. Schlossmacher. "This could explain why people with GBA mutations frequently develop Parkinson's symptoms four to five years earlier than those without them."

"These findings are particularly exciting because if they are confirmed by other researchers, they could significantly accelerate the development of new treatments for Parkinson's," he adds. "Several companies have developed or are actively working on drugs that target GBA for another disease called Gaucher disease, and our research suggests that these drugs could potentially be useful in Parkinson's, and in a related disease called Lewy body dementia."

In addition to researchers in Ottawa, this study also involved researchers from Brigham & Women's Hospital at Harvard Medical School (where the Schlossmacher team first began to explore the link), Genzyme Corporation, Cincinnati Children's Hospital Medical Centre, Christian-Albrechts University and Purdue University. It was funded by the Canada Research Chairs Program, The Ottawa Hospital Department of Medicine, the Michael J. Fox Foundation, the National Institutes of Health (USA), and Genzyme Corporation.

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Journal Reference:

1. Valerie Cullen, S. Pablo Sardi, Juliana Ng, Xu-Yu Hui, Ying Sun, Julianna J. Tomlinson, Piotr Kolodziej, Ilana Kahn, Paul Saftig, John Woulfe, Jean C. Rochet, Marcie A. Glicksman, Seng H. Cheng, Gregory L. Grabowski, Lamya S. Shihabuddin, Michael G. Schlossmacher. Acid β−glucosidase mutants linked to Gaucher disease, Parkinson's and Lewy body dementia alter α-synuclein processing. Annals of Neurology, 2011; DOI: 10.1002/ana.22400

Implanting electrodes into a pea-sized part of the brain can dramatically improve life for people with severe cervical dystonia — a rare but extremely debilitating condition that causes painful, twisting neck muscle spasms — according to the results of a pilot study led by Jill Ostrem, MD and Philip Starr, MD PhD at the University of California, San Francisco.

Today, people with cervical dystonia can be treated with medications or injections of botulinum toxin (e.g., Botox^®), which interrupt signals from the brain that cause these spasms. However, those treatments do not provide adequate relief for all patients.

Over the last decade, doctors at UCSF and elsewhere have turned to a technique called deep brain stimulation to help people with debilitating dystonia. Also used to treat Parkinson's disease and the neurological disorder essential tremor, the technique is like putting a pacemaker inside a heart patient's chest — except that deep brain stimulation requires a neurosurgeon to implant electrodes inside the brain.

Scientists are not sure exactly why deep brain stimulation works. The electrodes deliver electric current to tiny parts of the brain, likely altering abnormal brain circuitry and alleviating symptoms by overriding the signals coming from those parts of the brain.

Traditionally doctors have treated cervical dystonia with deep brain stimulation by targeting a brain nucleus known as the "globus pallidus internus." Reporting in the journal Neurology, the UCSF team described the results of the first detailed clinical study looking at deep brain stimulation targeting a completely different part of the brain: the "subthalamic nucleus."

"This target is very widely used for Parkinson's disease but not widely used for dystonia," said Starr, a professor of neurological surgery at UCSF and senior author of the paper.

The study, led by Ostrem, an associate professor of neurology at UCSF, involved nine patients followed for one year after surgery. "Patients in this study had failed medical treatments, but with the surgery, they were able to improve their movements and quality of life — as well as overcome some of their disability and pain," said Ostrem.

Video analysis and standard measures of dystonia showed the surgeries lowered pain, reduced spasms and improved the overall quality of life without causing serious side effects.

The team is now planning to enroll more patients into a longer study following outcomes for three years post-surgery.

"Medications and botulinum toxin injections still remain the first line of treatment," Ostrem said, "but for those who are really still suffering, we think DBS using this new stimulation location offers another choice for them."

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Journal Reference:

1. J. L. Ostrem, C. A. Racine, G. A. Glass, J. K. Grace, M. M. Volz, S. L. Heath, P. A. Starr. Subthalamic nucleus deep brain stimulation in primary cervical dystonia. Neurology, 2011; 76 (10): 870 DOI: 10.1212/WNL.0b013e31820f2e4

 Neurons have been derived from the skin of a woman with a genetic form of Parkinson's disease and have been shown to replicate some key features of the condition in a dish, say researchers at the Stanford University School of Medicine. The scientists hope to use the neurons to learn more about the disorder and to test possible treatments. Such a tool is critical because there are no good animal models for Parkinson's disease. It also validates the use of induced pluripotent stem cells, or iPS cells, to model various diseases.

"Now that we can see that these neurons exhibit some of the earliest signs of the disorder, we can begin to develop methods to screen for factors that might protect them," said Renee Reijo Pera, PhD, director of Stanford's Center for Human Embryonic Stem Cell Research and Education and co-senior author of the research, which will appear in the March issue of Cell Stem Cell.

The iPS cells are created by transforming skin or other specialized cells to look and act like embryonic stem cells. Many scientists and policy-makers have hoped that these cells, which can be created without the use of human embryos, could stand in for their more ethically fraught counterparts.

Recent research from Stanford and elsewhere, however, has begun to identify significant differences between the two classes of stem cells that call into question the ability of iPS cells to completely replace embryonic stem cells. Instead many researchers feel that the true strength of iPS cells may lie in their ability to create disease-specific cell lines for study from patients with a variety of disorders — something that would be difficult to do with embryonic stem cells.

Associate professor of neurosurgery Theo Palmer, PhD, is the other senior author of this new paper; the research was conducted in the labs of both Palmer and Reijo Pera, who is also a professor of obstetrics & gynecology. Ha Nam Nguyen, a former research associate now at John's Hopkins, along with graduate students Blake Byers and Branden Cord are joint first authors of the work.

"This is the first time that neurons from a Parkinson's disease patient have exhibited disease qualities in a petri dish," said Palmer. "And it provides hints of what to look for in patients who have different genetic mutations or where a cause has not been identified. By comparing neurons from patients with different forms of Parkinson's disease, we may find commonalities or differences that will help to optimize future treatments for each patient."

Parkinson's disease is a neurodegenerative disorder that causes the gradual loss of a certain type of neuron in the central nervous system. As the neurons are lost, the patient begins to experience the tremors, movement difficulties and rigidity that are the hallmarks of the condition. It affects about 1 percent of people over the age of 65, and about 5 percent of those over age 85. Currently there is no way to halt the progress of the disease, though some medications can help Parkinson's patients manage their symptoms for several years. Most cases of Parkinson's occur sporadically, but some (between 0.5 percent to about 8 percent) are caused by a genetic mutation.

Byers and his colleagues chose to collect skin cells from a 60-year-old woman with a genetic form of Parkinson's, reasoning that they would have better chance of replicating the signs of the disorder with her cells rather than the cells of someone with the sporadic form.

Byers coaxed the iPS cells from the patient to develop into the type of neurons that die off in Parkinson's disease. At first, the neurons looked and acted normally: They were able to generate electrical signals, they produced and secreted a messaging molecule called dopamine, and their gene expression profiles over time mimicked those of neurons created from "normal" iPS cells.

However, after about 30 to 60 days of culture, the neurons from the Parkinson's patient began to exhibit some unusual characteristics. They expressed higher levels of genes for proteins needed to deal with oxidative stress — a condition in which destructive molecules wreak havoc on DNA and proteins within a cell — and churned out elevated levels of a protein involved in abnormal clumps of protein called Lewy bodies that are found in the neurons of people with Parkinson's and Alzheimer's disorders. Oxidative stress has been previously associated with Parkinson's disease.

"We needed to stress the cells with exogenous factors to elicit a disease-related phenotype," said Byers. The upshot, the researchers concluded, is that the neurons from the Parkinson's patient seem to be replicating many of the common features of the disorder, but in a much shorter timeframe.

"Parkinson's disease takes decades to manifest itself as clinical symptoms in patients, so we were concerned about how rapidly these cells would change in culture," said Byers. "We needed to be able to identify abnormal characteristics of the cells in a reasonable timeframe, so that we could identify what pushes a Parkinson's-disease-affected neuron to degrade. As it turns out, the culture dish is a pretty stressful place for a cell to be. That environment, combined with the addition of selectively toxic chemical agents, probably accelerates the visible signs of the disorder. It's also likely that there are innate mechanisms within the body that protect against these changes and cause a more protracted disease course."

The researchers are now planning to begin testing various compounds to see if they can protect the neurons. They are also investigating whether they can see similar signs of disease in iPS-cell-derived neurons from patients with the non-genetic form of the disorder.

Additional Stanford scientists involved in the research include postdoctoral scholars Aleksandr Shcheglovitov, PhD, and Kehkooi Kee, PhD; former postdoctoral scholar James Byrne, PhD; research assistant Prachi Gujar; and associate professor of neurobiology Ricardo Dolmetsch, PhD.

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Journal Reference:

1. Ha Nam Nguyen, Blake Byers, Branden Cord, Aleksandr Shcheglovitov, James Byrne, Prachi Gujar, Kehkooi Kee, Birgitt Schüle, Ricardo E. Dolmetsch, William Langston et al. LRRK2 Mutant iPSC-Derived DA Neurons Demonstrate Increased Susceptibility to Oxidative Stress. Cell Stem Cell, Volume 8, Issue 3, 267-280, 4 March 2011 DOI: 10.1016/j.stem.2011.01.013

A new study by Harvard School of Public Health (HSPH) researchers shows that adults who regularly take ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), have about one-third less risk of developing Parkinson's disease than non-users.

"There is no cure for Parkinson's disease, so the possibility that ibuprofen, an existing and relatively non-toxic drug, could help protect against the disease is captivating," said senior author Alberto Ascherio, professor of epidemiology and nutrition at HSPH.

The study will be published online March 2, 2011, in Neurology and is scheduled to appear in the March 8, 2011, print issue.

Parkinson's disease, a progressive nervous disease occurring generally after age 50, affects at least half a million Americans, according to the National Institute of Neurological Disorders and Stroke. About 50,000 new cases are reported each year, with the number expected to increase as the U.S. population ages. It is hypothesized that ibuprofen may reduce inflammation in the brain that may contribute to the disease.

Prior studies showed a reduced Parkinson's disease risk among NSAIDS users, but most did not differentiate between ibuprofen and other non-aspirin NSAIDs.

In the new study, Ascherio, lead author Xiang Gao, research scientist at HSPH and associate epidemiologist in the Channing Laboratory at Brigham and Women's Hospital, and colleagues analyzed data from nearly 99,000 women enrolled in the Brigham and Women's Hospital-based Nurses' Health Study and over 37,000 men in the Health Professionals Follow-Up Study. The researchers identified 291 cases (156 men and 135 women) of Parkinson's disease during their six-year follow-up study (1998-2004 in women; 2000-2006 in men). Based on questionnaires, the researchers analyzed the patients' use of ibuprofen (e.g. Advil, Motrin, Nuprin), aspirin or aspirin-containing products, other anti-inflammatory pain relievers (e.g., Aleve, Naprosyn), and acetaminophen (e.g., Tylenol). (Although not an NSAID, acetaminophen was included because it's similarly used to treat pain.) Age, smoking, diet, caffeine, and other variables also were considered.

"We observed that men and women who used ibuprofen two or more times per week were about 38% less likely to develop Parkinson's disease than those who regularly used aspirin, acetaminophen, or other NSAIDs," Gao said. "Our findings suggest that ibuprofen could be a potential neuroprotective agent against Parkinson's disease, however, the exact mechanism is unknown."

These findings raise hope that a readily available, inexpensive drug could help to treat Parkinson's disease. "Because the loss of brain cells that leads to Parkinson's disease occurs over a decade or more, a possible explanation of our findings is that use of ibuprofen protects these cells. If so, use of ibuprofen could help slow the disease's progression," Gao said.

The findings do not mean that people who already have Parkinson's disease should begin taking ibuprofen, Ascherio added. "Although generally perceived as safe, ibuprofen can have side effects, such as increased risk of gastrointestinal bleeding. Whether this risk is compensated by a slowing of the disease progression should be investigated under rigorous supervision in a randomized clinical trial," he said.

Support for the study was provided by the National Institutes of Health's (NIH) National Institute of Neurological Disorders and Stroke and the Intramural Research Program of NIH's National Institute of Environmental Health Sciences.

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Journal Reference:

1. Xiang Gao, Honglei Chen, Michael A. Schwarzschild, and Alberto Ascherio. Use of Ibuprofen and Risk of Parkinson's Disease. Neurology, March 8, 2011 DOI: 10.1212/WNL.0b013e31820f2d79

 A protein pathway that may hold the secret to understanding Parkinson's disease has been discovered and explained by Iowa State University researchers.

Anumantha Kanthasamy, a distinguished professor of biomedical sciences and the W. Eugene and Linda R. Lloyd Endowed Chair in Neurotoxicology at the ISU College of Veterinary Medicine, has been working to understand the complex mechanisms of the disease for more than a decade. He believes this recent discovery offers hope for the cure.

Parkinson's disease sufferers lack a sufficient amount of a brain chemical called dopamine. In previous research, Kanthasamy has shown that a novel protein — known as protein kinase-C (specifically PKCδ) — kills essential dopamine-producing cells in the brain.

Now, Kanthasamy has shown how to modify the production of the kinase-C, and, more important, how to inhibit it.

The process begins with a protein called alpha-synuclein (ά-synuclein) that — after interacting with other proteins in cells — becomes part of the protein complex that modifies kinase-C level in the cells.

One of the proteins that alpha-synuclein interacts with inside the cell is known as p300.

By changing the activity of p300 protein, Kanthasamy believes that production of the destructive kinase-C will be inhibited.

"We have identified an essential pathway that regulates the survival of dopamine-producing nerve cells," he said.

"This p300 is an intermediate protein that is implicit in the Parkinson's disease," he said. "By modifying this protein, we can potentially reduce the expression of kinase-C and the associated destructive effects on dopamine-producing cells."

"We found the mechanism," said Kanthasamy of the pathway. "Now we can focus on finding chemicals that may be able to control the mechanism."

Parkinson's disease strikes around 50,000 people each year, and approximately 1 million people have the disease. Parkinson's sufferers include actor Michael J. Fox and former boxing champion Muhammad Ali.

Currently, there is no cure for Parkinson's and available therapies only treat the symptoms.

Symptoms of Parkinson's disease include trembling in hands, arms, legs, jaw, and face; rigidity or stiffness of the limbs and trunk; slowness of movement; and impaired balance and coordination. As these symptoms become more pronounced, patients may have difficulty walking, talking, or completing other simple tasks. Because the disease typically affects people over the age of 50, the National Institutes of Health anticipates the incidence of Parkinson's will increase as the nation's population ages.

The research was funded by the National Institutes of Health and is published in the Journal of Neuroscience.

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Journal Reference:

1. H. Jin, A. Kanthasamy, A. Ghosh, Y. Yang, V. Anantharam, A. G. Kanthasamy.  -Synuclein Negatively Regulates Protein Kinase C  Expression to Suppress Apoptosis in Dopaminergic Neurons by Reducing p300 Histone Acetyltransferase Activity. Journal of Neuroscience, 2011; 31 (6): 2035 DOI: 10.1523/JNEUROSCI.5634-10.2011

For the last several years, neurologists have been probing a connection between Parkinson's disease and problems with mitochondria, the miniature power plants of the cell.

Toxins that mimic Parkinson's effects act specifically to poison mitochondria, and mitochondria appear to be damaged in the brain cells that are endangered in the disease. But one unresolved question has been: are mitochondria simply the vulnerable "canaries in the coal mine" or is their deterioration a key step on the way to neurodegeneration?

Now researchers at Emory University School of Medicine have found that a protein called MEF2D, which helps brain cells withstand stress and toxins, also plays an unexpected role inside mitochondria. MEF2D's ability to keep mitochondria well tuned appears to be especially sensitive to impairment in Parkinson's disease, the research team found.

The results will be published online in the Journal of Clinical Investigation.

"Our data suggest that problems with MEF2D in mitochondria could represent one of the earlier steps in the progress of the disease," says senior author Zixu Mao, PhD, associate professor of pharmacology and neurology at Emory University School of Medicine. Postdoctoral researcher Hua She, PhD, was the first author.

The Emory team showed that MEF2D binds one particular mitochondrial gene, ND6, which is necessary for assembly of complex I. Complex I begins the electron transport process that is necessary for mitochondria to function.

Mitochondria are thought to have evolved from bacteria that once lived independently, but were engulfed and harnessed by a primitive cell millions of years ago. Mao and his colleagues found an example of how this symbiosis has extended to having proteins like MEF2D turn on genes inside mitochondria.

"Our findings make a convincing and very intriguing case that dysregulation of mitochondrial DNA gene expression contributes to Parkinson's," Mao says.

Genes in the nucleus (that is, outside mitochondria) now encode most of the proteins that go into mitochondria. However, mitochondria still make a few of their own proteins, such as ND6.

In addition to showing how MEF2D functions in mitochondria, the team showed that toxins such as MPTP and the natural pesticide rotenone, which interfere with complex I and bring on Parkinson's in animals, also block MEF2D from working in mitochondria.

Mao's laboratory's previous research found that in Parkinson's, MEF2D levels are increased in the cell because of defects in a recycling process called autophagy. Now, they show that in the brains of Parkinson's patients, even when MEF2D levels are increased in the cell as a whole, they are reduced in mitochondria.

Because disruptions in mitochondria have been linked to other neurodegenerative diseases and heart disease as well, Mao says probing MEF2D's involvement in those disease processes may yield new insights.

The research was funded by the National Institutes of Health, the Woodruff Health Sciences Center Fund, and the Michael J. Fox Foundation.

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Journal Reference:

1. H. She, Q. Yang, K. Shepherd, Y. Smith, G. Miller, C. Testa and Z. Mao. Direct regulation of complex I by mitochondrial MEF2D is disrupted in a mouse model of Parkinson disease and in human patients. J. Clin. Invest.,

New research shows a link between use of two pesticides, rotenone and paraquat, and Parkinson's disease. People who used either pesticide developed Parkinson's disease approximately 2.5 times more often than non-users.

The study was a collaborative effort conducted by researchers at the National Institute of Environmental Health Sciences (NIEHS), which is part of the National Institutes of Health, and the Parkinson's Institute and Clinical Center in Sunnyvale, Calif.

"Rotenone directly inhibits the function of the mitochondria, the structure responsible for making energy in the cell," said Freya Kamel, Ph.D., a researcher in the intramural program at NIEHS and co-author of the paper appearing online in the journal Environmental Health Perspectives. "Paraquat increases production of certain oxygen derivatives that may harm cellular structures. People who used these pesticides or others with a similar mechanism of action were more likely to develop Parkinson's disease.

The authors studied 110 people with Parkinson's disease and 358 matched controls from the Farming and Movement Evaluation (FAME) Study to investigate the relationship between Parkinson's disease and exposure to pesticides or other agents that are toxic to nervous tissue. FAME is a case-control study that is part of the larger Agricultural Health Study, a study of farming and health in approximately 90,000 licensed pesticide applicators and their spouses. The investigators diagnosed Parkinson's disease by agreement of movement disorder specialists and assessed the lifelong use of pesticides using detailed interviews.

There are no home garden or residential uses for either paraquat or rotenone currently registered. Paraquat use has long been restricted to certified applicators, largely due to concerns based on studies of animal models of Parkinson's disease. Use of rotenone as a pesticide to kill invasive fish species is currently the only allowable use of this pesticide.

"These findings help us to understand the biologic changes underlying Parkinson's disease. This may have important implications for the treatment and ultimately the prevention of Parkinson's disease," said Caroline Tanner, M.D., Ph.D., clinical research director of the Parkinson's Institute and Clinical Center, and lead author of the article.

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Journal Reference:

1. Caroline M. Tanner, Freya Kamel, G. Webster Ross, Jane A. Hoppin, Samuel M. Goldman, Monica Korell, Connie Marras, Grace S. Bhudhikanok, Meike Kasten, Anabel R. Chade, Kathleen Comyns, Marie Barber Richards, Cheryl Meng, Benjamin Priestley, Hubert H. Fernandez, Franca Cambi, David M. Umbach, Aaron Blair, Dale P. Sandler, J. William Langston. Rotenone, Paraquat and Parkinson’s Disease. Environmental Health Perspectives, 2011; DOI: 10.1289/ehp.1002839

Scientists from the Florida campus of The Scripps Research Institute have produced the first known compound to show significant effectiveness in protecting brain cells directly affected by Parkinson's disease, a progressive and fatal neurodegenerative disorder.

Although the findings were in animal models of the disease, the effectiveness of the compound, combined with its potential to be taken orally, offers the tantalizing possibility of a potentially useful future therapy for Parkinson's disease patients. The results were published in two separate studies in the journal ACS Chemical Neuroscience.

"These studies present compelling data on the first oral, brain-penetrating inhibitor to show significant efficacy in preventing neurodegeneration in both mouse and rat models of Parkinson's disease," said team leader Philip LoGrasso, a professor in the Department of Molecular Therapeutics and senior director for drug discovery at Scripps Florida. "The compound offers one of the best opportunities we have for the development of an effective neuroprotective treatment."

The new small molecule — labeled SR-3306 — is aimed at inhibiting a class of enzymes called c-jun-N-terminal kinases (JNK). Pronounced "junk," these enzymes have been shown to play an important role in neuron (nerve cell) survival. As such, they have become a highly viable target for drugs to treat neurodegenerative disorders such as Parkinson's disease.

"A drug like SR-3306 that prevents neurodegeneration would be a quantum leap in the clinical treatment of Parkinson's because all current therapies treat only the symptoms of the disease, not the underlying pathologies," LoGrasso said.

Patients with Parkinson's disease suffer from the loss of a group of neurons in the substantia nigra pars compacta (SNpc), part of the midbrain involved in motor control. These cells produce dopamine, a neurotransmitter that plays a key role in motor reflexes and cognition. The disease also affects projecting nerve fibers in the striatum, a part of the forebrain filled with cells that interact with dopamine. Stopping the Progression of Neuron Destruction in Animal Models

The SR-3306 compound, which has been in development at Scripps Florida for several years, performed well in both cell culture and animal models. In cell culture, the compound showed greater than 90 percent protection against induced cell death of primary dopaminergic neurons, while in mouse models of induced neuron death, the compound showed protective levels of approximately 72 percent.

The scientists went one step further, testing the new compound in a rat model, which duplicates the physical symptoms often seen with the human disease — a pronounced and progressive loss of motor skills. The results showed SR-3306 provided a protection level of approximately 30 percent in the brain, a level that reduced the dysfunctional motor responses by nearly 90 percent.

"It was a surprise that level of neuroprotection reduced the behavioral impact so strongly," LoGrasso said, "but it's indicative of how it might perform in human patients. While SR-3306 doesn't represent a cure, it does appear to have the potential of stopping the progression of the disease."

The new studies are part of a $7.6 million multiyear grant awarded to LoGrasso in 2008 by the National Institutes of Neurological Disorders and Stroke (NINDS). The grant will enable Scripps Research and potential partners to file an application for an investigational new drug (IND) — the first step in the lengthy clinical trials process required by the U.S. Food and Drug Administration before a new drug can be brought to market.

The first authors of the study, "Small Molecule c-jun-N-terminal Kinase (JNK) Inhibitors Protect Dopaminergic Neurons in a Model of Parkinson's Disease," are Jeremy W. Chambers and Alok Pachori of Scripps Research. Other authors include Shannon Howard, Michelle Ganno, Donald Hansen Jr., Ted Kamenecka, Xinyi Song, Derek Duckett, Weimin Chen, Yuan Yuan Ling, Lisa Cherry, Michael D. Cameron, Li Lin, and Claudia H. Ruiz, also of Scripps Research.

The first author of the study, "JNK Inhibition Protects Dopamine Neurons and Provides Behavioral Improvement in a Rat 6-hydroxydopamine Model of Parkinson's Disease," is Candice E. Crocker of Dalhousie University, Halifax, Nova Scotia, Canada. Other authors include Susan Khan and Michael D. Cameron of Scripps Research, and Harold A. Robertson and George S. Robertson of Dalhousie.

Both studies were supported by the National Institutes of Health. Harold A. Robertson and George S. Robertson were supported by funding from the Atlantic Innovation Fund.

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Journal References:

1. Jeremy W. Chambers, Alok Pachori, Shannon Howard, Michelle Ganno, Donald Hansen, Ted Kamenecka, Xinyi Song, Derek Duckett, Weimin Chen, Yuan Yuan Ling, Lisa Cherry, Michael D. Cameron, Li Lin, Claudia H. Ruiz, Philip LoGrasso. Small Molecule c-jun-N-Terminal Kinase Inhibitors Protect Dopaminergic Neurons in a Model of Parkinson’s Disease. ACS Chemical Neuroscience, 2011; 110207090626012 DOI: 10.1021/cn100109k
2. Candice E. Crocker, Susan Khan, Michael D. Cameron, Harold A. Robertson, George S. Robertson, Philip LoGrasso. JNK Inhibition Protects Dopamine Neurons and Provides Behavioral Improvement in a Rat 6-Hydroxydopamine Model of Parkinson’s Disease. ACS Chemical Neuroscience, 2011; DOI: 10.1021/cn1001107

Targeting the neuroinflammatory causes of Parkinson's disease with a naturally present brain chemical signal could offer a better understanding of the clinical mechanisms of the disease and open a future therapeutic window, reports a team of researchers from the University of South Florida Department Neurosurgery and Brain Repair and the James A. Haley Veterans' Administration Hospital, Tampa.

Their findings are published online in the Journal of Neuroinflammation.

Brain inflammation has been clearly shown in PD, and the brain's microglia — small cells that regulate the chemical environment of neural cells — play a role in the inflammatory process and disease progression, said study lead author Paula C. Bickford, PhD, professor of neurosurgery at USF and a senior research career scientist at the Haley VA Hospital.

"In the brain, one aspect of immune regulation occurs through neurons," said Dr. Bickford. "Immune cells called microglia can damage neurons by producing bioactive molecules. On the other hand, a neuron-generated signaling chemical, or fractalkine, also called CX3CL1, suppresses the activation of microglia. Our study examined whether adding CX3CL1 beyond normal levels could decrease microglial activation and, therefore, play a neuroprotective role by helping prevent the loss of important neural cells in an animal model of Parkinson's disease."

Using rat models of Parkinson's with known inflammatory components, the researchers added CX3CL1 in varying doses and found that, in all cases, CX3CL1 (which has a single receptor — CX3CR1 found on microglia) reduced the loss of dopamine cells. The loss of dopamine rich nerve fibers in the brain is a key aspect of Parkinson's, leading to movement-related symptoms such as tremors, muscle stiffness, balance problems and slowness.

"This was likely mediated by the accompanying change in microglial-induced inflammation," said USF doctoral student Mibel Pabon, a study co-author.

"This suggests that the communication between neurons and glial cells may play a role in Parkinson's disease neurodegeneration," said Carmelina Gemma, PhD, co-lead scientist for the study, assistant professor in USF's Department of Neurosurgery and Brain Repair, and a research biologist at the James A. Haley Veterans' Hospital. "We found that even small increases in CX3CL1 can be neuroprotective by suppressing microglia activation and, therefore, reducing inflammation."

The researchers concluded that the CX3CR1/CX3CL1 "axis" may be an important target for drug discovery efforts aimed at modulating microglia activation associated with Parkinson's disease."

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Journal Reference:

1. Mibel M Pabon, Adam D Bachstetter, Charles E Hudson, Carmelina Gemma and Paula C Bickford. CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson's disease. Journal of Neuroinflammation, 2011, 8:9 DOI: 10.1186/1742-2094-8-9