Coffee could offer key ingredient for new treatments for Parkinson's disease

Treatments and Experiments

Monday, September 12, 2011

Scientists from Heptares Therapeutics have used Diamond Light Source, the UK’s national synchrotron facility, to understand the structure of a protein involved in Parkinson’s disease and other neurological disorders. Their findings, published this week in the journal Structure, could pave the way for a new generation of targeted drug treatments.

The team used Diamond’s Microfocus Macromolecular Crystallography (MX) beamline (I24) to reveal the complex structure of the vital adenosine A2A receptor and show how xanthine-based drugs such as caffeine bind to their target. Adenosine A2A receptors regulate the effects of neurotransmitters in the brain, cardiovascular and immune systems, and are of particular interest as a drugtarget for Parkinson’s disease. Although it was known that caffeine inhibits the action of the adenosine, the exact molecular mechanism involved was not fully understood.

“These co-structures of xanthines in complex with the adenosine A2A receptor advance our understanding of what is happening at the molecular level when the drug binds to its target and blocks the receptor’s response. Along with novel chemotypes discovered by our team, the structural data we collected at Diamond is enabling us to develop highly optimised next-generation drug candidates for Parkinson’s disease and other neurological disorders,” said Dr. Fiona Marshall, Chief Scientific Officer at Heptares.

The adenosine A2A receptor is a G-protein-coupled receptor (GPCR). GPCRs are responsible for transmitting chemical signals into a variety of different cell types. There are over 700 GPCRs encoded in the human genome and as many as 75 of these have clinical validation, presenting a wide range of opportunities as therapeutic targets in areas including cancer, diabetes, central nervous system disorders, obesity and pain.

Dr. Andrew Doré, Senior Scientist at Heptares, says: “GPCRs represent the single most important family of drug targets in the human body because they are central to so many biological processes. The design of drugs for GPCRs is hampered by the lack of structural information so access to a facility like the Diamond synchrotron is vital to our research. It has enabled us to solve the 3D structure of the adenosine A2A receptor in complex with caffeine and other xanthines as well as our own novel drug candidates.”

Caffeine is a methylxanthine, a stimulant derivative of xanthine, as is theophylline (in tea), and theobromine (in chocolate).  Methylxanthines are among the most widely consumed substances in the world. Caffeine is present in many foods and drinks and reportedly consumed at an average rate of 200mg per day by Americans (Ref. 1). In 2000, the Journal of the American Medical Association(JAMA) published research showing a correlation between higher intake of caffeine and lower incidence of Parkinson’s disease, a devastating and incurable neurological disorder (Ref. 2).

While caffeine exerts a broad range of adverse effects, and is therefore poorly suited for use as a drug, pharmaceutical researchers have generated more potent and selective adenosine receptor modulators. A2A receptor antagonists, in particular, have shown clinical efficacy in the treatment of Parkinson’s disease. First generation A2A antagonists using older furan and xanthine type chemical structures have been associated with various safety, tolerability, and pharmacokinetic limitations. Heptares have used structural information to generate the next-generation of A2A antagonists.

References: 
Daly, GW. Caffeine analogs: biomedical impact. Cell. Mol. Life Sci. (2007) 64(16), 2153-2169 
Ross, GW et al. Association of Coffee and Caffeine Intake with the Risk of Parkinson’s Disease. JAMA (2000) 283(20), 2674-2679

The Best Diet to Alleviate Insomnia in Parkinson's Patients

Monday, September 12, 2011

Overview

Parkinson's disease is a brain condition involving nerve degeneration. This progressive health problem affects between 4 and 6 million people throughout the world, reports the National Parkinson Foundation. The Foundation also notes that 50,000 to 60,000 new cases of Parkinson's disease are diagnosed annually. Diet and nutrition may be helpful in treating some Parkinson's disease symptoms, such as insomnia, although you should always check with your doctor before using nutrition therapy for this purpose.

About Parkinson's and Insomnia

Common signs and symptoms associated with Parkinson's disease include tremors, lack of facial expression, muscle aches and constipation. Insomnia, notes a 2007 study by M.D. Gjerstad and colleagues published in the "Journal of Neurology, Neurosurgery and Psychiatry," is a common complaint among people with Parkinson's disease, varies in severity over time and may be caused by numerous factors. Many people who have Parkinson's disease-related insomnia may also be depressed, note the researchers.

Helpful Dietary Practices

Some dietary practices may be helpful in treating your insomnia. According to Phyllis A. Balch, a certified nutritional consultant and author of "Prescription for Nutritional Healing," consuming certain foods in the evening -- dates, figs, bananas, milk, nut butters, tuna, turkey, yogurt and whole grain crackers -- may be useful for this health purpose, as these foods contain sleep-promoting substances. Balch suggests avoiding consumption of large meals within two hours of bedtime and avoiding intake of caffeine and alcohol four to six hours before you go to sleep.

Highlighted Food

Turkey may be a particularly helpful food in treating your insomnia. Turkey, notes nutritionist and biologist George Mateljan, author of "The World's Healthiest Foods," is a concentrated source of sleep-promoting tryptophan -- an important amino acid that must be obtained through your diet. Turkey is rich in numerous nutrients, including selenium, protein, phosphorus and vitamins B-3 and B-6. More scientific research evidence may be needed to evaluate the true efficacy of this food for this health purpose.

Additional Information

Insomnia by itself does not necessarily mean that you have Parkinson's disease, but you should not avoid visiting your doctor if you develop this health problem. Your doctor can assess your symptoms and order relevant tests, refer you to other healthcare practitioners and counsel you on your treatment options. Diet alone may not be enough to alleviate your Parkinson's disease-related insomnia, but it may be a helpful adjunct therapy for this health purpose. Ask your doctor if dietary changes are appropriate for you and your health problem.

References

• National Parkinson Foundation: Parkinson's Disease Overview
• "Journal of Neurology, Neurosurgery and Psychiatry"; Insomnia in Parkinson's Disease; M.D. Gjerstad et al.; May 2007
• "Prescription for Nutritional Healing"; Phyllis A. Balch, C.N.C.; 2010
• "The World's Healthiest Foods"; George Mateljan; 2007

About this Author

Martin Hughes is a chiropractic physician and freelance writer based out of Durham, N.C. He writes about health, fitness, diet, lifestyle, travel and outdoor pursuits. He earned his Bachelor of Science degree in kinesiology at the University of Waterloo and his doctoral degree from Western States Chiropractic College in Portland, Ore.

Read more:http://www.livestrong.com/article/539464-the-best-diet-to-alleviate-insomnia-in-parkinsons-patients/#ixzz1XkuxGbzh

Scientists Discover Genetic Mutation That Causes Parkinson's Disease

 A large team of international researchers have identified a new genetic cause of inherited Parkinson's disease that they say may be related to the inability of brain cells to handle biological stress. The study, published in the September issue of the American Journal of Human Genetics, continues to fill in the picture of Parkinson's disease as a complex disorder influenced by multiple genes, say neuroscientists at Mayo Clinic's campus in Florida who helped lead the investigation.

Although to date, only a small number of families have been identified with this form of Parkinson's disease, the scientists say the study offers a direct insight into how the gene, EIF4G1, can lead to death of brain cells, resulting in Parkinson's disease and related neurodegenerative disorders.

This gene is unlike others that have been found to cause Parkinson's disease in that it controls the levels of proteins that help a cell to cope with different forms of stress, such as those routinely found in aging cells, says Justus C. Daechsel, Ph.D., a Mayo neuroscientist who is the study's co-lead investigator.

Given the function of this gene, this discovery opens up a new area of research within Parkinson's disease and other neurodegenerative diseases, adds study co-author Owen Ross, Ph.D., a Mayo Clinic neuroscientist. The insights gained from how mutations in EIF4G1 lead to cell death might help us develop new therapies to treat or slow Parkinson's disease.

This study began with the identification by French researchers of a large family in northern France with inherited Parkinson's disease. Researchers discovered the EIF4G1 mutation in the French family and in other affected families in the U.S., Canada, Ireland, and Italy.

Much is already known about the protein, EIF4G1. For example, when a cell is undergoing stress the EIF4G1 protein helps initiate the production of other proteins to help the cell cope. Such stresses occur naturally as people age, and if a brain cell cannot adequately respond, it will die. That inability to adapt led to Parkinson's disease in the families studied, Dr. Daechsel says.

This is the third gene that Mayo researchers have found which causes Parkinson's disease, according to Dr. Ross. He adds that Mayo researchers have also identified a number of genetic variants that increase a person's risk of developing the more common sporadic late-onset form of the disease.

We believe that many of the genes implicated in familial Parkinson's disease may be playing a role in the sporadic form of the disease, because as many as 20 percent of individuals with Parkinson's report a first-degree relative with the disorder, Dr. Ross says. This latest finding adds another piece in the complex Parkinson's puzzle.

###

The study's other co-lead investigator is Marie-Christine Chartier-Harlin, Ph.D., from the University of Lille Nord, France. The senior investigator, Matthew Farrer, Ph.D., worked on this study while at Mayo Clinic in Florida; he has since moved to the University of British Columbia in Vancouver. None of the co-authors have a financial interest related to this work.

The research at Mayo Clinic in Florida was financed by the National Institutes of Health, the Michael J. Fox Foundation, and a gift from Herb Geist for Lewy body research.

html

Source: Mayo Clinic

New Target for Treating Symptoms of Parkinson's Disease

ScienceDaily (Sep. 11, 2011) — A scientist at the Gladstone Institutes has identified how the lack of a brain chemical known as dopamine can rewire the interaction between two groups of brain cells and lead to symptoms of Parkinson's disease. This discovery offers new hope for treating those suffering from this devastating neurodegenerative disease.

---

In a paper being published online September 8 in Neuron, Gladstone Investigator Anatol Kreitzer, PhD, identifies how the loss of dopamine alters the wiring of a small group of brain cells, kicking off a chain of events that eventually leads to difficulties controlling movement -- a hallmark of Parkinson's disease. More than a half-million people suffer from Parkinson's in the United States, including the boxer Muhammad Ali and the actor Michael J. Fox.

"The development of truly effective and well-tolerated therapies for Parkinson's has proven difficult," said Lennart Mucke, MD, who directs neurological disease research at the Gladstone Institutes, a leading and independent biomedical-research organization. Dr. Mucke is also a professor of neurology and neuroscience at the University of California, San Francisco (UCSF), with which Gladstone is affiliated. "Dr. Kreitzer's discovery sheds new light on the intricate processes that underlie motor problems in this disabling condition and will hopefully lead to the development of more effective medicines."

Normally, two types of brain cells called medium spiny neurons, or MSNs, work together to coordinate body movements, with one type acting like a gas pedal and the other as a brake. It has been thought that a reduction in dopamine, an important chemical in the brain, throws off the balance between the two opposing MSN forces, leading to problems with movement. But Dr. Kreitzer wondered if another factor might also be involved. To better understand the relationship between dopamine and MSNs in people with Parkinson's, Dr. Kreitzer artificially removed dopamine from the brains of laboratory mice and monitored the specific changes in the brain that followed.

Just as happens in humans, the mice without dopamine began to experience the motor symptoms of Parkinson's, including tremors, problems with balance and slowed movement. But Dr. Kreitzer found that decreased dopamine levels didn't just throw off the balance between the two types of MSNs, as was already known, but they also changed the interaction between MSNs and another group of neurons called fast-spiking neurons, or FSNs.

Dr. Kreitzer's experiments showed that under normal circumstances, FSNs connect to both types of MSNs in a similar way. But without dopamine, the signaling between the FSN circuits gets rewired and the neurons begin to target one type of MSN over the other. Dr. Kreitzer used computer simulations to show that this small shift disrupts the timing of MSN activity, which is key to normal movement. Ultimately, this rewiring may be an important factor in the development of Parkinson's motor problems.

"Our research has uncovered how an entirely different group of neurons can play a role in the development of Parkinson's disease symptoms," said Dr. Kreitzer, who is also an assistant professor of physiology and neurology at UCSF. "We hope to target the changes among these neurons directly with drug therapies, in order to help relieve some of Parkinson's most debilitating symptoms."

Other scientists who participated in the research at Gladstone include Aryn Gittis, Giao Hang, Eva LaDow and Steven Finkbeiner. Funding for the research came from a wide variety of organizations, including the Tourette Syndrome Association, the National Institutes of Health, the Pew Biomedical Scholars Program, the W.M. Keck Foundation and the McKnight Foundation.

Dr. Kreitzer is an Assistant Investigator at the Gladstone Institute of Neurological Disease and an Assistant Professor of Physiology and Neurology at UCSF. The Kreitzer lab focuses on understanding the neural mechanisms that control motor planning, learning and movement. Their long-term goal is to understand how circuitry and activity in the brain shapes motor behavior and how disorders such as Parkinson's disease and Huntington's disease affect circuits in the brain.

Recommend this story on Facebook, Twitter,
and Google +1:

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Gladstone Institutes.

---

Journal Reference:

1.     Aryn H. Gittis, Giao B. Hang, Eva S. LaDow, Liza R. Shoenfeld, Bassam V. Atallah, Steven Finkbeiner, Anatol C. Kreitzer. Rapid Target-Specific Remodeling of Fast-Spiking Inhibitory Circuits after Loss of Dopamine. Neuron, September 8, 2011 DOI: 10.1016/j.neuron.2011.06.035

Gladstone Institutes (2011, September 11). New target for treating symptoms of Parkinson's disease. ScienceDaily. Retrieved September 12, 2011, from http://www.sciencedaily.com­ /releases/2011/09/110908081242.htm

Dr. Kreitzer found that as the supply of dopamine decreased, the brain's fast-spiking neurons grew new branches and rewired their connections, disrupting precisely timed activity patterns in a part of a brain that controls movement. (Credit: Image courtesy of Gladstone Institutes)