DUODOPA WITH COMT INHIBITORS FOR PARKINSON'S DISEASE

10th December 2011 - New research

European Journal of Neurology [2011] Dec 5 [Epub ahead of print] (D.Nyholm, A.Johansson, H.Lennernäs, H. Askmark)

Duodopa is a combination of L-dopa and carbidopa in the form of a gel. It is administered throughout the day using a portable pump directly into the small intestine through a surgically placed tube. This ensures a flow of L-dopa that can be adjusted according to the person's needs. It enables more consistent plasma concentrations of L-dopa. The side effects of Duodopa are similar to those observed with oral administration of L-dopa and carbidopa.

COMT inhibitors (Catechol-O-methyltransferase inhibitors) may be used to decrease the need for L-dopa, because they reduce its breakdown. COMT inhibitors have already been successfully used orally as Stalevo, which is a combination of L-dopa and carbidopa (the same as Sinemet), plus a COMT inhibitor (Entacapone). So researchers have investigated whether COMT inhibitors can also be taken orally in order to reduce the L-dopa requirement used with Duodopa. Both major COMT inhibitors (entacapone and tolcapone) were tested. The additional oral use of either of the COMT inhibitors was found to reduce the need of L-dopa by 20%. They did this without altering plasma L-dopa concentrations, reducing symptoms, or by reducing "off" time.  

SMOKING REDUCES THE RISK OF PARKINSON'S DISEASE

19th November 2011 - New research

SMOKING REDUCES THE RISK OF PARKINSON'S DISEASE

Fukuoka Igaku Zasshi [2011] 102 (8) : 254-265 (Kiyohara C, Kusuhara S.) 

Movement Disorders [2011] Nov 16 [Epub ahead of print] (Searles Nielsen S, Gallagher LG, Lundin JI, Longstreth WT Jr, Smith-Weller T, Franklin GM, Swanson PD, Checkoway H.)

The risk of developing Parkinson's Disease has been found to be far lower in people that smoke. Current smokers reduce the risk of developing Parkinson's Disease down to 31%. Those people that have ever been smokers reduce the risk down to 55%. Former smokers reduce the risk to 72%. The risk of Parkinson's Disease therefore effectively increases over time if somebody gives up smoking. These results were obtained by assessing all the possible studies concerning smoking and Parkinson's Disease. Even the risk for passive smokers was reduced to only 34%. What the results do not show is whether those people inclined to be smokers are for some reason less likely to develop Parkinson's Disease, or if smoking has an effect on the biochemistry involved in Parkinson's Disease.

Tobacco smoke contains chemicals that are MAO inhibitors. MAO inhibitors are a type of drug (such as Selegiline and Rasagiline) used commonly in Parkinson's Disease. MAO inhibitors affect Parkinson's Disease by maintaining dopamine levels. The main drug in tobacco, which is nicotine, is heavily involved in the activity of acetylcholine, a chemical in the body that affects the activity of dopamine.

PRAMIPEXOLE CLINICAL TRIAL RESULTS

Neurology [2011] 77 (8) : 767-774 (A.H.Schapira, P.Barone, R.A.Hauser, Y.Mizuno, O.Rascol, M.Busse, L.Salin, N.Juhel, W.Poewe)

Clinical trials compared the clinical efficacy in Parkinson's Disease of the more convenient to use extended-release (ER) formulation of the dopamine agonist pramipexole, and the standard immediate-release (IR) pramipexole. Pramipexole is also known as Mirapex, Mirapexin, or Sifrol. For more information go to Mirapex and Mirapex ER. In the first clinical trial, both forms of pramipexole were more effective than a placebo. Both formulations (extended release and immediate release) were similarly effective in Parkinson's Disease and were equally tolerated. In the second clinical trial, both forms of pramipexole were more effective than a placebo. Off times decreased by up to 150 minutes per day, but a placebo achieved an 84 minute reduction in off times, thereby lessening the actual reduction in off time to just over an hour per day. Immediate release pramipexole was slightly more effective than extended-release pramipexole, but otherwise, extended-release pramipexole could be readily substituted for immediate-release pramipexole.

14 November- New blog

THE DOPAMINE CHRONICLES

The Dopamine Chronicles is the new Parkinson's Disease blog of cartoonist Martin Bee. His blog specialises in Parkinson's Disease cartoons. In the words of Martin Bee "Any of you diagnosed with this disease probably can relate to the reaction. The Dopamine Chronicles is all about me continuing my art, my toons and so on. So I decided to do (almost) a cartoon a day about Parkinson’s and me." Martin Bee is a 60 year old Vietnam Veteran who was a Navy Corpsman stationed with the 1st Marine Division whilst he was in Vietnam. After leaving the Navy, he graduated in Art and then worked in design and illustration. Despite being diagnosed with Parkinson's Disease, which included a shaking right hand, he could still draw. Although Parkinson's Disease hindered his drawing technique, he altered the techniques he used in order to overcome the problems it caused him. 

TRICHLOROETHYLENE MULTIPLIES THE RISK OF PARKINSON'S DISEASE

Annals of Neurology [2011] Nov 14 [Epub ahead of print] (S.M.Goldman, P.J.Quinlan, G.W.Ross, C.Marras, C.Meng, G.S.Bhudhikanok, K.Comyns, M.Korell, A.R.Chade, M.Kasten, B.Priestley, K.L.Chou, H.H.Fernandez, F.Cambi, J.W.Langston, C.M.Tanner)

Exposure to the solvent Trichloroethylene has been found to multiply the risk of Parkinson's Disease by six times. Results were similar for estimates of exposure duration and cumulative lifetime exposure. Trichloroethylene is a solvent that is used extensively in industry and the military and is a common environmental contaminant. It has been used to extract vegetable oils, in coffee decaffeination, and in the preparation of flavouring extracts from hops and spices. Much of its use has been banned because of toxicity. Trichloroethylene is the most common organic contaminant in groundwater, and so can cause toxicity via the water supply. Around 30% of U.S. water supplies are contaminated by Trichloroethylene. For more information go to Trichloroethylene.

A previous study showed that workers with workstations adjacent to the source of Trichloroethylene and who were subjected to chronic inhalation and dermal exposure from handling Trichloroethylene soaked metal parts all had Parkinson's disease. Lesser chronic respiratory exposure to Trichloroethylene led to many features of Parkinsonism.

Dr. Robert Hauser has recently penned an outstanding paper reviewing all the new therapies in the Parkinson's disease pipeline.

Dr. Robert Hauser has recently penned an outstanding paper reviewing all the new therapies in the Parkinson's disease pipeline.  Dr. Hauser is professor at the NPF Center of Excellence at the University of South Florida in Tampa.


Int J Neurosci. 2011;121 Suppl 2:53-62.
Future Treatments for Parkinson's Disease: Surfing the PD Pipeline.
Hauser RA.
Source
Departments of Neurology, Molecular Pharmacology and Physiology, College of Medicine , University of South Florida, Tampa, Florida USA.
Abstract
ABSTRACT Our current wish list for the treatment of Parkinson's disease (PD) includes therapies that will provide robust and sustained antiparkinsonian benefit through the day, ameliorate or prevent dyskinesia, and slow or prevent the progression of the disease. In this article, I review selected new therapies in clinical development for motor features or treatment complications of PD, and some that may slow disease progression. These include adenosine 2a (A2a) antagonists (istradefylline, preladenant, and SYN115), levodopa/carbidopa intestinal gel (LCIG), IPX066-an extended-release formulation of carbidopa/levodopa, XP21279-a sustained-release levodopa prodrug, ND0611-a carbidopa subcutaneous patch, safinamide-a mixed mechanism of action medication that may provide both MAO-B and glutamate inhibition, PMY50028-an oral neurotrophic factor inducer, antidyskinesia medications (AFQ056 and fipamezole), and gene therapies (AAV2-neurturin and glutamic acid decarboxylase gene transfer). Some of these therapies will never be proven efficacious and will not come to market while others may play a key role in the future treatment of PD.

Exposure to Toxic Solvents Linked to Parkinson's Disease

HealthDay – 9 hours ago

MONDAY, Nov. 14 (HealthDay News) -- Exposure to the industrial solvent trichloroethylene (TCE) appears to greatly increase the risk of Parkinson's disease, and exposure to two other solvents also boosts the chances of developing the neurodegenerative disorder, a new study indicates.
As many as 500,000 people in the United States have Parkinson's disease and more than 50,000 new cases are diagnosed in the country each year. Some research suggests that genetic and environmental factors might trigger Parkinson's, and several studies have reported that exposure to solvents may increase the risk.
In this new study, U.S. researchers interviewed 99 pairs of elderly twins about their lifetime occupations and hobbies. Exposure to TCE was associated with a sixfold increased risk of Parkinson's disease. Exposure to perchloroethylene (PERC) and carbon tetrachloride (CCI4) were also associated with increased risk.
The study was led by researchers at The Parkinson's Institute in Sunnyvale, Calif., and was published Nov. 14 in the journal Annals of Neurology.
"Our findings, as well as prior case reports, suggest a lag time of up to 40 years between TCE exposure and onset of [Parkinson's], providing a critical window of opportunity to potentially slow the disease process before clinical symptoms appear," said Dr. Samuel Goldman and colleagues in a journal news release.
While this study focused on job-related exposure, the solvents are common in soil, groundwater and the air in the United States. For example, TCE is detected in up to 30 percent of the nation's drinking water supplies, according to the researchers.
"Our study confirms that common environmental contaminants may increase the risk of developing [Parkinson's], which has considerable public health implications," Goldman and colleagues said.
All three solvents linked to Parkinson's are used extensively worldwide and TCE is a common agent in paints, adhesives, carpet cleaners and dry-cleaning solutions. In the United States, millions of pounds of TCE are released into the environment each year.

NEUROPATHY IS COMMON IN PARKINSON'S DISEASE

November 5,2011

Neuropathy has been found to be nearly seven times more prevalent in Parkinson's Disease. Neuropathy is the malfunction of nerves throughout the body. Neuropathy can cause a pins-and-needles sensation, numbness, burning pain, loss of vibration sense, and a loss of position sense, which is not knowing where the arms and legs are. Walking and even standing can become unsteady. The effects of neuropathy can progress to far more widespread and serious symptoms. For more information go to Polyneuropathy. The researchers found that Vitamin B12 deficiency was a more common cause of neuropathy. Vitamin B12 levels were found to be significantly lower in people with Parkinson's Disease. They believed that the Vitamin B12 deficiency in Parkinson's Disease could be related to the effect of long term use of L-dopa. They consequently suggested that both Vitamin B and Vitamin B12 monitoring and supplementation, as well as serial clinical assessment for neuropathy, may be advisable in people with Parkinson's Disease..

Structure of Parkinson's disease protein identified

Tuesday, November 01, 2011

A team of researchers from the Petsko-Ringe and Pochapskylaboratories at Brandeis have produced and determined the structureof alpha-synuclein, a key protein associated with Parkinson’s disease.

Their findings, recently published in Proceedings of the National Academy of Sciences(PNAS), provide information that may someday be used to produce a newkind of treatment for the incurable degenerative brain disorder.

Alpha-synuclein is found in large quantities in the brain. Its association with Parkinson’s disease has stirred curiosity since it was discovered in 1997.

“Nobody knows what it does, but there’s a lot of it,” says Pochapsky.“The question is whether the unfolded or coagulated Lewy body proteinjust represents the pathological form of something that’s normally doingsomething.”

To explore that question, the scientists wanted to find out what theform alpha-synuclein is in before it turns into Lewy body clumps,figuring that if it is possible to stabilize, the progression ofParkinson’s disease could be either slowed or reversed.

“Even if we don’t know what it is, we at least want to know in whatform alpha-synuclein protein should be under normal conditions,” saysPochapsky.

By Susan Chaityn Lebovits
http://medicalxpress.com/news/2011-10-parkinson-disease-protein.html

Abnormal oscillation in the brain causes motor deficits in Parkinson's disease

                                          
The research group headed by Professor Atsushi Nambu (The National Institute for Physiological Sciences) and Professor Masahiko Takada (Primate Research Institute, Kyoto University) has shown that the 'oscillatory' nature of electrical signals in subcortical nuclei, the basal ganglia, causes severe motor deficits in Parkinson's disease, by disturbing the information flow of motor commands. The group also found that chemical inactivation of the subthalamic nucleus (a structure of the basal ganglia) in parkinsonian monkeys improved the motor impairments by reducing the 'oscillations.' The results of this study were reported in European Journal of Neuroscience, November 2011 issue.

New test helps identify Parkinson’s disease

Monday, October 10, 2011

A new test is giving doctors and patients a clearer picture of Parkinson’s disease, and Parkinson’s syndrome. Nuclear medicine specialists at Orlando Regional Medical Center (ORMC) are now using DaTscan – the first Food and Drug Administration-approved imaging agent to help diagnose patients with suspected Parkinsonian syndromes, such as Parkinson’s disease — a neurodegenerative disorder that afflicts nearly 1.5 million Americans, with an additional 50,000 to 60,000 new cases identified each year. ORMC is the first hospital in Central Florida certified to perform the test.

“With a more timely diagnosis we can manage the disease earlier, which leads to better outcomes for patients,” said Mary Hart MD, nuclear medicine chair, ORMC.

DaTscan, by GE Healthcare, is performed by injecting a tiny dose of a radioactive tracer, followed by a painless imaging procedure called SPECT (single photon emission computed tomography), to search for dopamine transporters (DaT). Dopamine, a brain chemical responsible for movement control diminishes in patients with Parkinson’s disease causing tremor, slowness of movement, muscle stiffness and balance problems. The tracer binds to the dopamine transporters and the scan produces images that provide visual evidence of the presence of dopamine transporters. The entire procedure requires three to four hours.

“A normal image resembles two large commas or crescents in the brain,” said Dr. Hart. “Because dopamine levels drop in patients with Parkinson’s disease and other Parkinsonian syndromes, one or both of the normal crescents is not visible or may appear more like a period or oval.”

While a diagnosis of Parkinson’s syndromes presents a challenge, the confirmation of the correct diagnosis can make a difference in treatment and progression of the disease.

“DaTscan studies show upwards of 90 percent accuracy in diagnosing early, mid and late stages of Parkinson’s disease,” said Dr. Hart. “When presented with more reliable diagnostic data from the DaTscan, studies show that the treating physician alters his choice of treatment more than 40 percent of the time. This evidence based affect on clinical management is important because it shows that the procedure leads to more appropriate treatment for improved outcomes.”

More definitive testing may avoid or end years of expensive testing for a conclusive diagnosis, which can be delayed for as many as six years. Clinical examinations, particularly early in the disease when symptoms are slight, can be inconclusive or misleading. Incorrectly labeling Parkinson’s syndromes as an unrelated movement disorder, such as essential tremor, can delay effective treatment.

“‘Knowledge is power,’ especially in the case of medical conditions,” said Dr. Hart. “This test helps patients and their families face, and overcome the fears and frustrations inherent with uncertain diagnoses. If we can confirm that a patient does not have Parkinson’s disease, or Parkinson’s syndromes, it is a big relief. Confirmation of Parkinson’s disease is just as critical to know because it helps the patient and family members plan for the future.”

by Sabrina Childress

Virus destroys Parkinson's symptoms

YourNewsNow - Parkinson's disease is a progressive disorder of the nervous system that affects movement. It develops gradually, and often starts with a barely noticeable tremor in one hand. While tremors may be the most well-known sign of Parkinson's disease, the disorder also commonly causes a slowing or freezing of movement.

According to the Mayo Clinic, there's no cure for Parkinson's disease, but medications can help control some of the symptoms of Parkinson's disease, and in some cases, surgery may be helpful.

A small region deep within the brain is the source for the symptoms of Parkinson's disease. When brain neurons in that region of the brain begin to die, the cells can no longer manufacture the molecule dopamine -- a chemical critical for controlling movement.

The exact cause of Parkinson's disease is unknown, but several factors appear to play a role, including genes. Researchers have found specific genetic mutations that likely play a role in Parkinson's disease. In addition, scientists suspect that many more changes in genes -- whether inherited or caused by an environmental exposure -- may be responsible for Parkinson's disease. Exposure to toxins or certain viruses may trigger Parkinson's signs and symptoms.

For the first time, gene therapy has proven successful in Parkinson's patients. The therapy uses a virus that is stripped of its infectious properties and delivered with a thin tube into the brain's subthalamic nucleus -- a structure "the size of a pine nut" that is involved with movement.

Researchers followed 45 patients for six months after the procedure at seven U.S. medical centers. Half the patients showed improvements early on, which they still sustained six months later.

Most current therapies and research approaches target dopamine to treat motor symptoms associated with Parkinson's disease. In contrast, the focus of the current gene therapy strategy is on increasing GABA -- a brain neurotransmitter that regulates movement.

In Parkinson's disease, GABA is reduced in the area of the brain known as the subthalamic nucleus, causing it to be overactive. Investigators feel this might be a better way to help advanced Parkinson's disease. (SOURCE: Henry Ford Health System)

Children's Teeth Help Stem Cell Research

 

Tuesday, September 20, 2011

Experts say children's teeth might hold the key to effective treatments for diseases like Parkinson's disease and diabetes.

Children's teeth may be more valuable than a quarter under their pillow from the Tooth Fairy.

“It has been recently discovered that there are stem cells in the pulp chamber of these teeth” said Todd Flower, the director of research at GeneCell International.

The same type of stem cells used in research at the University of Miami to repair damaged hearts can be found in children's teeth, so officials at GeneCell International are reaching out to parents to bank the dental pulp stem cells in their freezers in West Kendall. 

“Ideally we would like to get the child’s tooth extracted once it becomes loose," Flower said. "If it falls out, you lose the blood supply to the tissue inside the tooth. Therefore the cells would die.”

A dentist would have to extract the loose tooth, put it in a special collection bottle, and send it to GeneCell's laboratory, where they process then store the cells at 340 degrees below zero.

Dr Jeffrey Kane is a dentist in Aventura who volunteers at The Robert Morgan Dental Clinic in Southwest Miami-Dade.

He sees an unneeded extraction as a concern.

“Even though you know it’s going to come out at a future date, to pull it prematurely may be a tough sell for a lot of children," he said. "I know for my children it would be a tough sell.”

He says another option would be using teeth that need to be extracted before braces or wisdom teeth.

There's also the issue of cost. Dental pulp services including processing and storage for up to four teeth at once runs from $695 for a year to $2,295 for 20 years. 

Flower points out that in the future “these cells probably could be used to treat many debilitating conditions like Parkinson’s, potentially spinal cord injury, even diabetes."

Dr. Joshua Hare, the director of the Interdisciplinary Stem Cell Institute at UM Miller School of medicine, said it's too early to say how much impact baby teeth can have on future medical breakthroughs.

While the research is extremely encouraging, Hare said "we can't say right now for sure it would be useful in the future, but it doesn't hurt to bank these cells if cost is not a problem."

He also points out it's unclear if frozen stem cells from a child's tooth will still be good to use 50 or 60 years later when they might be needed.

Fat happens to be another rich source of these promising stem cells. GeneCell says banking the fat extracted during liposuction might be in the near future.

By Diana Gonzalez

source: http://www.nbcmiami.com/news/local/Childrens-Teeth-Help-Stem-Cell-Research.html

Isotope Biomarkers Reveal Protein Fingerprints of Brain Disease

 

Monday, September 19, 2011

KineMed Inc. ( www.kinemed.com ) announced today that Dr. Patrizia Fanara, Vice President of Neuroscience, will present at the 5th Neurodegenerative Conditions Research and Development Conference on Sept 22nd, 2011 in San Francisco, CA, at 10.10am.

Dr. Fanara's presentation entitled "Novel Biomarkers that Monitor Brain Changes in Neurodegeneration and Translate into Humans" will discuss how KineMed's neuronal pathway-based biomarker approach has advanced the field of biomarker research and treatment of neurodegenerative disorders. Dr. Fanara will focus on KineMed's use of non-radioactive isotopic labeling to compare changes in the kinetics of biochemical processes between healthy and diseased states, thereby identifying pathways that are causal in pathogenesis.

"We will be presenting advances that represent a new future in this field through an unprecedented ability to measure not just one molecule but an entire pathway, and the flux of proteins within that pathway. This enables us to look directly into the immense complexity of neuronal function in vivo and obviates the need to create simplified disease models, with their inherent weaknesses. We are providing our collaborators with a rich and powerful toolset that reveals causal disease processes in their early stages, identifies trackable biomarkers and precisely measures the effects of drug perturbation on disease progression. KineMed is continuing to advance techniques that can therefore be applied both to the detection of neurological disorder and to the development of truly disease-modifying, effective therapeutic strategies to address Parkinson's, Alzheimer's, Huntington's, ALS and other neurodegenerative conditions," said Dr. Patrizia Fanara, Vice President of Neuroscience.

Dr. Fanara's presentation will provide an overview of:

Rational and exploratory biomarker discovery approaches through putative linkage with pathways relevant to neurodegeneration; Real-time indices of neuronal dysfunction and reparative processes; Ability to measure dynamic biological and biochemical processes occurring in neurodegeneration and to move quickly from animal studies to human trials; Information gained about the disease process from brain chemistry signatures from neurons and other cell types in humans that can be back-translated to preclinical models; Biomarkers that can be useful to clarify disease mechanisms and to discover new diagnostic biomarkers and therapeutic targets.

SOURCE: KineMed, Inc.

For more information, please visit: http:/ www.gtcbio.com

HEALING OF PARKINSON'S DISEASE THRU EXERCISE

  Exercise plays a key role in the management of Parkinson's disease (PD). If done regularly, it may slow down the progression of the disease. It usually includes stretching, strength training and aerobic activities. An exercise program should be individualized and should be based on the patient's ability level so as to maintain flexibility, mobility and general well-being. It is usually recommended by the rehabilitation specialist who works hand in hand with a physical therapist.

HEALING OF PARKINSON'S DISEASE THRU EXERCISE

Tuesday, September 20, 2011

Exercise plays a key role in the management of Parkinson's disease (PD). If done regularly, it may slow down the progression of the disease. It usually includes stretching, strength training and aerobic activities. An exercise program should be individualized and should be based on the patient's ability level so as to maintain flexibility, mobility and general well-being. It is usually recommended by the rehabilitation specialist who works hand in hand with a physical therapist.

Dr. M. Schenkman, et. al, did a a randomized, controlled trial in 1998 at the Duke University  Medical Center in Durham, North Carolina, USA, on how exercise can improve spinal flexibility and function for people with Parkinson's disease. The study showed improvements in axial mobility and physical performance within a 10-week exercise program for people in the early and midstages of PD.

In another study done by Dr. Victur Lun, et.al, in 2005, the effects of a self-supervised home exercise program were compared with the effects of a physiotherapist-supervised exercise program on the motor symptoms of Parkinson's disease. There was note of a statistifically significant improvement on the motor symptoms for both programs with similar effectiveness.

The above findings are important in the counseling of PD patients regarding adjunctive treatment of motor symptoms of PD with exercise.

Some of the benefits of regular exercise for the person with Parkinson’s disease are as follows: 

Improved control over gross motor movements, such as walking 
Increased muscle strength and flexibility 
Increased cardiovascular fitness  Improved coordination and balance 
Improved posture  Reduced muscle cramping 
Greater confidence in performing daily activities 
Reduced stress levels  Improved joint mobility

General recommendations on getting started are the following: 
Spend at least 15 minutes of exercise every day. 
A thorough stretching program that targets each joint and muscle group is recommended. 
Warm up and cool down for a few minutes like marching in place or stretching. 
Begin with the easiest exercises first and slowly perform the more difficult exercises as your fitness increases. 
Try to execute each movement to the best of your ability. 
Stop and rest if you get tired at any point during your exercise program to prevent worsening of your symptoms. 
Stop performing any exercise that causes you pain. 
If you get tired easily, try exercising earlier in the day. 
Try to make exercising fun by exercising with others or playing your favourite music.

If you are at risk of falling or freezing (sudden inability to move), general safety suggestions include the following:
Sit down when you do your exercises. 
Grab a chair when performing standing exercises. 
Avoid floor exercises if you can’t get up by yourself. 
Don't exercise alone even at home so you can ask help if necessary. 
Exercise with others. 
Call for assistance from a family member or friend.

Aim to build up to 8–10 repetitions of each exercise.

Ideally, the exercise program should target the following:
Overall fitness  Muscle flexibility
 Legs 
Head and shoulders 
Arms and torso 
Face 
Hands and wrists

References:1. Movement Disorders Volume 20, Issue 8, pages 971–975, August 2005

Source: http://parkinsonsdiseaseintheworld.blogspot.com/2011/09/healing-of-

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.

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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.

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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.

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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.

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

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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)