Potential drug lessens neurodegeneration in Parkinson's disease model

Date:

June 25, 2015

Source:

University of Alabama at Birmingham

Summary:

The first test in a mammalian model of a potential new class of drugs to treat Parkinson’s disease shows abatement of neurodegeneration in the brains of test rats and no significant toxicities.

The first test in a mammalian model of a potential new class of drugs to treat Parkinson's disease shows abatement of neurodegeneration in the brains of test rats and no significant toxicities, University of Alabama at Birmingham and Pfizer Inc. researchers report online in The Journal of Biological Chemistry.

At present, there are no therapies to slow or block the progression of Parkinson's disease, a common neurodegenerative disorder that affects 7 million to 10 million people worldwide.

The rat model overexpresses the protein α-synuclein in one side of the brain. This leads to degeneration of the dopamine-generating neurons of the substantia nigra region of the brain.

"Because our observations were limited to a four-week period, we are not sure whether neurodegeneration associated with α-synuclein is truly prevented or just delayed," senior author Andrew West, Ph.D., and colleagues wrote. "Either way, any interruption of neurodegeneration associated with Parkinson's disease might represent a significant therapeutic advance."

"For a patient with disease onset in the mid-60s, Parkinson's disease runs its course over 10 to 15 years," explained West, co-director of the Center for Neurodegeneration and Experimental Therapeutics, and the John A. and Ruth R. Jurenko Professor of Neurology at UAB. "So, if we can slow down the disease by even 50 percent, that may be effectively as good as a cure, given the available symptomatic treatments."

The rat model used mimics two cardinal features of Parkinson's disease: degeneration of dopamine neurons in the brain, and the accumulation of alpha-synuclein in surviving neurons. Patients with Parkinson's have significant degeneration of dopaminergic neurons in the substantia nigra, up to 70 percent losses at even mid-stages of their disease, and abnormal accumulation of α-synuclein in many of the surviving neurons that occurs years earlier. Details of how Parkinson's begins and how it progresses are still unclear.

The potential new class of drugs is kinase inhibitors that are active against the enzyme "leucine-rich repeat kinase 2" (LRRK2, pronounced "lark two"). Two clues point to LRRK2 as a possible target for therapy in Parkinson's. First, about 2 percent of Parkinson's disease patients have a specific mutation in LRRK2 called G2019S that increases the kinase activity of LRRK2; this suggests that increased activity plays a role in progression of the disease. Second, the West lab last year reported that gene "knockout" rats with no LRRK2 are completely protected from neurodegeneration in the α-synuclein-overexpression model, suggesting pharmacological inhibition may be a viable approach.

The model uses rats that express a cloned human G2019S-LRRK2 gene. Then these rats are injected in the brain (specifically a part of the brain called the substantia nigra) with a virus that expresses human α-synuclein. Test rats were fed the test inhibitor for four weeks, beginning at the time of infection. The small-molecule inhibitor easily passes through the blood-brain barrier to reach the brain from the bloodstream. Besides protecting against neurodegeneration, the inhibitor also lessened an inflammatory response by microglial cells seen in the brain in association with G2019S-LRRK2 expression.

West and colleagues also tested the inhibitor in outbred, wild-type rats, animals that are distinct from the strain that has the human G2019S-LRRK2. With the placebo, these rats showed about a 20 percent loss of neurons after four weeks of α-synuclein overexpression; but treatment with the inhibitor completely abated that loss. This result suggests that the inhibitor also has efficacy in the absence of the human G2019S-LRRK2.

"That is important because only 2 percent of Parkinson's disease patients have the G2019S mutation," West said. "These wild-type rats really excited us because it suggests the therapeutic action of the drug may extend to the majority of Parkinson's disease patients. This has invigorated our collaborative efforts with Pfizer Inc. and the Michael J. Fox Foundation for Parkinson's Research to invest more effort in LRRK2 inhibitors."

The Pfizer inhibitor is one of a number of LRRK2 inhibitors under development by drug companies, and also at UAB in collaboration with the Southern Research Institute. West says there will be room for several different inhibitors if this class of drugs shows promise in initial clinical trials, which hopefully will occur within the next year.

The next steps for the Pfizer inhibitor will be testing a variety of doses and testing what happens if treatment begins after the α-synuclein expression has already started. West notes that any possible therapy for Parkinson's disease will need to be incredibly safe because treatment would last for years.

"We have to be very careful with what our models can tell us," West cautioned about extrapolating from the rat model. "We need to think critically about what type of benefit we can expect to see in humans because there are recent examples where improper clinical trial design have hindered the development of a new class of drugs for years and sometimes decades."

For example, it is not clear where and how the inhibitor acts in the rat model, especially since inflammatory microglia cells in the brain also express LRRK2. Knowing such information might be critical to the success of these drugs in the clinic. In a separate trail of evidence, researchers, who include David Standaert, M.D.,Ph.D., have found that gene knockout of several neuroinflammatory processes can block α-synuclein neurodegeneration. Thus, the inhibitor may have an effect on just neurons or just microglia, or it may be a two-hit process affecting both neurons and microglia. Standaert is the John N. Whitaker Professor and chair of the Department of Neurology at UAB.

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Story Source:

The above post is reprinted from materials provided by University of Alabama at Birmingham. The original item was written by Jeff Hansen. Note: Materials may be edited for content and length.

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Journal Reference:

1. João P.L. Daher, Hisham A. Abdelmotilib, Xianzhen Hu, Laura A. Volpicelli-Daley, Mark S. Moehle, Kyle B. Faser, Elie Needle, Yi Chen, Stefanus J. Steyn, Paul Galatsis, Warren D. Hirst, Andrew B. West. LRRK2 Pharmacological Inhibition Abates α-Synuclein Induced Neurodegeneration. Journal of Biological Chemistry, 2015; jbc.M115.660001 DOI: 10.1074/jbc.M115.660001

http://www.sciencedaily.com/releases/2015/06/150625130316.htm

Augment Reality App to Treat Parkinson’s Disease

Jul 02, 2015

Parkinson’s disease is a movement disorder which affects the nerve cells and makes it impossible for the patients to move. Damaged posture and muscle tension cause them to lose balance and they face the risk of falling easily. They could also become frozen while walking and it will become difficult for them to regain their movement. All these problems could be overcome a bit using augmented reality technology along with dance. A Google Glass AR app has been developed which can be used to help patients suffering from Parkinson’s.

“Moving Through Glass”

Mark Morris Dance Group, based in New York launched Dance for Parkinson’s disease program, which is based on the idea that the training and movement used by professional dancers to develop coordination, power and balance, could also prove to be helpful for these types of patients. David Leventhal, the program director had applied for and got one of the five Explorer grants from Google for non-profit organizations to develop apps for Google Glass.

The group partnered with ad agency SS+K to design and develop this AR app which has been named Moving Through Glass. The app was developed to provide help to the patients 24/7.

Features of the App

To deal with difficulty in movement, the app could help patients do seated routines, first thing in the morning. Patients can do that right from their bed. They need to say “Ok, Glass… Warm me up.” Difficulty in maintaining body balance is another problem which can be fought with the AR app. As patients say “Ok, Glass… Balance me,” they can go through standing routines which will prep them up for walking. To unfreeze the patients in the middle of walking, they have to say “Ok, Glass… unfreeze me” and standing routines will take them out of a freeze gradually and help them resume their walking. With jerky movements, walking becomes difficult for patients suffering from Parkinson’s. As they use the app along with Google Glass and say “Ok, Glass… Walk with me,” they will get a walking guide which sets the pace to walk by providing visual stimulation with music.

Kevin Skobac, SVP, digital strategy and innovation at SS+K, said “Initially we built a very very detailed application, with a wide variety of controls and options. Our thinking was that these users would need to be able to minutely control and customize their experience. Very quickly, though, we realized that we needed instead to minimize required user inputs as much as possible. Ultimately, we created an application that can start a module and run a user through a full set of exercises with just two taps or, alternatively, two spoken commands.”

He added “Feedback from the medical community has also been tremendously supportive. Researchers at New York Presbyterian/Weill-Cornell Medical Center and Stanford University’s Movement Disorders Center have requested their own devices to test with patients. But most important and gratifying, has been the reaction from the Parkinson’s community. People with Parkinson’s who have used the application so far have been inspired by its ability to provide real-time, on demand assistance through a portable, intuitive interface.”

The app can be lent from MMDG and it is distributed through the Cornell Medical and Stanford’s Movement Disorders Center.

http://www.augmentedrealitytrends.com/ar-app/parkinsons-disease.html?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+artrends+(Augmented+Reality+Tren

The Silent/Silenced Ugly Truth About Parkinson’s Disease

Normally I wouldn't post something like this, but I feel the truth should be told.

You almost never hear anyone in the Parkinson’s community say that you will die from this disease. In fact, the rally cry is, “I won’t die of Parkinson’s, I’ll die with Parkinson’s.” This is a powerfully positive message that is absolutely critical to those in the earlier stages of the disease, and I applaud all those who fight the good fight. I pray that it is true for them even though it stabs me in the heart every time I hear it.

You see, there is another side to the Parkinson’s story. The Ugly Truth that is silenced…both by those who mean well and chide you about not being negative, as well as those of us that self-censor. We don’t want our early onset friends to get discouraged. We don’t want people to think we’re negative. We don’t want to acknowledge the truth…people DO die of Parkinson’s. We are the caregivers for those with Avanced Parkinson’s. We have a front row seat to the end game. The ugly truth about how Parkinson’s slowly takes your life slaps us in the face every day. So we keep this truth to ourselves. We cry together in secret Advanced Parkinson’s Caregiver support groups. We hide our Parkies away to protect what is left of their dignity. We don’t talk to the rest of the Parkinsons’ community about being unable to walk, bedridden, unable to feed yourself, bathe yourself, toilet by yourself, or even remember yourself.

I believe that someday we will identify many types of Parkinson’s disease, each with it’s own progression. Until then, we’re all lumped in to one shaky bucket and ALL our voices are needed at the table. Only by telling the whole story, including both ends of the disease spectrum, will we truly raise awareness of this disease.

I’ve wanted to post this for a long time now. I know that I will get a lot of flack from the early onset community. Know that I love all of you. I will fight with you, and for you, until the day we find a cure. To my fellow Advanced PD Caregivers, you are not alone. It’s time to tell our story

https://thereallisabain.wordpress.com

ANTIEPILEPTIC IMPROVES WEARING-OFF IN PARKINSON'S DISEASE

2nd July 2015 - 

Zonisamide, despite being an anti-epileptic, reduced "off" time in Parkinson's Disease during clinical trials. Zonisamide is presently being assessed for use in the treatment of Parkinson's Disease. Zonisamide activates dopamine biosynthesis by increasing the level of mRNA of tyrosine hydroxylase, which is the enzyme responsible for dopamine formation. For more information on zonisamide go to : http://www.rxlist.com/zonegran-drug.htm

To determine the efficacy of zonisamide for the treatment of "off" time in Parkinson's Disease, people with Parkinson's Disease who had wearing-off received a placebo for 4 weeks and were then treated for 12 weeks with either 25mg per day zonisamide, 50 mg per day zonisamide, or placebo, in addition to their previous therapy. The "off" time significantly reduced by 45 minutes when taking 50mg zonisamide per day.

Although the incidence of somnolence was just a bit higher for zonisamide, the incidences of other adverse events, including dyskinesia or hallucinations, for zonisamide were comparable to those of only a placebo.

The study provides evidence that confirms the efficacy of zonisamide 50 mg per day for reduction in "off" time in people with Parkinson's Disease with wearing-off phenomena.

Reference : Movement Disorders [2015] Jun 12 [Epub ahead of print] (M.Murata, K. Hasegawa, I.Kanazawa, J.Fukasaka, K.Kochi, R.Shimazu)

Complete abstract : http://www.ncbi.nlm.nih.gov/pubmed/26094993 

http://www.viartis.net/parkinsons.disease/news.htm

Study Links Hitler's Fatal Decisions to Parkinson's Disease

Did Parkinson's disease lose Hitler the war? Study claims the condition made the Fuhrer reckless and violent

• By the end of his life, Hitler had a pronounced tremor in his hands
• 
  
• This has led some scientists to question whether he had Parkinson's
• Latest study says horrific murders were influenced by the disease
• 
  
• The condition may have led him to attack Russia prematurely in 1941
• 
  

By ELLIE ZOLFAGHARIFARD FOR DAILYMAIL.COM

PUBLISHED: 30 June 2015 | 

By the end of his life, Adolf Hitler had a pronounced tremor in his hands, particularly his left hand, which has caused a number of scientists to question whether he had the disease (right).  A new study claims the neurological disease influenced some of the dictator's biggest decisions, making lose World War II

The study was led by Raghav Gupta and a team at the University of Pittsburgh and recently published in the journal World Neurosurgery.

'The possibility of Hitler suffering from Parkinson's has long been the subject of debate,' writes Gupta

'Video evidence depicts that Hitler exhibited progressive motor function deterioration from 1933 to 1945.'

By the end of his life, Hitler had a pronounced tremor in his hands, particularly his left hand, which has caused a number of scientists to question whether he had the disease.

Parkinson's can also cause a slow gait, bent posture and a dull stare, along with cognitive disorders such as a lack of imagination and a general apathy.

The researchers suggest that Hitler's condition may have led him to attack Russia prematurely in 1941, according to a report in Discover.

A previous study claimed that Hitler's decision to invade Russia, before defeating Britain on the western front, was a direct result of his failing health.

The study points to other bad decisions of Hitler's such the failure to defend Normandy in 1944, alongside keeping his forces in Stalingrad in 1942.

They say this was the result of the dictator's 'volatile temperament' which may have been aggravated by his Parkinson's.

The study also goes on to suggest that Hitler's lack of remorse and sympathy can be associated with his Parkinson's.

'Hitler's inhumane personality, marked by a true lack of sympathy and remorse, can also be ascribed to his condition, often compelling him to act in ways that we today characterise as brutal, callous, and unethical,' the authors say.

As Discover points out, the problem with this theory is that it can't explain Hitler's behaviour before 1933, as Hitler had shown signs of his destructive temperament long before that.

Dr John Murphy, executive vice president of Danbury Hospital, has previously put forward the same theory.

He argues the root cause of Hitler's Parkinson's disease may have been a condition known as Von Economo's encephalitis, which a swelling of the brain that can occur after an infection.

That infection may have been picked up by Hitler in the 1918 influenza epidemic, which killed 50 million people.

Chilling footage shows Adolf Hitler taking power

Read more:

• Did Parkinson's Disease Influence Hitler? - Neuroskeptic

Read more: http://www.dailymail.co.uk/sciencetech/article-3145166/Did-Parkinson-s-disease-change-Hitler-s-behaviour-Study-claims-condition-Fuhrer-reckless-violent.html#ixzz3efHIFBat

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July 1, 2015

Adolf Hitler suffering from Parkinson's disease played a crucial role in the defeat of Nazi Germany in World War II, according to a new study by American scientists.

A group of American neurologists from the University of Pittsburgh led by Raghav Gupta claim that some of Adolf Hitler's most disastrous decisions were influenced by his Parkinson's disease; playing a significant role in the defeat of Nazi Germany in the Second World War, according to research published by the World Neurosurgery journal.

Even though there is nothing new in the idea that Hitler suffered from Parkinson’s by the end of his life, the new study argues that the disease may have had an impact on large parts of Hitler's career, prompting him to take impulsive and reckless decisions, and finally causing him lose World War II.

"We purport that Germany's defeat in World War II was influenced by Hitler's questionable and risky decision-making and his inhumane and callous personality, both of which were likely affected by his Parkinson's condition," the authors of the study said.

They mentioned a spate of common symptoms of the disease, such as "a reduction in control of voluntary movements, rigidity and tremors [in hands]" that are "marked by a severe deterioration in motor function." There is still a big question mark over what causes Parkinson's disease.

As for Hitler, his deteriorating health may have prodded him to attack Russia prematurely in 1941, according to the researchers.

They argue that Hitler's "volatile temperament" may have been exacerbated by his Parkinson’s, something that resulted in Hitler taking a raft of bad decisions. These include his refusal to allow his forces to withdraw from Stalingrad in 1942 and the failure to defend Normandy in 1944.

The authors of the study go even further and suggest that his suffering from Parkinson's added to Hitler's "inhumane" nature.

"Hitler’s inhumane personality, marked by a true lack of sympathy and remorse, can also be ascribed to his condition, often compelling him to act in ways that we today characterize as brutal, callous, and unethical," they said.

Separately, the study suggests that that Hitler developed the early symptoms of Parkinson’s disease long before 1933.

According to the research, it occurred "sometime after World War I, including dyspepsia, colon spasms, and pathological sleep habits such as severe insomnia."

Read more: http://sputniknews.com/world/20150701/1024089730.html#ixzz3efC6DVto

http://health.einnews.com/article/273739232/PWonRDBnx2NklFBh

The Michael J. Fox Foundation and The Michael Stern Parkinson's Research Foundation Join Forces to Accelerate Novel Ideas in Parkinson's Research

NEW YORK, June 30, 2015 /PRNewswire-USNewswire/ -- 

The Michael J. Fox Foundation for Parkinson's Research (MJFF) and The Michael Stern Parkinson's Research Foundation (MSPRF) announced today the merging of their organizations to advance cutting-edge research focused on the underlying cause, diagnosis and treatment of Parkinson's disease (PD). The partnership creates the Michael Stern Discovery Grants in Parkinson's Science to support high-risk discovery work as the backbone of drug development. 

"For nearly 15 years, The Michael Stern Parkinson's Research Foundation has championed a strategic approach to advancing the PD research field. We share a dedication to progress and to ensuring the most promising research gets the right support from critical early stages," said Todd Sherer, PhD, CEO of The Michael J. Fox Foundation. "In forming this partnership, our Foundation will work to continue Michael Stern and MSPRF's legacy in the Parkinson's and scientific community."

Honoring a Legacy of Supporting Scientific Breakthroughs

Today, unprecedented scientific opportunities exist that can dramatically improve scientists' understanding of PD and fill the drug development pipeline with new and promising targets. The merger will continue the vital work of MSPRF through grants funding neurological research with strong potential to develop novel disease-modifying and symptomatic targets.

The Michael Stern Parkinson's Research Foundation was founded by Rome- and New York-based journalist, filmmaker and philanthropist Michael Stern with a vision of uncovering the cause and improving treatments for PD, and renewed its commitment after his passing in 2009. Since its inception in 2001, MSPRF has supported more than $46 million in research. 

"Our Foundation has always been driven by the profound need to identify discoveries in understanding and curing Parkinson's," said Margaret Stern, MSPRF Chair and CEO and Mr. Stern's daughter. "Our partnership with The Michael J. Fox Foundation reinforces our commitment to scientific collaboration and progress. My brother and I know that this merger is one that our father would have heartily approved of and fully endorsed."

Expanding a Commitment to Turn the Best Ideas Into Practical Treatments

The Michael Stern Discovery Grants in Parkinson's Science will provide strategic funding for novel PD discovery science and build on the initial findings around emerging targets, helping speed them forward in the drug development process. In alignment with its grant selection process, MJFF's expert on-staff research team will work in partnership with external experts through a peer-review system to identify, evaluate and award work with the greatest promise to propel development of transformative therapies for PD.  

The MJFF was represented by the law firm Schaner & Lubitz, PLLC in connection with the merger.

About The Michael J. Fox Foundation for Parkinson's Research

As the world's largest nonprofit funder of Parkinson's research, The Michael J. Fox Foundation is dedicated to accelerating a cure for Parkinson's disease and improved therapies for those living with the condition today. The Foundation pursues its goals through an aggressively funded, highly targeted research program coupled with active global engagement of scientists, Parkinson's patients, business leaders, clinical trial participants, donors and volunteers.  In addition to funding more than $450 million in research to date, the Foundation has fundamentally altered the trajectory of progress toward a cure. Operating at the hub of worldwide Parkinson's research, the Foundation forges groundbreaking collaborations with industry leaders, academic scientists and government research funders; increases the flow of participants into Parkinson's disease clinical trials with its online tool, Fox Trial Finder; promotes Parkinson's awareness through high-profile advocacy, events and outreach; and coordinates the grassroots involvement of thousands of Team Fox members around the world. 

For more information, visit us on the Web, Facebook, Twitter, LinkedIn and Pinterest.

About The Michael Stern Parkinson's Research Foundation

From founding in 2001, The Michael Stern Parkinson's Research Foundation has been a leading funder of science on Parkinson's disease, sponsoring research at top academic centers headed by the foremost leaders in Parkinson's research, with not less than 95% of every dollar raised going directly to research.

 http://www.prnewswire.com/news-releases/the-michael-j-fox-foundation-and-the-michael-stern-parkinsons-research-foundation-join-forces-to-accelerate-novel-ideas-in-parkinsons-research-300106296.html

SOURCE The Michael J. Fox Foundation for Parkinson's Research