Parkinson’s Disease Treatments Progress, Thanks to Michael J. Fox’s Activism

Parkinson’s disease treatments progress, thanks to Michael J. Fox’s activism

When he first noticed his little finger shaking, Michael J. Fox put it down to a hangover. A year later — at just 30 years old — he was diagnosed with Parkinson’s disease.

The Canadian-American teen idol of the 1980s, famous for his roles in the smash hit trilogy Back to the Future underwent a 360-degree turnaround. From being a movie star for five years and feeling “lucky” he was suddenly “peculiar.” Sure, he was used to being stared at, but this time, it was different. “I hated the way it (Parkinson’s) made me look,” he thought. “That means that I hated me.”

But Fox has come a long way from feeling down in the dumps since he was first diagnosed with neurodegenerative disease in 1991. Starting with a public disclosure in 1998, he then went on to become an activist for research toward finding a cure. This led him to create the Michael J. Fox Foundation — today, the leading Parkinson’s fundraiser in the United States that has been able to put US$140 million into research in the last eight years alone. On March 5, 2010, Sweden’s Karolinska Institutet gave him a honoris causa doctorate for his work in advocating for a Parkinson’s cure .

But 21 years after diagnosis — and despite his overwhelming optimism — every day is still a challenge. Even just how exactly his medications will work still surprises him: if the drugs don’t take effect, he becomes “akinetic”– seized by tremors and stiffness. If the medication is working all right but coincides with a natural surge of the neurotransmitter dopamine, he becomes “dyskinesic” — “rocking, dipping, diving.”

To illustrate the terrible effects of the disease, Fox once appeared unmedicated before Congress. He describes how he looked “as if an invisible bully were harassing me as I read my statement.”

Parkinson’s is suffering
Parkinson’s doesn’t involve a lot of physical pain — but still it’s a terrible disease. First off, it involves a lot of mental pain.

Beginning with motion problems in walking or talking, the disease is marked by trembling arms and legs, muscular rigidity and poor balance. Parkinson’s patients have difficulty sleeping at night — then feel drowsy during the daytime.

The disease worsens over time, and a third of sufferers go on to develop dementia — failing memory, short attention span and personality changes. The remainder who don’t, still suffer from a slowing down of information processing that makes it hard to complete simple mental tasks.

If that’s not enough, half of all people who suffer from Parkinson’s also endure clinical depression, anxiety and panic attacks — sudden, overpowering fears that come like storms together with breathlessness, sweating, chest pain, choking and dizziness.

Drugs can be used to alleviate the most troubling symptoms of Parkinson’s, but until today, there’s still no cure. That means that right now, nothing can stop the disease’s awful advance. That’s even when it’s the second most common neurodegenerative disorder after Alzheimer’s disease.

About 7.5 people worldwide suffer from Parkinson’s — 1.7 million in China, one million in the U.S., about 100,000 in Canada and 1.2 million Europeans. A chronic, progressive neurological disorder, it affects one in 100 people over the age 60 — but can affect people as young as 18.

Scientists believe that the death of cells in the substantia nigra — a structure in the brain’s mid region in charge of reward, addiction and movement — is what causes a shortage of dopamine that in turn causes Parkinson’s. Dopamine is a brain chemical involved in mood, sleep, memory and movement. How exactly these changes happen isn’t precisely known, but scientists think a combination of aging, genetic susceptibility and environmental factors lead to the development of the disease.

Traditionally, Parkinson’s disease has been treated with drugs that can be made into dopamine in the brain like Sinemet, or by drugs that seem to affect the use of dopamine in the brain like Symmetrel and Eldepryl. Newer drugs — called dopamine agonists — activate dopamine-sensitive brain cells. These include Parlodel, Permax, Mirapex and Requip. The most commonly administered drug to treat Parkinson’s symptoms is levodopa (also called L-dopa), which helps restore dopamine levels.

Promising Parkinson’s research at UCLA
But while several therapies have been developed to treat the disorder, none actually slows its progression.

Researchers at the University of California in Los Angeles have been investigating a type of “protein aggregation” by a protein known as α-synuclein that’s implicated in Parkinson’s disease. Scientists think the disease occurs when α-synuclein — which is naturally present throughout the brain — binds together in toxic clumps that destroy the brain’s neurons.

Researchers note that right now, various protein accumulations that are toxic to the brain and/or other organs are believed to cause more than 30 diseases that have no cure.

According to the UCLA researchers led by Parkinson’s expert neurologist Jeff Bronstein, α-synuclein’s “normal function isn’t well understood, but it may play a role in aiding communication between neurons.”

“The trick, then, is to prevent the α-synuclein protein aggregates and their toxicity without destroying α-synuclein’s normal function, along with, of course, other healthy areas of the brain,” he says.

Together with UCLA associate professor of neurology Dr. Gal Bitan and other researchers, the neurology professor and Parkinson’s expert recently developed a molecular “tweezer” that blocked α-synuclein aggregates from forming in a living animal model.

The researchers have named their tweezer CLR01. It’s a complex molecular compound that’s capable of binding to other proteins. Shaped like the letter “C,” it wraps around chains of lysine — a basic amino acid that is a constituent of most proteins.

They then went on to show — first, in tissue culture — that the molecular “tweezer” broke down the toxic accumulation of α-synuclein, reversing aggregates that had already formed in the brain, and countered the aggregates’ toxicity as well. Significantly, this process happened without disrupting normal brain function.

“We call this unique mechanism ‘process-specific,’ rather than the common protein-specific inhibition,” meaning the compound only attacked the targeted aggregates and nothing else,” Dr. Bronstein said.

After successfully conducting the experiment in tissue culture, the researchers then employed their “tweezers” in a living animal — zebrafish. A tropical freshwater fish commonly found in aquariums, zebrafish are commonly used in research because they are easy to manipulate genetically, they grow quickly and are transparent — making it easier to measure biological processes.

Dr. Bronstein and his team then developed a model for Parkinson’s disease in the fish and then added CLR01. To track the tweezer’s effect on the aggregations, fluorescent proteins were used.

What they found was that — just as it did in cell cultures — CLR01 prevented α-synuclein aggregation and neuronal death. In short, it halted the progression of the disorder in a living animal.

“Taken together, CLR01 holds great promise as a new drug that can slow or stop the progression of Parkinson’s and related disorders. This takes us one step closer to a cure,” Dr. Bronstein says. But while these are very encouraging and significant results, still, at the end of the day, “we’ve only stopped Parkinson’s in zebrafish,” Dr. Bronstein points out.

This is why the UCLA researchers have now embarked on the next phase of their research. A study of CLR01 in a mouse model of Parkinson’s is now ongoing — and researchers hope this experiment will lead to human clinical trials.

New drug to treat Parkinson’s
Dyskinesias — or uncontrollable movements — is one of the more distressing symptoms of Parkinson’s. But often, it’s also a side effect of levodopa, the most commonly used drug to treat the neurodegenerative condition. With prolonged use, about 80 percent of patients treated with levodopa develop dyskinesias.

“Dyskinesia is a top priority for our Foundation because of its significant negative impact on patients’ quality of life,” says Todd Sherer, CEO of The Michael J. Fox Foundation. “A successful treatment for PD- levodopa-induced dyskinesia — or LID — will change the way Parkinson’s disease is treated by enabling physicians to use levodopa earlier and more effectively,” he says.

And that’s exactly what a new experimental drug promises to do. In a mid-stage trial of 76 Parkinson’s patients, a new drug called dipraglurant was found to be safe and to reduce involuntary movements significantly, as well.

Data from the double-blind, placebo-controlled trial conducted in the U.S. and Europe showed that both 50mg and 100mg doses of dipraglurant were safe and well tolerated. They also significantly reduced LID severity.

The new drug was created by Geneva-based drugmaker Addex Therapeutics, a leading pioneer in allosteric modulation-based drug discovery and development.

Dipraglurant is a small molecule allosteric modulator in tablet form. It works by selectively inhibiting the metabotropic glutamate receptor 5 or mGluR5 — a Class C G-Protein Coupled Receptor (GPCR). According to Addex Therapeutics, the drug has the potential to be used in combination with levodopa or dopamine agonists or as a standalone drug — to treat PD-LID, PD-related motor symptoms, non-motor symptoms of PD, as well as other movement disorders.

“There is no drug approved for the treatment of PD-LID and dipraglurant is an exciting new approach,” says Dr. Olivier Rascol, professor of Clinical Pharmacology at the Toulouse University Hospital in France and the dipraglurant study’s coordinating investigator.

“The study was successful in achieving the primary objective of good safety and tolerability. In addition, these proof of concept data are promising and warrant further investigation of dipraglurant in Parkinson’s disease,” says Dr. Rascol, who is also one of the world’s leading experts on Parkinson’s treatments.

To measure the drug’s efficacy, the following were used:
• the modified Abnormal Involuntary Movement Scale (mAIMS)
• patient diaries documenting “off-time” (impaired voluntary movement), “on-time” (with or without dyskinesia) and sleep
• Unified Parkinson’s Disease Rating Scale (UPDRS)
• Clinician & Patient Global Impression of Change (CGIC & PGIC)

The mood of Parkinson’s patients’ was also measured using the Hospital Anxiety & Depression Score.

The trial was supported by a grant from The Michael J. Fox Foundation, and a full analysis will be presented at a scientific forum this year.

Meanwhile, other research studies showed effective natural therapies for Parkinson’s.

Curcumin can help prevent Parkinson’s protein clumping
A team of researchers from the Michigan State University found that curcumin — a compound found in the spice turmeric — can also effectively prevent the clumping of protein involved in Parkinson’s.

First, researchers led by MSU postdoctoral researcher Basir Ahmad found that slow-wriggling α-synuclein proteins are the cause of the clumping or aggregation that is the first step of diseases such as Parkinson’s. They made this discovery early this year, independent of the UCLA researchers.

Then, the team conducted a second study that showed that curcumin can help prevent the clumping. This new study is published in the Journal of Biological Chemistry.

Together with Dr. Lisa Lapidus, MSU associate professor of physics and astronomy, Ahmad used lasers to study protein folding.

As we know, proteins are chains of amino acids that do most of the work in cells. While scientists understand protein structure, they don’t know how these are built in a process called “folding.” By correlating the speed at which protein folds with its tendency to clump or bind with other proteins, the
MSU team is now shedding light on this process.

When curcumin attaches to the α-synuclein protein, it doesn’t only stops clumping. Instead, it also raises the protein’s folding or reconfiguration rate. By speeding this rate, curcumin moves the protein out of a dangerous “speed zone” — allowing it to avoid clumping with other proteins.

“Our research shows that curcumin can rescue proteins from aggregation, the first steps of many debilitating diseases,” says physicist Lapidus. “More specifically, curcumin binds strongly to the α-synuclein protein and prevents aggregation at body temperatures.”

If scientist can find a compound that can fix a protein when it first begins to misfold — then they may be able to develop a drug to treat Parkinson’s. But not just yet.

“Curcumin’s usefulness as an actual drug may be pretty limited since it doesn’t go into the brain easily where this misfolding is taking place,” says Lapidus. “But this kind of study showcases the technique of measuring reconfiguration and opens the door for developing drug treatments.”

Tai chi helps with balance
Involving gentle, flowing movements and postures, the ancient Chinese exercise tai chi reduces stress and improves balance and posture.

Researchers from the Oregon Research Institute looked at the effect of tai chi on balance, gait and daily function in patients with mild to moderate Parkinson’s disease — and they found that tai chi is an effective intervention.

Their study involved 195 Parkinson’s patients, 40 to 85 years old. The participants were randomized into three groups:
• One group was taught stretching
• One group was taught resistance training that targeted muscles involved in balance and posture
• One groups was taught a tai chi program tailored to Parkinson’s symptoms

For six month, all participants exercised for one hour, twice a week. At the start of the study and then again at three months, six months, as well as three months after the completion of the exercise program, the following factors were assessed: (1) posture and gait, (2) ability to move accurately and (3) falls.

Researchers found that the tai chi group excelled in standardized measures of balance and coordination. “The tai chi group performed consistently better than the resistance-training and stretching groups in terms of maximum excursion (distance) and directional control … (and) outperformed the resistance training group in stride length and functional reach.”

In reducing the incidence of falls, tai chi was also more helpful than stretching, but not resistance training. The study, published in the New England Journal of Medicine, found no serious negative effects.

Just as well as more strenuous forms of exercise, tai chi also improves strength, balance and general functioning in seniors. It also slows the loss of muscular functions. This low-impact exercise isn’t difficult to learn and doesn’t require any equipment.


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