Tagged: dyskinesias

Xenon: A bright light for dyskinesias?

A recent study published by French, British and Swiss researchers has grabbed the attention of some readers.

The report suggests that the inert/noble gas, Xenon, has powerful anti-dyskinetic properties in both mouse and primate models of Parkinson’s with L-DOPA-induced dyskinesias.

Dyskinesias are involuntary movements that can develop over time with prolonged used of L-DOPA treatments.

In today’s post, we will discuss what Xenon is, how it may be reducing dyskinesias, and we will consider some of the issues associated with using Xenon.


Dyskinesia. Source: JAMA Neurology

There is a normal course of events following a diagnosis of Parkinson’s.

Yes, I am grossly over-generalising, and no, I’m not talking from personal experience, but just go with me on this for the sake of discussion.

First comes the shock of the actual diagnosis. For many it is devastating news – an event that changes the course of their future. For others, however, the words ‘you have Parkinson’s‘ can provide a strange sense of relief that their current situation has a name and gives them something to focus on.

This initial phase is usually followed by the roller coaster of various emotions (including disbelief, sadness, anger, denial). It depends on each individual.

The emotional rollercoaster. Source: Asklatisha

And then comes the period during which many will try to familiarise themselves with their new situation. They will read books, search online for information, join Facebook groups (Click here for a good one), etc.

That search for information often leads to awareness of some of the realities of the condition.

And one potential reality that causes concern for many people (especially for people with early onset Parkinson’s) is dyskinesias.

What are dyskinesias?

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The aggregating antics of (some) anaesthetics

This is one of those posts that I am reluctant to write because there is the very real possibility of it being taken out of context and causing someone to panic. But several readers have asked me to address a new piece of research that was published this week which has them concerned.

Anaesthetics are very useful agents in medicine, but they have long been known to have biological effects beyond simply numbing/sedating individuals. Some of those effects are beneficial, while others….mmm, not so beneficial. And the new research published this week leans towards the latter: Certain anaesthetics apparently induce mutant protein aggregation in neurons and cause stress responses in those brain cells.

In today’s post, we will discuss what anaesthetics are, how (we think) they work, and what the results of this new research actually mean.


William Morton’s first public demonstration. Source: Pinterest

On Friday 16th October 1846, history was made.

On that date, an American dentist named William T. G. Morton (1819-1868) made the first public demonstration of the use of inhaled ether as a surgical anaesthetic.

William Morton. Source: Wikipedia

At this demonstration Dr. John Collins Warren painlessly removed a tumor from the neck of a Mr. Edward Gilbert Abbott. After finishing the operation and Abbott had regained consciousness, Warren asked Abbott how he felt.

John Collins Warren. Source: General-anaesthesia

Abbott replied, “Feels as if my neck’s been scratched.”

Warren then turned to the medical audience and said:

“Gentlemen, this is no Humbug”

This was an obvious shot at an unsuccessful demonstration of nitrous oxide as a anaesthesia the year before (by Horace Wells in the same theatre), which ended with the audience shouting “Humbug!” after they heard the patient groaning with pain during the procedure.

The important thing to appreciate here is the magnitude of Morton’s achievement within in the history of medicine.

Before 16th October 1846, surgical procedures were not very pleasant affairs.

After 16th October 1846,… well, to be honest, they are still not very pleasant affairs, but at least the patient can skip most of the painful parts of an operation.

Interesting. But what does this have to do with Parkinson’s?

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Is there NOP hope for Parkinson’s?

Please do not misread the title of this post!

Compounds targeting the Nociceptin receptor (or NOP) could provide the Parkinson’s community with novel treatment options in the not-too-distant future.

In pre-clinical models of Parkinson’s, compounds designed to block NOP have demonstrated neuroprotective properties, while drugs that stimulate NOP appear to be beneficial in reducing L-dopa induced dyskinesias. 

In today’s post we look at exactly what NOP is and what it does, we will review some of the Parkinson’s-based research that have been conducted so far, and we will look at what is happening in the clinic with regards to NOP-based treatments.


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Source: LUMS

On the surface of every cell in your body, there are lots of small proteins that are called receptors.

They are numerous and ubiquitous.

And they function act like a ‘light switch’ – allowing for certain biological processes to be initiated or inhibited. All a receptor requires to be activated (or blocked) is a chemical messenger – called a ligand – to come along and bind to it.

An example of a receptor on a cell. Source: Droualb

Each type of receptor has a particular structure, which is specific to certain shaped ligands (the chemical messenger I mentioned above). These ligands are floating around in the extracellular space (the world outside of the cell), having been released (or secreted) by other cells.

And this process represents one of the main methods by which cells communicate with each other.

By binding to a receptor, the ligand can either activate the receptor or alternatively block it. The activator ligands are called agonists, while the blockers are antagonists.

Agonists_and_antagonists

Agonist vs antagonist. Source: Psychonautwiki

Many of the drugs we currently have available in the clinic function in this manner.

For example, with Parkinson’s medications, some people will be taking Pramipexole (‘Mirapex’ and ‘Sifrol’) or Apomorphine (‘Apokyn’) to treat their symptoms. These drugs are Dopamine agonists because they bind to the dopamine receptors, and help with dopamine-mediated functions (dopamine being one of the chemicals that is severely in the Parkinsonian brain). As you can see in the image below the blue dopamine agonists can bypass the dopamine production process (which is reduced in Parkinson’s) and bind directly to the dopamine receptors on the cells that are the intended targets of dopamine.

Source: Bocsci

There are also dopamine antagonists (such as Olanzapine or ‘Zyprexa’) which blocks dopamine receptors. These drugs are not very helpful to Parkinson’s, but dopamine antagonist are commonly prescribed for people with schizophrenia.

Are there other receptors of interest in Parkinson’s?

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Trazodo or Trazodon’t?

“Repurposing” in medicine refers to taking drugs that are already approved for the treatment of one condition and testing them to see if they are safe and effective in treating other diseases. Given that these clinically available drugs have already been shown to be safe in humans, repurposing represents a method of rapidly acquiring new potential therapeutics for a particular condition. 

The antidepressant, Trazodone, has recently been proposed for repurposing to neurodegenerative conditions, such as Parkinson’s. 

In today’s post we will look at what Trazodone is, why it is being considered for repurposing, and we will review the results of a new primate study that suggests it may not be ideal for the task.


Opinions. Everyone has them. Source: Creativereview

I am regularly asked by readers to give an opinion on specific drugs and supplements.

And I usually cut and paste in my standard response: I can not answer these sorts of questions as I am just a research scientist not a clinician; and even if I was a clinician, it would be unethical for me to comment as I have no idea of your medical history.

In many of these cases, there simply isn’t much proof that the drug/supplement has any effect in Parkinson’s, so it is hard to provide any kind of “opinion”. But even if there was proof, I don’t like to give opinions.

Eleven out of every ten opinions are usually wrong (except in the head of the beholder) so why would my opinion be any better? And each individual is so different, why would one particular drug/supplement work the same for everyone?

In offering an answer to “my opinion” questions, I prefer to stick to the “Just the facts, ma’am” approach and I focus solely on the research evidence that we have available (Useless pub quiz fact: this catchphrase “Just the facts, ma’am” is often credited to Detective Joe Friday from the TV series Dragnet, and yet he never actually said it during any episode! – Source).

Detective Joe Friday. Source: Wikipedia

Now, having said all of that, there is one drug in particularly that is a regular topic of inquiry (literally, not a week goes by without someone asking about): an antidepressant called Trazodone.

What is Trazodone?

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Monthly Research Review – January 2018

Today’s (experimental) post provides something new – an overview of some of the major bits of Parkinson’s-related research that were made available in January 2018.


In January of 2018, the world was rocked by news that New Zealand had become the 11th country in the world to put a rocket into orbit (no really, I’m serious. Not kidding here – Click here to read more). Firmly cementing their place in the rankings of world superpowers. In addition, they became only the second country to have a prime minister get pregnant during their term in office (in this case just 3 months into her term in office – Click here to read more about this).

A happy New Zealand prime minister Jacinda Ardine

In major research news, NASA and NOAA announced that 2017 was the hottest year on record globally (without an El Niño), and among the top three hottest years overall (Click here for more on this), and scientists in China reported in the journal Cell that they had created the first monkey clones, named Zhong Zhong and Hua Hua (Click here for that news)

Zhong Zhong the cute little clone. Source: BBC

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Clinical trials: The Power of One

As the age of personalised medicine approaches, innovative researchers are rethinking the way we conduct clinical studies. “Rethinking” in radical ways – think: individualised clinical trials! 

One obvious question is: Can you really conduct a clinical trial involving just one participant?

In this post, we will look at some of the ideas and evaluate the strengths and weaknesses these approaches.


A Nobel prize medal. Source: Motley

In the annals of Nobel prize history, there are a couple winners that stands out for their shear….um, well,…audacity.

One example in particular, was the award given to physician Dr Werner Forssmann. In 1956, Andre Cournand, Dickinson Richards and Forssmann were awarded the Nobel Prize in Physiology or Medicine “for their discoveries concerning heart catheterisation and pathological changes in the circulatory system”. Forssmann was responsible for the first part (heart catheterisation).

Source: Nobelprize

In 1929, at the age of 25, Forssmann performed the first human cardiac catheterisation – that is a procedure that involves inserting a thin, flexible tube directly into the heart via an artery (usually in the arm, leg or neck). It is a very common procedure performed on a daily basis in any hospital today. But in 1929, it was revolutionary. And the audacious aspect of this feat was that Forssmann performed the procedure on himself!

And if you think that is too crazy to be true, please read on.

But be warned: this particular story gets really bonkers.

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The Agony and the Ecstasy

ecstasy

The contents of today’s post may not be appropriate for all readers. An illegal and potentially damaging drug is discussed. Please proceed with caution. 

3,4-Methylenedioxymethamphetamine (or MDMA) is more commonly known as Ecstasy, ‘Molly’ or simply ‘E’. It is a controlled Class A, synthetic, psychoactive drug that was very popular with the New York and London club scene of the 1980-90s.

It is chemically similar to both stimulants and hallucinogens, producing a feeling of increased energy, pleasure, emotional warmth, but also distorted sensory perception. 

Another curious effect of the drug: it has the ability to reduce dyskinesias – the involuntary movements associated with long-term Levodopa treatment.

In today’s post, we will (try not to get ourselves into trouble by) discussing the biology of MDMA, the research that has been done on it with regards to Parkinson’s disease, and what that may tell us about dyskinesias.


Carwash-image-07

Good times. Source: Carwash

You may have heard this story before.

It is about a stuntman.

His name is Tim Lawrence, and in 1994 – at 34 years of age – he was diagnosed with Parkinson’s disease.

_1169980_tim_lawrence_ecstasy300

Tim Lawrence. Source: BBC

Following the diagnosis, Tim was placed on the standard treatment for Parkinson’s disease: Levodopa. But after just a few years of taking this treatment, he began to develop dyskinesias.

Dyskinesias are involuntary movements that can develop after regular long-term use of Levodopa. There are currently few clinically approved medications for treating this debilitating side effect of Levodopa treatment. I have previously discussed dyskinesias (Click here and here for more of an explanation about them).

As his dyskinesias progressively got worse, Tim was offered and turned down deep brain stimulation as a treatment option. But by 1997, Tim says that he spent most of his waking hours with “twitching, spasmodic, involuntary, sometimes violent movements of the body’s muscles, over which the brain has absolutely no control“.

And the dyskinesias continued to get worse…

…until one night while he was out at a night club, something amazing happened:

Standing in the club with thumping music claiming the air, I was suddenly aware that I was totally still. I felt and looked completely normal. No big deal for you, perhaps, but, for me, it was a revelation” he said.

His dyskinesias had stopped.

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Tetrabenazine: A strategy for Levodopa-induced dyskinesia?

Dyk

For many people diagnosed with Parkinson’s disease, one of the scariest prospects of the condition that they face is the possibility of developing dyskinesias.

Dyskinesias are involuntary movements that can develop after long term use of the primary treatment of Parkinson’s disease: Levodopa

In todays post I discuss one experimental strategy for dealing with this debilitating aspect of Parkinson’s disease.


Dysco

Dyskinesia. Source: JAMA Neurology

There is a normal course of events with Parkinson’s disease (and yes, I am grossly generalising here).

First comes the shock of the diagnosis.

This is generally followed by the roller coaster of various emotions (including disbelief, sadness, anger, denial).

Then comes the period during which one will try to familiarise oneself with the condition (reading books, searching online, joining Facebook groups), and this usually leads to awareness of some of the realities of the condition.

One of those realities (especially for people with early onset Parkinson’s disease) are dyskinesias.

What are dyskinesias?

Dyskinesias (from Greek: dys – abnormal; and kinēsis – motion, movement) are simply a category of movement disorders that are characterised by involuntary muscle movements. And they are certainly not specific to Parkinson’s disease.

As I have suggested in the summary at the top, they are associated in Parkinson’s disease with long-term use of Levodopa (also known as Sinemet or Madopar).

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Sinemet is Levodopa. Source: Drugs

Continue reading

Are Dyskinesias days NAM-bered?

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Addex Therapeutics and the Michael J Fox Foundation are preparing to initiate a new clinical trial testing a new drug called Dipraglurant on levodopa-induced dyskinesia (Source).

Dipraglurant is a mGluR5 negative allosteric modulator (don’t panic, it’s not as complicated as it sounds).

In today’s post, we’ll explain what all of that means and look at the science behind this new treatment.


Dysco

An example of a person with dyskinesia. Source: JAMA Neurology

For anyone familiar with Parkinson’s disease, they will know that long term use of the treatment L-dopa can lead to two possible outcomes:

  1. The treatment loses it’s impact, requiring ever higher doses to be administered
  2. The appearance of dykinesias

Now, not everyone taking L-dopa will be affected by both of these outcomes, but people with young, onset Parkinson’s disease do seem to be at risk of developing L-dopa induced dykinesias.

What are Dyskinesias?

Dyskinesias (from Greek: dys – abnormal; and kinēsis – motion, movement) are simply a category of movement disorders that are characterised by involuntary muscle movements. And they are certainly not specific to Parkinson’s disease.

As we have suggested above, they are associated in Parkinson’s disease with long-term use of L-dopa.

Below is a video of two legends: the late Tom Isaacs (who co-founded the Cure Parkinson’s Trust) and David Sangster (he founded www.1in20Parkinsons.org.uk). They were both diagnosed with Parkinson’s disease in their late 20’s. Tom, having lived with Parkinson’s for 20 years at the time of this video provides a good example of what dyskinesias look like:

As you can see, dyskinesias are a debilitating issue for anyone who suffers them.

How do dyskinesias develop in Parkinson’s disease?

Before being diagnosed and beginning a course of L-dopa, the locomotion parts of the brain in a person with Parkinson’s disease gradually becomes more and more inhibited. This increasing inhibition results in the slowness and difficulty in initiating movement that characterises this condition. A person with Parkinson’s may want to move, but they can’t.

They are akinetic (from Greek: a-, not, without; and kinēsis – motion).

972px-Paralysis_agitans_(1907,_after_St._Leger)

Drawing of an akinetic individual with Parkinson’s disease, by Sir William Richard Gowers
Source: Wikipedia

L-dopa tablets provide the brain with the precursor to the chemical dopamine. Dopamine producing cells are lost in Parkinson’s disease, so replacing the missing dopamine is one way to treat the motor features of the condition. Simply giving people pills of dopamine is a non-starter: dopamine is unstable, breaks down too quickly, and (strangely) has a very hard time getting into the brain. L-dopa, on the other hand, is very robust and has no problem getting into the brain.

7001127301-6010801

Sinemet is L-dopa. Source: Drugs

Once inside the brain, L-dopa is quickly converted into dopamine. It is changed into dopamine by an enzyme called DOPA decarboxylase, and this change rapidly increases the levels of dopamine in the brain, allowing the locomotion parts of the brain to function more normally.

4INJ4aV

The chemical conversion of L-dopa to dopamine. Source: Nootrobox

In understanding this process, it is important to appreciate that when an L-dopa tablet is consumed and L-dopa enters the brain, there is a rapid increase in the levels of dopamine. A ‘spike’ in the supply of dopamine, if you will, and this will last for the next few hours, before the dopamine is used up.

As the effects of the L-dopa tablet wear off, another tablet will be required. This use of multiple L-dopa pills across the day gives rise to a wave-like shape to the dopamine levels in the brain over the course of the day (see the figure below). The first pill in the morning will quickly lift the levels of dopamine enough that the individual will no longer feel akinetic. This will allow them to be able to function with normal controlled movement for several hours before the L-dopa begins to wear off. As the L-dopa wears off, the dopamine levels in the brain drop back towards levels that will leave the person feeling akinetic and at this point another L-dopa tablet is required.

Dysk1

After several years of L-dopa use, many people with Parkinson’s disease will experience a weaker response to each tablet. They will also find that they have more time during which they will be unable to move (exhibiting akinesia). This is simply the result of the progression of Parkinson’s disease – L-dopa treats the motor features of the disease but only hides/masks the fact that the disease is still progressing.

To combat this shorter response time, the dose of L-dopa is increased. This will result in increasing levels of dopamine in the brain (as illustrated by the higher wave form over time in the image below). It will take more L-dopa medication induced dopamine to lift the individual out of the akinetic state.

Dyskinesias3

This increasing of L-dopa dosage, however, is often associated with the gradual development of abnormal involuntary movements that appear when the levels of L-dopa induced dopamine are the highest.

These are the dyskinesias.

Are there different types of dyskinesias?

Yes there are.

Dyskinesias have been broken down into many different subtypes, but the two main types of dyskinesia are:

Chorea – these are involuntary, irregular, purposeless, and unsustained movements. To an observer, Chorea will look like a very disorganised/uncoordinated attempt at dancing (hence the name, from the Greek word ‘χορεία’ which means ‘dance’). While the overall activity of the body can appear continuous, the individual movements are brief, infrequent and isolated. Chorea can cause problems with maintaining a sustained muscle contraction,  which may result in affected people dropping things or even falling over.

Dystonia – these are sustained muscle contractions. They often occur at rest and can be either focal or generalized. Focal dystonias are involuntary contractions in a single body part, for example the upper facial area. Generalized dystonia, as the name suggests, are contraction affecting multiple body regions at the same time, typically the trunk, one or both legs, and another body part. The intensity of muscular movements in sufferers can fluctuate, and symptoms usually worsen during periods of fatigue or stress.

We have previously discussed the current treatment options for dyskinesias (click here to see that post).

Ok, so what clinical trials are Addex Therapeutics and the Michael J Fox Foundation preparing and why?

They are preparing to take a drug called Dipraglurant through phase III testing for L-dopa inducing dyskinesias in Parkinson’s disease. Dipraglurant is a mGluR5 negative allosteric modulator.

And yes, I know what you are going to ask next: what does any of that mean?

Ok, so mGluR5 (or Metabotropic glutamate receptor 5) is a G protein-coupled receptor. This is a structure that sits in the skin of a cell (the cell membrane), with one part exposed to the outside world – waiting for a chemical to bind to it – while another part is inside the cell, ready to act when the outside part is activated. The outside part of the structure is called the receptor.

Metabotropic receptors are a type of receptor that is indirectly linked with channels in cell membrane. These channels open and close, allowing specific elements to enter the cell. When a chemical (or agonist) binds to the receptor and it becomes activated, the part of the structure inside the cell will send a signal to the channel via a messenger (called a G-protein).

The chemical that binds to mGluR5 is the neurotransmitter glutamate.

U4.cp2.1_nature01307-f1.2

Metabotropic glutamate receptor 5 activation. Source: Nature

But what about the “negative allosteric modulator” part of ‘mGluR5 negative allosteric modulator’

Good question.

This is the key part of this new approach. Allosteric modulators are a new class of orally available small molecule therapeutic agents. Traditionally, most marketed drugs bind directly to the same part of receptors that the body’s own natural occurring proteins attach to. But this means that those drugs are competing with those endogenous proteins, and this can limit the potential effect of the drug.

Allosteric modulators get around this problem by binding to a different parts of the receptor. And instead of simply turning on or off the receptor, allosteric modulators can either turn up the volume of the signal being sent by the receptor or decrease the signals. This means that when the body’s naturally occurring protein binds in the receptor, allosteric modulators can either amplify the effect or reduce it depending on which type of allosteric modulators is being administered.

allosteric_modulation_mechanism

How Allosteric modulators work. Source: Addrex Thereapeutics

There are two different types of allosteric modulators: positive and negative. And as the label suggests, positive allosteric modulators (or PAMs) increase the signal from the receptor while negative allosteric modulators (or NAMs) reduce the signal.

So Dipraglurant turns down the volume of the signal from the mGluR5 receptor?

Exactly.

By turning down the volume of the glutamate receptor mGluR5, researchers believe that we can reduce the severity of dyskinesias.

But hang on a second. Why are we looking at glutamate in dyskinesias? Isn’t dopamine the chemical of interest in Parkinson’s disease?

So almost 10 years ago, some researchers noticed something interesting in the brains of Parkinsonian monkeys that had developed dyskinesias:

Monkey2
Title: mGluR5 metabotropic glutamate receptors and dyskinesias in MPTP monkeys.
Authors: Samadi P, Grégoire L, Morissette M, Calon F, Hadj Tahar A, Dridi M, Belanger N, Meltzer LT, Bédard PJ, Di Paolo T.
Journal: Neurobiol Aging. 2008 Jul;29(7):1040-51.
PMID: 17353071

The researchers conducting this study induced Parkinson’s disease in monkeys using a neurotoxin called MPTP, and they then treated the monkeys with L-dopa until they began to develop dyskinesias. At this point when they looked in the brains of these monkeys, the researchers noticed a significant increase in the levels of mGluR5, which was associated with the dyskinesias. This finding led the researchers to speculate that reducing mGluR5 levels might reduce dyskinesias.

And it did!

Subsequent preclinical research indicated that targeting mGluR5 might be useful in treating dyskinesias, especially with negative allosteric modulators:

Monkey
Title: The mGluR5 negative allosteric modulator dipraglurant reduces dyskinesia in the MPTP macaque model
Authors: Bezard E, Pioli EY, Li Q, Girard F, Mutel V, Keywood C, Tison F, Rascol O, Poli SM.
Journal: Mov Disord. 2014 Jul;29(8):1074-9.
PMID: 24865335

In this study, the researchers tested the efficacy of dipraglurant in Parkinsonian primates  that had developed L-dopa induced dyskinesias. They tested three different doses of the drug (3, 10, and 30 mg/kg).

Dipraglurant significantly reduced dyskinesias in the monkeys, with best effect being reached using the 30 mg/kg dose. Importantly, the dipraglurant treatment had no impact on the efficacy of L-dopa which was still being used to treat the monkeys Parkinson’s features.

This research lead to a clinical trials in man, and last year Addex Therapeutics published the results of their phase IIa clinical trial of Dipraglurant (also called ADX-48621):

NAM

Title: A Phase 2A Trial of the Novel mGluR5-Negative Allosteric Modulator Dipraglurant for Levodopa-Induced Dyskinesia in Parkinson’s Disease.
Authors: Tison F, Keywood C, Wakefield M, Durif F, Corvol JC, Eggert K, Lew M, Isaacson S, Bezard E, Poli SM, Goetz CG, Trenkwalder C, Rascol O.
Journal: Mov Disord. 2016 Sep;31(9):1373-80.
PMID: 27214664

The Phase IIa double-blind, placebo-controlled, randomised trial was a dose escalation study, conducted in 76 patients with Parkinson’s disease L-dopa-induced dyskinesia – 52 subjects were given dipraglurant and 24 received a placebo treatment. The dose escalation assessment of dipraglurant started at 50 mg once daily to 100 mg 3 times daily. The study was conducted over 4 weeks.

The investigators found that dipraglurant significantly reduced the dyskinesias on both day 1 of the study and on day 14, and this treatment did not result in any worsening of the Parkinsonian features. And remember that this was a double blind study, so both the investigators and the participants had no idea which treatment was being given to each subject. Thus little bias can influence the outcome, indicating that dipraglurant really is having a beneficial effect on dyskinesias.

The company suggested that dipraglurant’s efficacy in reducing L-dopa-induced dyskinesia warrants further investigations in a larger number of patients. And this is what the company is now doing with the help of the Michael J. Fox Foundation (MJFF). In addition, dipraglurant’s potential benefits on dystonia are also going to be investigated with support from the Dystonia Medical Research Foundation (DMRF).

And the really encouraging aspect of this research is that Addex Therapeutics are not the only research group achieving significant beneficial results for dykinesias using this treatment approach (click here to read about other NAM-based clinical studies for dyskinesias).

Fingers crossed for more positive results here.

What happens next?

L-dopa induced dyskinesias can be one of the most debilitating aspects of living with Parkinson’s disease, particularly for the early-onset forms of the condition. A great deal of research is being conducted in order to alleviate these complications, and we are now starting to see positive clinical results starting to flow from that research.

These results are using new type of therapeutic drug that are designed to increase or decrease the level of a signal occurring in a cell without interfering with the normal functioning of the chemicals controlling the activation of that signal.

This is really impressive biology.


The banner for today’s post was sourced from Steam

Disco-needs-ya – the science of dyskinesias

This is Tom Isaacs. He is the charismatic founder of the Cure Parkinson’s trust.

tom isaacs

Tom Isaacs. Source: GrannyButtons

He’s a dude.

The man walked the entire coastline of the UK to raise money/awareness for Parkinson’s disease! Trust me, he’s a dude.

The title of today’s post is a salute to Tom’s efforts to offer a humourous label to what is a very serious and debilitating aspect of Parkinson’s disease.

In this post, we will discuss the science of dyskinesias


For the last 50 years, Levodopa (L-dopa) has been the “gold standard” treatment for Parkinson’s disease. By replacing the lost dopamine, L-dopa allows for the locomotion parts of the brain to become less inhibited and for people with Parkinson’s disease to feel more in control of their movements.

This miraculous treatment, however, comes at a terrible cost.

After long-term use of the drug, abnormal and involuntary movements can begin to appear. These movements are called dyskinesias.

Dykinesias

An example of a person with dyskinesia. Source: JAMA Neurology

What are Dyskinesias?

Dyskinesias (from Greek: dys/dus – difficulty, abnormal; and kinēsis – motion, movement) are simply a category of movement disorders that are characterized by involuntary muscle movements. They are certainly not specific to just Parkinson’s disease.

In Parkinson’s disease, they are associated with long-term use of L-dopa.

An example of dyskinesia can be seen in this video of Tom Isaacs and David Sangster discussing life with Parkinson’s disease (Tom was diagnosed at age 26 years of age and has lived with Parkinson’s for 20 years – he has dyskinesias. David was diagnosed in 2011 at age 29; since diagnosis he foundered www.1in20Parkinsons.org.uk. He’s also a dude!).

How do dyskinesias develop in Parkinson’s disease?

Before beginning a course of L-dopa, the locomotion parts of the brain in people with Parkinson’s disease is pretty inhibited. This results in the slowness and difficulty in initiating movement. They want to move, but they can’t. They are akinetic.

L-dopa tablets provide the brain with the precursor to the chemical dopamine. Dopamine producing cells are lost in Parkinson’s disease, so replacing the missing dopamine is one way to treat the motor features of the condition. Simply giving people pills of dopamine is a non-starter: dopamine is unstable, breaks down too quickly, and (strangely) has a very hard time getting into the brain. L-dopa, on the other hand, is very robust and has no problem getting into the brain.

Once inside the brain, L-dopa is quickly converted – via an enzymatic reaction – into dopamine allowing the locomotion parts of the brain to function close to normal. In understanding this process, it is important to appreciate that when a tablet is taken and L-dopa  enters the brain, there is a sudden rush of dopamine. A spike in it’s supply, and for the next few hours this gradually wears off as the dopamine is used up. This tablet approach to L-dopa treatment gives a wave like shape to the L-dopa levels in the brain over the course of the day (see the figure below).

After prolonged use of L-dopa (7-10 years on average), the majority of people with Parkinson’s disease will experience a shorter response to each dose of L-dopa. They will also find that they have more time during which they will be unable to move (exhibiting akinesia). This is simply the result of the disease progression – L-dopa treats the motor features of the disease but hides the fact that the disease is still progressing.

This shortening of response is often associated with subtle abnormal involuntary movements that appear when the levels of l-DOPA are highest (usually soon after taking a tablet). It is as if there is too much dopamine for the system to handle.

Gradually, the response time (during which normal movement is possible) will grow shorter and to combat this the dose of L-dopa is increased. But with increased levels of L-dopa, there is an increase in the involuntary movements, or dyskinesias.

Dyskinesia

This figure illustrates the course of Parkinson’s disease for some people on L-dopa. The waving line indicates the level of L-dopa in the blood (as a result of taking L-dopa medication). The white space is the area where normal movement is possible, while the grey area illustrates periods of akinesia (inability to move). Without L-dopa, people with Parkinson’s disease would be stuck in this area, and as the L-dopa pill wears off (during the downward part of the waving line) they fall back into the akinesia area, thus requiring another pill. As the disease progresses, the akinetic (grey) area increases, requiring higher levels of L-dopa to be administered in order to escape it. The tan coloured area in the top right corner demonstrates the introduction of dyskinesias.

Are there different types of dyskinesias?

Yes there are. Dyskinesias have been broken down into many different subtypes, but the two main types of dyskinesia are:

Chorea – these are involuntary, irregular, purposeless, and unsustained movements. To an observer, Chorea will look like a very disorganised/uncoordinated attempt at dancing (hence the name, from the Greek word ‘χορεία’ which means ‘dance’). While the overall activity of the body can appear continuous, the individual movements are brief, infrequent and isolated. Chorea can cause problems with maintaining a sustained muscle contraction,  which may result in affected people dropping things or even falling over.

Dystonia – these are sustained muscle contractions. They often occur at rest and can be either focal or generalized. Focal dystonias are involuntary contractions in a single body part, for example the upper facial area. Generalized dystonia, as the name suggests, are contraction affecting multiple body regions at the same time, typically the trunk, one or both legs, and another body part. The intensity of muscular movements in sufferers can fluctuate, and symptoms usually worsen during periods of fatigue or stress.

When were Dyskinesias first discovered?

Ironically but unsurprisingly, L-dopa induced dyskinesias were first reported by the same scientists who first reported the drug’s amazing effects in Parkinson’s disease:

Dyskinesia_title

Title: Modification of Parkinsonism – chronic treatment with L-dopa.
Authors: Cotzias GC, Papavasiliou PS, Gellene R.
Journal: New England Journal of Medicine. 1969 Feb 13;280(7):337-45.
PMID: 4178641

George Cotzias was one of the first physicians to give L-dopa to people with Parkinson’s disease.

50396550-1200x800

Dr George Cotzias. Source: NewScientist

Cotzias and colleagues administered L-dopa to 28 people with Parkinson’s disease (17 males and 11 females) and observed modest to moderate response in 8 of them, a marked response in 10, and dramatic responses in the other 10 people. During their two year observation period, they also reported seeing involuntary movements (dyskinesias) in half of the subjects in the study (14/28). They ranged from rare and fleeting (eg. grimacing or gnawing and wave-like motions of the head) to severe (eg. full body/limb movements). They noted that the dyskinesias were most severe in the people with the longest duration of the disease.

It should be noted that the speed with which some of the patients (that Cotzias was treating) developed their dyskinesias – less than 2 years – was a reflection on the late stage of the condition at which the treatment was begun. When the administration of L-dopa is started at an earlier stage, the window of effective treatment is generally longer (5-10 years, depending on individual cases).

So what causes the dyskinesias?

Oh boy.

This question is the source of much debate.

Volumes of text have been bashed out and sides have been taken. We are going to have to tread very carefully here for fear of upsetting folks is the world of Parkinson’s research.

There is some agreement, however, that the factors associated with the development of L-dopa-induced dyskinesias include:

  • the duration of the disease
  • the severity of the disease
  • the dose of L-dopa (cue the debating)
  • young age onset

There are also some genetic forms of Parkinson’s disease that can have an impact on the chances of developing dyskinesias.

Duration/severity of the disease – Experimental studies in animal models of Parkinson’s disease indicate that, if L-dopa is given to the animals, involuntary movements will only develop when the loss of dopamine in the brain exceeds 80–85% of normal. Clinical observations, however, indicate that the severe loss of dopamine in the brain is not sufficient for patients to develop dyskinesias.

This has lead to theories regarding intact part of the brain, suggesting that there are changes in the neurons that the dopamine is acting on. And indeed postmortem analysis of brains from people with & without dyskinesias suggests that there are differences in the neurons that dopamine act on (Click here and here for more on this).

The dose of L-dopa – in a large clinical study, the researchers found that an average daily L-dopa dose of 338 mg was not associated with dyskinesias, while an average daily dose of 387 mg was (Click here and here to read more on this).

Young age onset – Given the length of time that people with early-onset Parkinson’s disease will be on L-dopa, there is a strong association between early-onset and dyskinesias.


EDITORIAL NOTE: We are now about to discuss what can be done to alleviate dyskinesias. Before doing so, we here at the Science of Parkinson’s disease would just like to repeat our standard warning that the contents provided on this website is of an informative nature, and no actions should be taken based on what you have read without first consulting your doctor. Please seek medical advice before changing or experimenting with your treatment regime.


And what can be done to alleviate dyskinesias?

There are several methods of reducing dyskinesias:

Reducing L-dopa dose

Obviously, one can lower the dose of L-dopa. This almost always results in a reduction of dyskinesias. BUT, this almost always results in a worsening of Parkinson’s disease motor features, so it can’t really be considered a solution.

Dopamine receptor agonists

Rather than giving the brain L-dopa or dopamine, chemicals that behave exactly like dopamine can be administered. Dopamine receptor agonists are drugs that act on the receptors of dopamine that are present on the cells that dopamine acts on. These drugs have a longer half‐life than levodopa, meaning that they hang around in the brain for longer (eg. they are not broken down or used up as quickly as L-dopa).

In a large double‐blind study that compared the safety and efficacy of a dopamine receptor agonist – ‘Ropinirole’ – with that of levodopa over a period of five years, researchers found that the incidence of dyskinesia (regardless of levodopa supplementation) was 20% in the ropinirole group and 45% in the levodopa-only group (Click here for more on that study, and click here for a similar study with the dopamine agonist pramipexole).

One cautionary note – Dopamine agonists have been associated with the development of compulsive and impulsive behaviours (Click here for more on this).

Drugs acting on NMDA receptors

N-methyl-D-aspartate receptors (NMDA receptors) are receptors of the chemical glutamate. They are widely found in the brain, but during dyskinesias they appear to become more abundant. As a result, researchers have used drugs that block NMDA receptors (called NMDA receptor antagonists) as potential treatment for dyskinesias. And they appear to help in many cases.

In a double‐blind, placebo‐controlled study of 18 people with Parkinson’s disease, researchers found that the NMDA receptor antagonist ‘Amantidine’ reduced the duration of L-dopa-induced dyskinesias by 60% (Click here for more on this).

Drugs acting on serotonergic systems

Recently there has been a lot of attention focused on the role in dyskinesias of another chemical in the brain: serotonin. There is significant loss of serotonergic cells and fibres in the brain of people with Parkinson’s disease, though not to the same scale as dopamine.

A recent clinical study investigating the use of drugs that prolong the serotonin floating around in the brain (called selective serotonin reuptake inhibitors or SSRIs), found that they did not protect people with Parkinson’s disease from dyskinesias, but may delay their onset (Click here for more on this). There are also clinical trials investigating the use of serotonin receptor agonists in Parkinson’s disease with dyskinesias, based on positive results from preclinical studies (Click here for more on this).

More recently researchers have been investigating the role of serotonin cells in the production of dopamine from L-dopa. Serotonin cells are known to absorb L-dopa and to convert it into dopamine, but they do not have any means of storing it and they release it in an uncontrolled fashion. Recent studies in rodent models of L-dopa-induced dyskinesias have reported reductions in dyskinetic behaviour as a result of lesioning the serotonin cells or blocking specific serotonin receptors. The clinical relevance of these finding is yet to be tested, however.

Neurosurgery

The use of ‘pacemaker’ surgeries (such as deep brain stimulation targeting regions such as the globus pallidum or subthalamic nucleus) have been shown to be effective in treating advanced Parkinson’s disease. The resulting motor improvements are also associated with a reduction in dyskinesias.

A blinded pilot study comparing the safety and efficacy of deep brain stimulation in people with advanced Parkinson’s disease reported a 60-90% reduction in dyskinesias, depending on the region of the brain that was targeted (Click here for more on this).

Surgical lesions targeting the thalamus, globus pallidum or subthalamic nucleus have also been used in the treatment of advanced Parkinson’s disease, with reductions in dyskinesias also being observed. It is effective in both young as well as elderly subjects, with benefit persisting for up to 5 years. These surgical lesion procedures, however, are irreversible.

Recent advances in our understanding

We always like to bring you new research here at the Science of Parkinson’s disease and recently there have been some interesting results published. For example, this one:

Roussakis_title

Title: Serotonin-to-dopamine transporter ratios in Parkinson disease: Relevance for dyskinesias.
Authors: Roussakis AA, Politis M, Towey D, Piccini P.
Journal: Neurology. 2016 Published Feb 26.
PMID: 26920358

The researchers in this study conducted brain imaging on people with Parkinson’s disease who did have dyskinesias (17 people) and did not have dyskinesias (11 people). Specifically they were looking to see the difference in the density of dopamine and serotonin fibres in particular areas of the brain affected by dyskinesias. They found that people with Parkinson’s disease AND dyskinesias had a higher ratio of serotonin fibres to dopamine fibres than people with Parkinson’s disease but no dyskinesias. This result adds further support to the role that serotonin cells are playing in the development of L-dopa-induced dyskinesias.


 

Phew, long post.

If you have got this far and you are still reading – thanks! We hope it was informative.

In (shorter) future posts, we will be assessing new research dealing the mechanisms of and novel ways to treat dyskinesias. This post was meant to be an introduction that we will refer back to from time to time.

Stay tuned!