PARK2 and the big C

May 14, 2017May 15, 2017 ~ Simon ~ 1 Comment

cancer

Recently it has been announced that the Parkinson’s disease-associated gene PARK2 was found to be mutated in 1/3 of all types of tumours analysed in a particular study.

For people with PARK2 associated Parkinson’s disease this news has come as a disturbing shock and we have been contacted by several frightened readers asking for clarification.

In today’s post, we put the new research finding into context and discuss what it means for the people with PARK2-associated Parkinson’s disease.

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The As, the Gs, the Ts, and the Cs. Source: Cavitt

The DNA in almost every cell of your body provides the template for making a human being.

All the necessary information is encoded in that amazing molecule. The basic foundations of that blueprint are the ‘nucleotides’ – which include the familiar A, C, T & Gs – that form pairs (called ‘base pairs’) and which then join together in long strings of DNA that we call ‘chromosomes’.

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The basics of genetics. Source: CompoundChem

If DNA provides the template for making a human being, however, it is the small variations (or ‘mutations’) in our individual DNA that ultimately makes each of us unique. And these variations come in different flavours: some can simply be a single mismatched base pair (also called a point-mutation or single nucleotide variant), while others are more complicated such as repeating copies of multiple base pairs.

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Lots of different types of genetic variations. Source: Nature

Most of the genetic variants that define who we are, we have had since conception, passed down to us from our parents. These are called ‘germ line’ mutations. Other mutations, which we pick up during life and are usually specific to a particular tissue or organ in the body (such as the liver or blood), are called ‘somatic’ mutations.

germlinesomatic1

Somatic vs germ line mutations. Source: AutismScienceFoundation

In the case of germ line mutations, there are several sorts. A variant that has to be provided by both the parents for a condition to develop, is called an ‘autosomal recessive‘ variant; while in other cases only one copy of the variant – provided by just one of the parents – is needed for a condition to appear. This is called an ‘autosomal dominant’ condition.

Auto

Autosomal dominant vs recessive. Source: Wikipedia

Many of these tiny genetic changes infer benefits, while other variants can result in changes that are of a more serious nature.

What does genetics have to do with Parkinson’s disease?

Approximately 15% of people with Parkinson disease have a family history of the condition – a grandfather, an aunt or cousin. For a long time researchers have noted this familial trend and suspected that genetics may play a role in the condition.

About 10-20% of Parkinson’s disease cases can be accounted for by genetic variations that infer a higher risk of developing the condition. In people with ‘juvenile-onset’ (diagnosed under the age 20) or ‘early-onset’ Parkinson’s disease (diagnosed under the age 40), genetic variations can account for the majority of cases, while in later onset cases (>40 years of age) the frequency of genetic variations is more variable.

For a very good review of the genetics of Parkinson’s disease – click here.

There are definitely regions of DNA in which genetic variations can increase one’s risk of developing Parkinson’s disease. These regions are referred to as ‘PARK genes’.

What are PARK genes?

We currently know of 23 regions of DNA that contain mutations associated with increased risk of developing Parkinson’s disease. As a result, these areas of the DNA have been given the name of ‘PARK genes’.

The region does not always refer to a particular gene, for example in the case of our old friend alpha synuclein, there are two PARK gene regions within the stretch of DNA that encodes alpha synuclein – that is to say, two PARK genes within the alpha synuclein gene. So please don’t think of each PARK genes as one particular gene.

There can also be multiple genetic variations within a PARK gene that can increase the risk of developing Parkinson’s disease. The increased risk is not always the result of one particular mutation within a PARK gene region (Note: this is important to remember when considering the research report we will review below).

In addition, some of the mutations within a PARK gene can be associated with increased risk of other conditions in addition to Parkinson’s disease.

And this brings us to the research report that today’s post is focused on.

One of the PARK genes (PARK2) has recently been in the news because it was reported that mutations within PARK2 were found in 2/3 of the cancer tumours analysed in the study.

Here is the research report:

MolCell2

Title: PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation
Authors: Gupta A, Anjomani-Virmouni S, Koundouros N, Dimitriadi M, Choo-Wing R, Valle A, Zheng Y, Chiu YH, Agnihotri S, Zadeh G, Asara JM, Anastasiou D, Arends MJ, Cantley LC, Poulogiannis G
Journal: Molecular Cell, (2017) 65, 6, 999–1013
PMID: 28306514 (This article is OPEN ACCESS if you would like to read it)

The investigators who conducted this study had previously found that mutations in the PARK2 gene could cause cancer in mice (Click here to read that report). To follow up this research, they decided to screen the DNA from a large number of tumours (more than 20,000 individual samples from at least 28 different types of tumours) for mutations within the PARK2 region.

Remarkably, they found that approximately 30% of the samples had PARK2 mutations!

In the case of lung adenocarcinomas, melanomas, bladder, ovarian, and pancreatic, more than 40% of the samples exhibited genetic variations related to PARK2. And other tumour samples had significantly reduced levels of PARK2 RNA. For example, two-thirds of glioma tumours had significantly reduced levels of PARK2 RNA.

Hang on a second, what is PARK2?

PARK2 is a region of DNA that has been associated with Parkinson’s disease. It lies on chromosome 6. You may recall from high school science class that a chromosomes is a section of our DNA, tightly wound up to make storage in cells a lot easier. Humans have 23 pairs of chromosomes.

Several genes fall within the PARK2 region, but most of them are none-protein-coding genes (meaning that they do not give rise to proteins). The PARK2 region does produce a protein, which is called Parkin.

PARK2Fig1

The location of PARK2. Source: Atlasgeneticsoncology

Particular genetic variants within the PARK2 regions result in an autosomal recessive early-onset form of Parkinson disease (diagnosed before 40 years of age). One recent study suggested that as many as half of the people with early-onset Parkinson’s disease have a PARK2 variation.

Click here for a good review of PARK2-related Parkinson’s disease.

Ok, so if PARK2 was about Parkinson’s disease, what is it doing in cancer?

In Parkinson’s disease, Parkin – the protein of PARK2 – is involved with the removal/recycling of rubbish from the cell. But Parkin has also been found to have other functions. Of particular interest is the ability of Parkin to encourage dividing cells to…well, stop dividing. We do not see this function in neurons, because neurons do not divide. In rapidly dividing cells, however, Parkin can apparently stop the cells from dividing:

divide

Title: Parkin induces G2/M cell cycle arrest in TNF-α-treated HeLa cells
Authors: Lee MH, Cho Y, Jung BC, Kim SH, Kang YW, Pan CH, Rhee KJ, Kim YS.
Journal: Biochem Biophys Res Commun. 2015 Aug 14;464(1):63-9.
PMID: 26036576

This discovery made researchers re-designate PARK2 as a ‘tumour suppressor‘ – a gene that encodes a protein which can block the development of tumours. Now, if there is a genetic variant within a tumour suppressor – such as PARK2 – that blocks it from stopping dividing cells, there is the possibility of the cells continuing to divide and developing into a tumour.

Without a properly functioning Parkin protein, rapidly dividing cells may just keep on dividing, encouraging the growth of a tumour.

Interestingly, the reintroduction of Parkin into cancer cells results in the death of those cells – click here to read more on this.

Oh no, I have a PARK2 mutation! Does this mean I am going to get cancer?

No.

Let us be very clear: It does not mean you are ‘going to get cancer’.

And there are two good reasons why not:

Firstly, location, location, location – everything depends on where in the Parkin gene a mutation actually lies. There are 10 common mutations in the Parkin gene that can give rise to early-onset Parkinson’s disease, but only two of these are associated with an increased risk of cancer (they are R24P and R275W – red+black arrow heads in the image below – click here to read more about this).

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Comparing PARK2 Cancer and PD associated mutations. Source: Nature

Parkin (PARK2) is one of the largest genes in humans (of the 24,000 protein encoding genes we have, only 18 are larger than Parkin). And while size does not really matter with regards to genetic mutations and cancer (the actual associated functions of a gene are more critical), given the size of Parkin it isn’t really surprising that it has a high number of trouble making mutations. But only two of the 13 cancer causing mutations are related to Parkinson’s.

Thus it is important to beware of exactly where your mutation is on the gene.

Second, in general, people with Parkinson’s disease actually have a 20-30% decreased risk of cancer (after you exclude melanoma, for which there is an significant increased risk and everyone in the community should be on the lookout for). There are approximately 140 genes that can promote or ‘drive’ tumour formation. But a typical tumour requires mutations in two to more of these “driver gene” for a tumour to actually develop. Thus a Parkin cancer-related mutation alone is very unlikely to cause cancer by itself.

So please relax.

The new research published this week is interesting, but it does not automatically mean people with a PARK2 mutation will get cancer.

What does it all mean?

So, summing up: Small variations in our DNA can play an important role in our risk of developing Parkinson’s disease. Some of those Parkinson’s associated variations can also infer risk of developing other diseases, such as cancer.

Recently new research suggested that genetic variations in a Parkinson’s associated genetic region called PARK2 (or Parkin) are found in many forms of cancer. While the results of this research are very interesting, in isolation this information is not useful except in frightening people with PARK2 associated Parkinson’s disease. Cancers are very complex. The location of a mutation within a gene is important and generally more than cancer-related gene needs to be mutated before a tumour will develop.

The media needs to be more careful with how they disseminate this information from new research reports. People who are aware that they have a particular genetic variation will be sensitive to any new information related to that genetic region. They will only naturally take the news badly if it is not put into proper context.

So to the frightened PARK2 readers who contacted us requesting clarification, firstly: keep calm and carry on. Second, ask your physician about where exactly your PARK2 variation is exactly within the gene. If you require more information from that point on, we’ll be happy to help.

The banner for today’s post was sourced from Ilovegrowingmarijuana

Rotten eggs, Rotorua and Parkinson’s disease

May 13, 2017May 13, 2017 ~ Simon ~ 3 Comments

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Being a proud kiwi, I am happy to highlight and support any research coming out of New Zealand.

Recently a new commentary has been published suggesting that living in the NZ city of Rotorua (‘Roto-Vegas‘ to the locals) may decrease the risk of developing Parkinson’s disease.

In today’s post, we will review the research behind the idea and discuss what it could mean for people with neurodegenerative conditions, like Parkinson’s disease.

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The geothermal wonderlands of Rotorua. Source: Audleytravel

Rotorua is a small city in the central eastern area of the North Island of New Zealand (Aotearoa in the indigenous Māori language).

The name Rotorua comes from the Māori language (‘roto’ meaning lake and rua meaning ‘two’). The full Māori name for the spot is actually Te Rotorua-nui-a-Kahumatamomoe. The early Māori chief and explorer Ihenga named it after his uncle Kahumatamomoe. But given that it was the second major lake found in Aotearoa (after lake Taupo in the centre of the North Island), the name that stuck was Rotorua or ‘Second lake’.

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Maori culture. Source: TamakiMaoriVillage

Similar to lake Taupo, Rotorua is a caldera resulting from an ancient volcanic eruption (approximately 240,000 years ago). The lake that now fills it is about 22 km (14 mi) in diameter.

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Lake Rotorua. Source: Teara

The volcano may have disappeared, but the surrounding region is still full of geothermal activity (bubbling mud pools and geysers), providing the region with abundant renewable power and making the city a very popular tourist destination.

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Tourist playing with mud. Source: Rotoruanz

Before visiting the city, however, travellers should be warned that Rotorua’s other nicknames include “Sulphur City” and “Rotten-rua”, because of the smell that results from the geothermal activity.

And speaking from personal experience, the “rotten eggs” smell is prevalent.

Interesting, but what has this got to do with the science of Parkinson’s disease?

Well, the rotten egg smell is the result of hydrogen sulfide emissions, and recently it has been suggested that this pungent gas may be having positive benefits on people, particularly with regards to Parkinson’s disease.

This idea has been proposed by Dr Yusuf Cakmak at the University of Otago in a recent commentary:

Yusuf

Title: Rotorua, hydrogen sulphide and Parkinson’s disease-A possible beneficial link?
Author: Cakmak Y.
Journal: N Z Med J. 2017 May 12;130(1455):123-125.
PMID: 28494485

In his write up, Dr Cakmak points towards two studies that have been conducted on people from Rotorua. The first focused on examining whether there was any association between asthma and chronic obstructive pulmonary disease and exposure to hydrogen sulfide in Rotorua. By examining air samples and 1,204 participants, the investigators of that study no association (the report of that study is OPEN ACCESS and can be found by clicking here).

The second study is the more interesting of the pair:

roto

Title: Chronic ambient hydrogen sulfide exposure and cognitive function.
Authors: Reed BR, Crane J, Garrett N, Woods DL, Bates MN.
Journal: Neurotoxicol Teratol. 2014 Mar-Apr;42:68-76.
PMID: 24548790 (This article is OPEN ACCESS if you would like to read it)

In this study, the investigators recruited 1,637 adults (aged 18-65 years) from Rotorua. They conducted neuropsychological tests on the subjects, measuring visual and verbal episodic memory, attention, fine motor skills, psychomotor speed and mood. The average amount of time the participants had lived in the Rotorua region was 18 years (ranging from 3-64 years). The researchers also made measurements of hydrogen sulfide levels at the participants homes and work sites.

While the researchers found no association between hydrogen sulfide exposure and cognitive ability, they did notice something interesting in the measures of fine motor skills: individuals exposed to higher levels of hydrogen sulfide displayed faster motor response times on tasks like finger tapping. Finger tapping speed is an important part of Parkinson’s Motor Rating Scale examination tests.

The investigators behind the study concluded that the levels of hydrogen sulfide in Rotorua do not have any detrimental effect on the individuals living in the area,

Dr Cakmak, however, wondered whether “relatively high, but safe, hydrogen sulfide levels in Rotorua could help protect the degradation of dopaminergic neurons associated with Parkinson’s Disease?” (based on the better performance on the motor response time).

Hang on a second, what exactly is hydrogen sulfide?

Hydrogen sulfide (chemical symbol: H2S) is a colourless gas. Its production often results from the the breaking down of organic material in the absence of oxygen, such as in sewers (this process is called anaerobic digestion. It also occurs in volcanic and geothermal conditions.

Hydrogen_sulfide

H2S. Source: Wikipedia

About 15 years ago, it was found in various organs in the body and termed a gasotransmitter. A gasotransmitter is a molecule that can be used to transmit chemical signals from one cell to another, which results in certain physiological reactions (oxygen, for example, is a gasotransmitter).

Hydrogen sulfide is now known to be cardioprotective (protection of the heart), and many years of research have demonstrated beneficial aspects of using it in therapy, such as vasodilation and lowering blood pressure, increasing levels of antioxidants, inhibiting inflammation, and activation of anti-apoptotic (anti-cell death) pathways. For a good review of hydrogen sulfide’s cardioprotective properties – click here.

F1.large

Source: Clinsci

The demonstration of the protective properties of hydrogen sulfide in other bodily organs have led neuroscientists to start investigating whether these same benefits could be utilised in treating disorders of the brain.

And the good news is: hydrogen sulfide can have positive benefits in the brain – Click here for a good review of the brain-related research.

Has other research been conducted on hydrogen sulfide regarding Parkinson’s disease?

Yes. And here is where the story starts to get really interesting.

Initially, there were reports that hydrogen sulfide could protect cells grown in culture from exposure to various neurotoxins (Click here and here for examples).

Then hydrogen sulfide was tested in rodent models of Parkinson’s disease:

SH1

Title: Neuroprotective effects of hydrogen sulfide on Parkinson’s disease rat models.
Authors: Hu LF, Lu M, Tiong CX, Dawe GS, Hu G, Bian JS.
Journal: Aging Cell. 2010 Apr;9(2):135-46.
PMID: 20041858 (This article is OPEN ACCESS if you would like to read it)

In this study, the researchers firstly looked at what happens to hydrogen sulfide in the brains of rodent models of Parkinson’s disease. When rats were injected with a neurotoxin (6-OHDA) that kills dopamine neurons, the investigators found a significant drop in the level of hydrogen sulfide in the region where the dopamine cells reside (called the substantia nigra – an area of the brain severely affected in Parkinson’s disease).

Next the researchers gave some rodents the neurotoxin, waited three weeks and then began administering sodium hydrosulfide – which is a hydrogen sulfide donor – every day for a further 3 weeks. They found that this treatment significantly reduced the dopamine cell loss, motor problems and inflammation in the sodium hydrosulfide treated animals. Interestingly, they saw the same neuroprotective effect when they repeated the study with a different neurotoxin (Rotenone). The investigators concluded that hydrogen sulfide “has potential therapeutic value for treatment of Parkinson’s disease”.

And this first study was followed up one year later by a study investigating inhaled hydrogen sulfide:

SH2
Title: Inhaled hydrogen sulfide prevents neurodegeneration and movement disorder in a mouse model of Parkinson’s disease.
Authors: Kida K, Yamada M, Tokuda K, Marutani E, Kakinohana M, Kaneki M, Ichinose F.
Journal: Antioxid Redox Signal. 2011 Jul 15;15(2):343-52.
PMID: 21050138 (This article is OPEN ACCESS if you would like to read it)

In this study, the investigators gave mice a neurotoxin (MPTP) and then had them breathe air with or without hydrogen sulfide (40 ppm) for 8 hours per day for one week. The mice that inhaled hydrogen sulfide displayed near normal levels of motor behaviour performance and significantly reduced levels of neurodegeneration (dopamine cell loss).

Inhalation of hydrogen sulfide also prevented the MPTP-induced activation of the brain’s helper cells (microglia and astrocytes) and increased levels of detoxification enzymes and antioxidant proteins (including heme oxygenase-1 and glutamate-cysteine ligase). Curiously, hydrogen sulfide inhalation did not significantly affect levels of reduced glutathione (we will come back to this in an upcoming post).

These first two preclinical results have been replicated many times now confirming the initial findings (Click here, here, here and here for examples). The researchers of the second ‘inhalation’ study concluded the study by suggesting that the potential therapeutic effects of hydrogen sulfide inhalation now needed to be examined in more disease relevant models of Parkinson’s disease.

And this is exactly what researchers did next:

HS5

Title: Sulfhydration mediates neuroprotective actions of parkin.
Authors: Vandiver MS, Paul BD, Xu R, Karuppagounder S, Rao F, Snowman AM, Ko HS, Lee YI, Dawson VL, Dawson TM, Sen N, Snyder SH.
Journal: Nat Commun. 2013;4:1626. doi: 10.1038/ncomms2623.
PMID: 23535647 (This article is OPEN ACCESS if you would like to read it)

The researchers conducting this study were interested in the interaction of hydrogen sulfide with the Parkinson’s disease-associated protein Parkin (also known as PARK2). They found that hydrogen sulfide actively modified parkin protein – a process called sulfhydration – and that this enhances the protein’s level of activity.

They also noted that the level of Parkin sulfhydration in the brains of patients with Parkinson’s disease is markedly reduced (a 60% reduction). These finding imply that drugs that increase levels of hydrogen sulfide in the brain may be therapeutic.

Interestingly, cells with genetic mutations in another Parkinson’s disease related gene, DJ-1, also produce less hydrogen sulfide (click here to read more about this).

Has anyone ever looked at hydrogen sulfide and alpha synuclein?

Not that we are aware of.

Alpha synuclein is the Parkinson’s disease associated protein that clusters in the Parkinsonian brain and forms Lewy bodies.

But researchers have looked at hydrogen sulfide and amyloid formation:

HS4
Title: Hydrogen sulfide inhibits amyloid formation
Authors: Rosario-Alomar MF, Quiñones-Ruiz T, Kurouski D, Sereda V, Ferreira EB, Jesús-Kim LD, Hernández-Rivera S, Zagorevski DV, López-Garriga J, Lednev IK.
Journal: J Phys Chem B. 2015 Jan 29;119(4):1265-74.
PMID: 25545790 (This article is OPEN ACCESS if you would like to read it)

Amyloid formations are large clusters of misfolded proteins that are associated with neurodegenerative conditions, like Alzheimer’s disease and Parkinson’s disease. The researchers who conducted this study were interested in the behaviour of these misfolded protein in the presence of hydrogen sulfide. What they found was rather remarkable: the addition of hydrogen sulfide completely inhibited the formation amyloid fibrils (amyloid fibril plaques are found in brains of people with Alzheimer’s disease).

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Source: NCBI

If the addition of hydrogen sulfide can reduce the level of clustered proteins in a model of Alzheimer’s disease, it would be interesting to see what it would do to alpha synuclein.

NOTE: Hydrogen sulfide levels are also reduced in the brains of people with Alzheimer’s disease (click here to read more on this topic)

Has hydrogen sulfide ever been tested in the clinic?

There are currently 17 clinical trials investigating hydrogen sulfide in various conditions (not Parkinson’s disease though).

So where can I get me some of that hydrogen sulfide?

Ok, so here is where we come in with the health warning section.

You see, hydrogen sulfide is a very dangerous gas. It is really not to be played with.

Blakely_June_Hydrogen-Sulfide

Source: Blakely

The gas is both corrosive and flammable. More importantly, at high concentrations, hydrogen sulfide gas can be fatal almost immediately (>1000 parts per milllion – source: OSHA). And the gas only exhibits the “rotten eggs” smell at low concentrations. At higher concentrations it becomes undetectable due to olfactory paralysis (luckily for the folks in Rotorua, the levels of hydrogen sulfide gas there are between 20-25 parts per billion).

Thus, we do not recommend readers to rush out and load up on hydrogen sulfide gas.

There are many foods that contain hydrogen sulfide.

For example, garlic is very rich in hydrogen sulfide. Another rich source is cooked beef, which has about 0.6mg of hydrogen sulfide per pound – cooked lamb has closer to 0.9 milligrams per pound. Heated dairy products, such as skim milk, can have approximately 3 milligrams of hydrogen sulfide per gallon, and cream has slightly more than double that amount.

Any significant change in diet by a person with Parkinson’s disease should firstly be discussed with a trained medical physician as we can not be sure what impact such a change would have on individualised treatment regimes.

What does it all mean?

Summing up: It would be interesting to look at the frequency of Parkinson’s disease in geothermal region of the world (the population of Rotorua is too small for such an analysis – 80,000 people).

Researchers believe that components of the gas emissions from these geothermal areas may be neuroprotective. Of particular interest is the gas hydrogen sulfide. At high levels, it is a very dangerous gas. At lower levels, however, researchers have shown that hydrogen sulfide has many beneficial properties, including in models of neurodegenerative conditions. These findings have led many to propose testing hydrogen sulfide in clinical trials for conditions like Parkinson’s disease.

Dr Cakmak, who we mentioned near the top of this post, goes one step further. He hypothesises that hydrogen sulfide may actually be one of the active components in the neuroprotective affect of both coffee and smoking – and with good reason. It was recently demonstrated that the certain gut bacteria, such as Prevotella, are decreased in people with Parkinson’s disease (see our post on this topic by clicking here). The consumption of coffee has been shown to help improve the Prevotella population in the gut, which may in term increase the levels of Prevotella-derived hydrogen sulfide. Similarly smokers have a decreased risk of developing Parkinson’s disease and hydrogen sulfide is a component of cigarette smoke.

All of these ideas still needs to be further tested, but we are curious to see where this research could lead. An inhaled neuroprotective treatment for Parkinson’s disease may have benefits for other neurodegenerative conditions.

Oh, and if anyone is interested, we are happy to put readers in contact with real estate agents in sunny ‘Rotten-rua’, New Zealand. The locals say that you gradually get used to the smell.

EDITOR’S NOTE: Under absolutely no circumstances should anyone reading this material consider it medical advice. The material provided here is for educational purposes only. Before considering or attempting any change in your treatment regime, PLEASE consult with your doctor or neurologist. While some of the drugs/molecules discussed on this website are clinically available, they may have serious side effects. We therefore urge caution and professional consultation before any attempt to alter a treatment regime. SoPD can not be held responsible for any actions taken based on the information provided here.

The banner for today’s post was sourced from Trover

New drug approved for ALS

May 7, 2017May 7, 2017 ~ Simon ~ 5 Comments

ice-bucket-challenge

The Federal Drug Administration (FDA) in the USA has approved the first drug in 22 years for treating the neurodegenerative condition of Amyotrophic lateral sclerosis (ALS).

The drug is called Edaravone, and it is only the second drug approved for ALS.

In today’s post we’ll discuss what this announcement could mean for Parkinson’s disease.

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Lou Gehrig. Source: NBC

In 1969, Henry Louis “Lou” Gehrig was voted the greatest first baseman of all time by the Baseball Writers’ Association. He played 17 seasons with the New York Yankees, having signed with his hometown team in 1923.

For 56 years, he held the record for the most consecutive games played (2,130), and he was only prevented from continuing that streak when he voluntarily took himself out of the team lineup on the 2nd May, 1939, after his ability to play became hampered by the disease that now often bears his name. A little more than a month later he retired, and a little less than two years later he passed away.

Amyotrophic lateral sclerosis (or ALS), also known as Lou Gehrig’s disease and motor neuron disease, is a neurodegenerative condition in which the neurons that control voluntary muscle movement die. The condition affects 2 people in every 100,000 each year, and those individuals have an average survival time of two to four years.

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ALS in a nutshell. Source: Walkforals

In addition to Lou Gehrig, you may have heard of ALS via the ‘Ice bucket challenge‘ (see image in the banner of this post). In August 2014, an online video challenge went viral.

By July 2015, the ice bucket campaign had raised an amazing $115 million for the ALS Association.

Another reason you may have heard of ALS is that theoretical physicist, Prof Stephen Hawking also has the condition:

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Source: BBC

He was diagnosed with in a very rare early-onset, slow-progressing form of ALS in 1963 (at age 21) that has gradually left him wheel chair bound.

This is very interesting, but what does it have to do with Parkinson’s disease?

Individuals affected by ALS are generally treated with a drug called Riluzole (brand names Rilutek or Teglutik). Approved in December of 1995 by the FDA, this drug increases survival by approximately two to three months.

Until this last week, Riluzole was the only drug approved for the treatment of ALS.

So what happened this week?

On the 5th May, the FDA announced that they had approved a second drug for the treatment of ALS (Click here for the press release).

It is called Edaravone.

What is Edaravone?

Edaravone is a free radical scavenger – a potent antioxidant – that is marketed as a neurovascular protective agent in Japan by Mitsubishi Tanabe Pharma Corporation.

An antioxidant is simply a molecule that prevents the oxidation of other molecules.

Molecules in your body often go through a process called oxidation – losing an electron and becoming unstable. This chemical reaction leads to the production of what we call free radicals, which can then go on to damage cells.

What is a free radical?

A free radical is simply an unstable molecule – unstable because they are missing electrons. They react quickly with other molecules, trying to capture the needed electron to re-gain stability. Free radicals will literally attack the nearest stable molecule, stealing an electron. This leads to the “attacked” molecule becoming a free radical itself, and thus a chain reaction is started. Inside a living cell this can cause terrible damage, ultimately killing the cell.

Antioxidants are thus the good guys in this situation. They are molecules that neutralize free radicals by donating one of their own electrons. The antioxidant don’t become free radicals by donating an electron because by their very nature they are stable with or without that extra electron.

Thus when we say ‘Edaravone is a free radical scavenger’, we mean it’s really good at scavenging all those unstable molecules and stabilising them.

It is an intravenous drug (injected into the body via a vein) and administrated for 14 days followed by 14 days drug holiday.

So, again what has this got to do with Parkinson’s disease?

Well, it is easier to start a clinical trial of a drug if it is already approved for another disease.

And the good news is: Edaravone has been shown to be neuroprotective in several models of Parkinson’s disease.

In this post, we’ll lay out some of the previous research and try to make an argument justifying the clinical testing of Edaravone in Parkinson’s disease

Ok, so what research has been done so far in models of Parkinson’s disease?

The first study to show neuroprotection in a model of Parkinson’s disease was published in 2008:

2008-1

Title: Role of reactive nitrogen and reactive oxygen species against MPTP neurotoxicity in mice.
Authors: Yokoyama H, Takagi S, Watanabe Y, Kato H, Araki T.
Journal: J Neural Transm (Vienna). 2008 Jun;115(6):831-42.
PMID: 18235988

In this first study, the investigators assessed the neuroprotective properties of several drugs in a mouse model of Parkinson’s disease. The drugs included Edaravone (described above), minocycline (antibiotic discussed in a previous post), 7-nitroindazole (neuronal nitric oxide synthase inhibitor), fluvastatin and pitavastatin (both members of the statin drug class).

With regards to Edaravone, the news was not great: the investigators found that Edaravone (up to 30mg/kg) treatment 30 minutes before administering a neurotoxin (MPTP) and then again 90 minutes afterwards had no effect on the survival of the dopamine neurons (compared to a control treatment).

Not a good start for making a case for clinical trials!

This research report, however, was quickly followed by another from an independent group in Japan:

BMC

Title: Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons.
Authors: Yuan WJ, Yasuhara T, Shingo T, Muraoka K, Agari T, Kameda M, Uozumi T, Tajiri N, Morimoto T, Jing M, Baba T, Wang F, Leung H, Matsui T, Miyoshi Y, Date I.
Journal: BMC Neurosci. 2008 Aug 1;9:75.
PMID: 18671880 (This article is OPEN ACCESS if you would like to read it)

These researchers did find a neuroprotective effect using Edaravone (both in cell culture and in a rodent model of Parkinson’s disease), but they used a much higher dose than the previous study (up to 250 mg/kg in this study). This increase in dose resulted in a graded increase in neuroprotection – interestingly, these researchers also found that 30mg/kg of Edaravone had limited neuroprotective effects, while 250mg/kg exhibited robust dopamine cell survival and rescued the behavioural/motor features of the model even when given 24 hours after the neurotoxin.

The investigators concluded that “Edaravone might be a hopeful therapeutic option for PD, although several critical issues remain to be solved, including high therapeutic dosage of Edaravone for the safe clinical application in the future”

This results was followed by several additional studies investigating edaravone in models of Parkinson’s disease (Click here, here and here to read more on this). Of particular interest in all of those follow up studies was a report in which Edaravone treatment resulted in neuroprotective in genetic model of Parkinson’s disease:

2013-1

Title: Edaravone prevents neurotoxicity of mutant L166P DJ-1 in Parkinson’s disease.
Authors: Li B, Yu D, Xu Z.
Journal: J Mol Neurosci. 2013 Oct;51(2):539-49.
PMID: 23657982

DJ-1 is a gene that has been associated Parkinson’s disease since 2003. The gene is sometimes referred to as PARK7 (there are now more than 20 Parkinson’s associated genomic regions, which each have a number and are referred to as the PARK genes). Genetic mutations in the DJ-1 gene can result in an autosomal recessive (meaning two copies of the mutated gene are required), early-onset form of Parkinson disease. For a very good review of DJ-1 in the context of Parkinson’s disease, please click here.

The exact function of DJ-1 is not well understood, though it does appear to play a role in helping cells deal with ‘oxidative stress’ – the over-production of those free radicals we were talking about above. Now given that edaravone is a potent antioxidant (reversing the effects of oxidative stress), the researchers conducting this study decided to test Edaravone in cells with genetic mutations in the DJ-1 gene.

Their results indicated that Edaravone was able to significantly reduce oxidative stress in the cells and improve the functioning of the mitochondria – the power stations in each cell, where cells derive their energy. Furthermore, Edaravone was found to reduce the amount of cell death in the DJ-1 mutant cells.

More recently, researchers have begun digging deeper into the mechanisms involved in the neuroprotective effects of Edaravone:

2015-1

Title: Edaravone leads to proteome changes indicative of neuronal cell protection in response to oxidative stress.
Authors: Jami MS, Salehi-Najafabadi Z, Ahmadinejad F, Hoedt E, Chaleshtori MH, Ghatrehsamani M, Neubert TA, Larsen JP, Møller SG.
Journal: Neurochem Int. 2015 Nov;90:134-41.
PMID: 26232623 (This article is OPEN ACCESS if you would like to read it)

The investigators who conducted this report began by performing a comparative two-dimensional gel electrophoresis analyses of cells exposed to oxidative stress with and without treatment of Edaravone.

Um, what is “comparative two-dimensional gel electrophoresis analyses”?

Good question.

Two-dimensional gel electrophoresis analyses allows researchers to determine particular proteins within a given solution. Mixtures of proteins are injected into a slab of gel and they are then separated according to two properties (mass and acidity) across two dimensions (left-right side of the gel and top-bottom of the gel).

A two-dimensional gel electrophoresis result may look something like this:

4000716f1

Two-dimensional gel electrophoresis. Source: Nature

As you can see, individual proteins have been pointed out on the image of this slab of gel.

In comparative two-dimensional gel electrophoresis, two samples of solution are analysed by comparing two slabs of gel that have been injected with protein mix solution from two groups of cells treated exactly the same except for one variable. Each solution gets its own slab of gel, and the differences between the gel product will highlight which proteins are present in one condition versus the other (based on the variable being tested).

In this experiment, the variable was Edaravone.

And when the researchers compared the proteins of Edaravone treated cells with those of cells not treated with Edaravone, they found that the neuroprotective effect of Edaravone was being caused by an increase in a protein called Peroxiredoxin-2.

Now this was a really interesting finding.

You see, Peroxiredoxin proteins are a family (there are 6 members) of antioxidant enzymes. And of particular interest with regards to Parkinson’s disease is the close relationship between DJ-1 (the Parkinson’s associated protein discussed above) and peroxiredoxin proteins (Click here, here, here and here to read more about this).

In addition, there are also 169 research reports dealing with the peroxiredoxin proteins and Parkinson’s disease (Click here to see a list of those reports).

So, what do you think about a clinical trial for Edaravone in Parkinson’s disease?

Are you convinced?

Regardless, it an interesting drug huh?

Are there any downsides to the drug?

One slight issue with the drug is that it is injected via a vein. Alternative systems of delivery, however, are being explored.A biotech company in the Netherlands, called Treeway is developing an oral formulation of edaravone (called TW001) and is currently in clinical development.

Edaravone was first approved for clinical use in Japan on May 23, 2001. With almost 17 years of Edaravone clinical use, a few adverse events including acute renal failure have been noted, thus precautions should be taken with individuals who have a history of renal problems. The most common side effects associated with the drug, however, are: fatigue, nausea, and some mild anxiety.

Click here for a good overview of the clinical history of Edaravone.

So what does it all mean?

The announcement from the FDA this week regarding the approval of Edaravone as a new treatment for ALS represents a small victory for the ALS community, but it may also have a significant impact on other neurodegenerative conditions, such as Parkinson’s disease.

Edaravone is a potent antioxidant agent, which has been shown to have neuroprotective effects in various models of Parkinson’s disease and other neurodegenerative conditions. It could be interesting to now test the drug clinically for Parkinson’s disease. Many of the preclinical research reports indicate that the earlier Edaravone treatment starts, the better the outcomes, so any initial clinical trials should focus on recently diagnosed subjects (perhaps even those with DJ-1 mutations).

The take home message of this post is: given that Edaravone has now been approved for clinical use by the FDA, it may be advantageous for the Parkinson’s community to have a good look at whether this drug could be repurposed for Parkinson’s disease.

It’s just a thought.

The banner for today’s post was sourced from Forbes

The Antibiotic and Parkinson’s: Oppsy, they got doxy!

May 5, 2017May 6, 2017 ~ Simon ~ 10 Comments

maxresdefault

The general population are wrong to look up to scientists as the holders of the keys to some kind of secret knowledge that allows them to render magic on a semi-irregular basis.

All too often, the great discoveries are made by accident.

A while back, some researchers from Germany and Brazil made an interesting discovery that could have important implications for Parkinson’s disease. But they only made this discovery because their mice were feed the wrong food.

Today we’ll review their research and discuss what it could mean for Parkinson’s disease.

image-title1

Sir Alexander Fleming. Source: Biography

Sir Alexander Fleming is credited with discovering the antibiotic properties of penicillin.

But, as it is often pointed out, that the discovery was a purely chance event – an accident, if you like.

After returning from a two week holiday, Sir Fleming noticed that many of his culture dishes were contaminated with fungus, because he had not stored them properly before leaving. One mould in particular caught his attention, however, as it was growing on a culture plate with the bacteria staphylococcus. Upon closer examination, Fleming noticed that the contaminating fungus prevented the growth of staphylococci.

In an article that Fleming subsequently published in the British Journal of Experimental Pathology in 1929, he wrote, “The staphylococcus colonies became transparent and were obviously undergoing lysis … the broth in which the mould had been grown at room temperature for one to two weeks had acquired marked inhibitory, bactericidal and bacteriolytic properties to many of the more common pathogenic bacteria.”

photograph_from_1929_paper_by_fleming

Penicillin in a culture dish of staphylococci. Source: NCBI

Fleming isolated the organism responsible for prohibiting the growth of the staphylococcus, and identified it as being from the penicillium genus.

He named it penicillin and the rest is history.

Fleming himself appreciated the serendipity of the finding:

“When I woke up just after dawn on Sept. 28, 1928, I certainly didn’t plan to revolutionise all medicine by discovering the world’s first antibiotic, or bacteria killer. But I guess that was exactly what I did.” (Source)

And this gave rise to his famous quote:

“One sometimes finds what one is not looking for” (Source)

While Fleming’s discovery of the antibiotic properties of penicillin was made as he was working on a completely different research problem, the important thing to note is that the discovery was made because the evidence came to a prepared mind.

Louis-Pasteur-Quotes-1

Pasteur knew the importance of a prepared mind. Source: Thequotes

And this is the purpose of all the training in scientific research – not acquiring ‘the keys to some secret knowledge’, but preparing the investigator to notice the curious deviation.

That’s all really interesting. But what does any of this have to do with Parkinson’s disease?

Three things:

Serendipity
Prepared minds
Antibiotics.

Huh?

Five years ago, a group of Brazilian and German Parkinson’s disease researchers made a serendipitous discovery:

While modelling Parkinson’s disease in some mice, they noticed that only two of the 40 mice that were given a neurotoxic chemical (6-OHDA) developed the motor features of Parkinson’s disease, while the rest remained healthy. This result left them scratching their heads and trying to determine what had gone wrong.

Then it clicked:

“A lab technician realised the mice had mistakenly been fed chow containing doxycycline, so we decided to investigate the hypothesis that it might have protected the neurons.” (from the press release).

The researchers had noted the ‘curious deviation’ and decided to investigate it further.

They repeated the experiment, but this time they added another group of animals which were given doxycycline in low doses (via injection) and fed on normal food (not containing the doxycycline).

And guess what: both group demonstrated neuroprotection!

Hang on a second. Two questions: 1. What exactly is 6-OHDA?
6-hydroxydopamine (or 6-OHDA) is one of several chemicals that researchers use to cause dopamine cells to die in an effort to model the cell death seen in Parkinson’s disease. It shares many structural similarities with the chemical dopamine (which is so severely affected in the Parkinson’s disease brain), and as such it is readily absorbed by dopamine cells who unwittingly assume that they are re-absorbing excess dopamine.

Once inside the cell, 6-OHDA rapidly transforms (via oxidisation) into hydrogen peroxide (H2O2 – the stuff folk bleach their hair with) and para-quinone (AKA 1,4-Benzoquinone). Neither of which the dopamine neurons like very much. Hydrogen peroxide in particular quickly causes massive levels of ‘oxidative stress’, resulting in the cell dying.
6OHDA

Transformation of the neurotoxin 6-OHDA. Source: NCBI

Think of 6-OHDA as a trojan horse, being absorbed by the cell because it looks like dopamine, only for the cell to work out (too late) that it’s not.

Ok, and question 2. What is doxycycline?

Doxycycline is an antibiotic that is used in the treatment of a number of types of infections caused by bacteria.

doxycycline100-1-1k_1

Remind me again, what is an antibiotic?

Antibiotics are a class of drugs that either kill or inhibit the growth of bacteria. They function in one of several ways, either blocking the production of bacterial proteins, inhibiting the replication of bacterial DNA (nuclei acid in the image below), or by rupturing/inhibiting the repair of the bacteria’s outer membrane/wall.

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The ways antibiotics function. Source: FastBleep

So the researchers accidentally discovered that the a bacteria-killing drug called doxycycline prevented a trojan horse called 6-OHDA from killing dopamine cells?

Basically, yeah.

And then these prepared minds followed up this serendipitous discovery with a series of experiments to investigate the phenomenon further, and they published the results recently in the journal ‘Glial’:

Glial

Title: Doxycycline restrains glia and confers neuroprotection in a 6-OHDA Parkinson model.
Authors: Lazzarini M, Martin S, Mitkovski M, Vozari RR, Stühmer W, Bel ED.
Journal: Glia. 2013 Jul;61(7):1084-100. doi: 10.1002/glia.22496. Epub 2013 Apr 17.
PMID: 23595698

In the report of their research, the investigators noted that doxycycline significantly protected the dopamine neurons and their nerve branches (called axons) in the striatum – an area of the brain where dopamine is released – when 6-OHDA was given to mice. Both oral administration and peripheral injections of doxycycline were able to have this effect.

They also reported that doxycycline inhibited the activation of astrocytes and microglial cells in the brains of the 6-OHDA treated mice. Astrocytes and microglial cells are usually the helper cells in the brain, but in the context of disease or injury these cells can quickly take on the role of judge and executioner – no longer supporting the neurons, but encouraging them to die. The researchers found that doxycycline reduced the activity of the astrocytes and microglial cells in this alternative role, allowing the dopamine cells to recuperate and survive.

The researchers concluded that the “neuroprotective effect of doxycycline may be useful in preventing or slowing the progression of Parkinson’s disease”.

Wow, was this the first time this neuroprotective effect of doxycycline has been observed?

Curiously, No.

We have known of doxycycline’s neuroprotective effects in different models of brain injury since the 1990s (Click here, here and here for more on this). In fact, in their research report, the German and Brazilian researchers kindly presented a table of all the previous neuroprotective research involving doxycycline:

table1

And there was so much of it that the table carried on to a second page:

Table2

Source: Glia

And as you can see from the table, the majority of these reports found that doxycycline treatment had positive neuroprotective effects.

Is doxycycline the only antibiotic that exhibits neuroprotective properties?

No.

Doxycycline belongs to a family of antibiotics called ‘tetracyclines‘ (named for their four (“tetra-“) hydrocarbon rings (“-cycl-“) derivation (“-ine”)), and other members of this family have also been shown to display neuroprotection in models of Parkinson’s disease:

MPTP

Title: Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model ofParkinson’s disease.
Authors: Du Y, Ma Z, Lin S, Dodel RC, Gao F, Bales KR, Triarhou LC, Chernet E, Perry KW, Nelson DL, Luecke S, Phebus LA, Bymaster FP, Paul SM.
Journal: Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14669-74.
PMID: 11724929 (This article is OPEN ACCESS if you would like to read it)

In this study, the researchers treated mice with an antibiotic called minocycline and it protected dopamine cells from the damaging effects of a toxic chemical called MPTP (or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). MPTP is also used in models of Parkinson’s disease, as it specifically affects the dopamine cells, while leaving other cells unaffected.

The researchers found that the neuroprotective effect of minocycline is associated a reduction in the activity of proteins that initiate cell death (for example, Caspace 1). This left the investigators concluding that ‘tetracyclines may be effective in preventing or slowing the progression of Parkinson’s disease’.

Importantly, this result was quickly followed by two other research papers with very similar results (Click here and here to read more about this). Thus, it would appear that some members of the tetracycline class of antibiotics share some neuroprotective properties.

So what did the Brazilian and German researchers do next with doxycycline?

They continued to investigate the neuroprotective effect of doxycycline in different models of Parkinson’s disease. They also got some Argentinians and Frenchies involved in the studies. And these lines of research led to their recent research report in the journal Scientific Reports:

Doxy1
Title: Repurposing doxycycline for synucleinopathies: remodelling of α-synuclein oligomers towards non-toxic parallel beta-sheet structured species.
Authors: González-Lizárraga F, Socías SB, Ávila CL, Torres-Bugeau CM, Barbosa LR, Binolfi A, Sepúlveda-Díaz JE, Del-Bel E, Fernandez CO, Papy-Garcia D, Itri R, Raisman-Vozari R, Chehín RN.
Journal: Sci Rep. 2017 Feb 3;7:41755.
PMID: 28155912 (This article is OPEN ACCESS if you would like to read it)

In this study, the researchers wanted to test doxycycline in a more disease-relevant model of Parkinson’s disease. 6-OHDA is great for screening and testing neuroprotective drugs. But given that 6-OHDA is not involved with the underlying pathology of Parkinson’s disease, it does not provide a great measure of how well a drug will do against the disease itself. So, the researchers turned their attention to our old friend, alpha synuclein – the protein which forms the clusters of protein (called Lewy bodies) in the Parkinsonian brain.

What the researchers found was fascinating: Doxycycline was able to inhibit the disease related clustering of alpha synuclein. In fact, by reshaping alpha synuclein into a less toxic version of the protein, doxycycline was able to enhance cell survival. The investigators also conducted a ‘dosing’ experiment to determine the most effect dose and they found that taking doxycycline in sub-antibiotic doses (20–40 mg/day) would be enough to exert neuroprotection. They concluded their study by suggesting that these novel effects of doxycycline could be exploited in Parkinson’s disease by “repurposing an old safe drug”.

Wow, has doxycycline ever been used in clinical trials for brain-related conditions before?

Yes.

From 2005-12,there was a clinical study to determine the safety and efficacy of doxycycline (in combination with Interferon-B-1a) in treating Multiple Sclerosis (Click here for more on this trial). The results of that study were positive and can be found here.

More importantly, the other antibiotic to demonstrate neuroprotection in models of Parkinson’s disease, minocycline (which we mentioned above), has been clinically tested in Parkinson’s disease:

title1

Title: A pilot clinical trial of creatine and minocycline in early Parkinson disease: 18-month results.
Authors: NINDS NET-PD Investigators..
Journal: Clin Neuropharmacol. 2008 May-Jun;31(3):141-50.
PMID: 18520981 (This article is OPEN ACCESS if you would like to read it)

This research report was the follow up of a 12 month clinical study that can be found by clicking here. The researchers had taken two hundred subjects with Parkinson’s disease and randomly sorted them into the three groups: creatine (an over-the-counter nutritional supplement), minocycline, and placebo (control). All of the participants were diagnosed less than 5 years before the start of the study. At 12 months, both creatine and minocycline were noted as not interfering with the beneficial effects of symptomatic therapy (such as L-dopa), but a worrying trend began with subjects dropping out of the minocycline arm of the study.

At the 18 month time point, approximately 61% creatine-treated subjects had begun to take additional treatments (such as L-dopa) for their symptoms, compared with 62% of the minocycline-treated subjects and 60% placebo-treated subjects. This result suggested that there was no beneficial effect from using either creatine or minocycline in the treatment of Parkinson’s disease, as neither exhibited any greater effect than the placebo. In addition, the investigators suggested that the decreased tolerability of minocycline was a concern.

Ok, so where do I sign up for the next doxy clinical trial?

Well, the researchers behind the Scientific reports research (discussed above) are hoping to begin planning clinical trials soon.

But theoretically speaking, there shouldn’t be a trial.

Huh?!?

There’s a good reason why not.

In fact, if you look at the comments section under the research article, a cautionary message has been left by Prof Paul M. Tulkens of the Louvain Drug Research Institute in Belgium. He points out that:

“…using antibiotics at sub-therapeutic doses is the best way to trigger the emergence of resistance (supported by many in vitro and in vivo studies). Using an antibiotic for other indications than an infection caused by a susceptible bacteria is something that should be discouraged”

And he is correct.

We recklessly over use antibiotics all over the world at the moment and they are one of the few lines of defence that we have against the bacterial world. Long term use (which Parkinson’s disease would probably require) of an antibiotic at sub-therapeutic levels will only encourage the rise of antibiotic resistant bacteria (possibly within individuals).

The resistance of bacteria to antibiotics can occur spontaneously via several means (for example, through random genetic mutations during cell division). With the right mutation (inferring antibiotic resistance), an individual bacteria would then have a natural advantage over their friends and it would survive our attempts to kill it with antibiotics. Being resistant to antibiotic would leave that bacteria to wreak havoc upon us.

Its the purest form of natural selection.

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How bacteria become resistant to antibiotics. Source: Reactgroup

And antibiotic resistant bacteria are fast becoming a major health issue for us, with the number of species of bacteria developing resistance increasing every year (Click here for a good review on factors contributing to the emergence of resistance, and click here for a review of the antibiotic resistant bacteria ‘crisis’).

But don’t be upset on the Parkinson’s disease side of things. Prof Tulken adds that:

“If doxycycline really acts as the authors propose, the molecular targets are probably very different from those causing antibacterial activity. it should therefore be possible to dissociate these effect from the antibacterial effects and to get active compounds devoid of antibacterial activity This is where research must go to rather than in trying to use doxycycline itself.”

And he is correct again.

Rather than tempting disaster, we need to take the more prudent approach.

Independent researchers must now attempt to replicate the neuroprotective results in carefully controlled conditions. At the same time, chemists should conduct an analysis of the structure of doxycycline to determine which parts of it are having this neuroprotective effect.

The structure of doxycycline. Source: Wikipedia

If researchers can isolate those neuroprotective elements and those same parts are separate from the antibiotic properties, then we may well have another experimental drug for treating Parkinson’s disease.

And the good news is that researchers are already reasonably sure that the mechanisms of the neuroprotective effect of doxycycline are distinct from its antimicrobial action.

So what does it all mean?

Researchers have once again identified an old drug that can perform a new trick.

The bacteria killing antibiotic, doxycycline, has a long history of providing neuroprotection in models of brain disease, but recently researchers have demonstrated that doxycycline may have beneficial effects on particular aspects of Parkinson’s disease.

Given that doxycycline is an antibiotic, we must be cautious in our use of it. It will be interesting to determine which components of doxycycline are neuroprotective, and whether other antibiotics share these components. Given the number of researchers now working in this area, it should not take too long.

We’ll let you know when we hear something.

EDITOR’S NOTE: Under absolutely no circumstances should anyone reading this material consider it medical advice. The material provided here is for educational purposes only. Before considering or attempting any change in your treatment regime, PLEASE consult with your doctor or neurologist. While some of the drugs discussed on this website are clinically available, they may have serious side effects. We therefore urge caution and professional consultation before any attempt to alter a treatment regime. SoPD can not be held responsible for any actions taken based on the information provided here.

The banner for today’s post was sourced from Youtube

Trying to digest gut research

May 3, 2017 ~ Simon ~ 7 Comments

Our first ever posting here on the SoPD dealt with the curious relationship between the gut and Parkinson’s disease (Click here to see that post). Since then, there have been a string of interesting research reports adding to the idea that the gastrointestinal system may be somehow influencing the course of Parkinson’s disease.

In today’s post we will review the most recent helpings and discuss how they affect our understanding of Parkinson’s disease.

Source: Qz

Interesting fact: The human digestive system is about 26 feet long – approximately 8 meters – from mouth to anus.

Recent research indicates that our brains are heavily influenced by the activities of this food consuming tract. Not just the nutrients that it takes in, but also by the bugs that live within those 26 feet.

Another interesting fact: The human gut hosts tens of trillions of microorganisms, including at least 1000 species of bacteria (which is a guess-timate as we are not really sure how many species there are). They make up as much as 2 kg of your total weight.

And those bacteria have influence!

In December of last year, we reviewed a study in which the researchers demonstrated that mice genetically engineered to display features of Parkinson’s disease performed as well as normal mice if they were raised with reduced levels of bacteria in their gut (either in a germ-free environment or using antibiotics). That study also showed that transplanting bacteria from the gut of people with Parkinson’s disease into mice raised in a germ-free environment resulted in those mice performing worse on the behavioural tasks than mice injected with gut samples from healthy human subjects (Click here to read that post).

Wow, so what new gut research has been reported?

A little bit of history first:

Two years ago, some Danish researchers published this research report:

Gut3

Title: Vagotomy and Subsequent Risk of Parkinson’s Disease.
Authors: Svensson E, Horváth-Puhó E, Thomsen RW, Djurhuus JC, Pedersen L, Borghammer P, Sørensen HT.
Journal: Annals of Neurology, 2015, May 29. doi: 10.1002/ana.24448.
PMID: 26031848

In their report, the researchers highlighted the reduced risk of Parkinson’s disease following a truncal vagotomy.

So what’s a truncal vagotomy?

A vagotomy is a surgical procedure in which the vagus nerve is cut. It is typically due to help treat stomach ulcers.

The vagus nerve runs from the lining of the stomach to the brain stem, near the base of the brain.

A diagram illustrating the vagal nerve connection with the enteric nervous system which lines the stomach. Source: NCBI

A vagotomy comes in two forms: it can be ‘truncal‘ (in which the main nerve is cut) or ‘superselective’ (in which specific branches of the nerve are cut, which the main nerve is left in tact).

A schematic demonstrating the vagal nerve surrounding the stomach. Image A. indicates a ‘truncal’ vagotomy, where the main vagus nerves are cut above the stomach; while image B. illustrates the ‘superselective’ vagotomy, cutting specific branches of the vagus nerve connecting with the stomach. Source: Score

And what did the Danish scientists find?

Exploring the public health records, the Danish researcher found that between 1975 and 1995, 5339 individuals had a truncal vagotomy and 5870 had superselective vagotomy. Using the Danish National registry (which which stores all of Denmark’s medical information), they then looked for how many of these individuals went on to be diagnosed with Parkinson’s disease. They compared these vagotomy subjects with more than 60,000 randomly-selected, age-matched controls.

They found that subjects who had a superselective vagotomy had the same chance of developing Parkinson’s disease as anyone else in the general public (a hazard ratio (or HR) of 1 or very close to 1).

But when they looked at the number of people in the truncal vagotomy group who were later diagnosed with Parkinson’s disease, the risk had dropped by 35%. Furthermore, when they followed up the truncal group 20 years later, checking to see who had been diagnosed with Parkinson’s in 2012, they found that their rate was half that of both the superselective group and the control group (see table below; HR=0.53). The researchers concluded that a truncal vagotomy reduces the risk of developing Parkinson’s disease.

Source: Svensson et al (2015) Annals of Neurology – Table 2.

Then last year, at the meeting in Berlin, data was presented that failed to replicate the findings in a separate group of people (Sweds).

Vagotomy

Title: Vagotomy and Parkinson’s disease risk: A Swedish register-based matched cohort study
Authors: B. Liu, F. Fang, N.L. Pedersen, A. Tillander, J.F. Ludvigsson, A. Ekbom, P. Svenningsson, H. Chen, K. Wirdefeldt
Abstract Number: 476 (click here to see the original abstract – OPEN ACCESS)

The Swedish researchers collected information regarding 8,279 individuals born in Sweden between 1880 and 1970 who underwent vagotomy between 1964 and 2010 (3,245 truncal and 5,029 selective). For each vagotomized individual, they collected medical information for 40 control subjects matched for sex and year of birth (at the date of surgery). They found that vagotomy was not associated with Parkinson’s disease risk.

Truncal vagotomy was associated with a lower risk more than five years after the surgery, but that result was not statistically significant. The researcher suggested that the findings needs to be verified in larger samples.

The results of that study have now been published (this week):

Swedish
Title: Vagotomy and Parkinson disease: A Swedish register-based matched-cohort study
Authors: Liu B, Fang F, Pedersen NL, Tillander A, Ludvigsson JF, Ekbom A, Svenningsson P, Chen H, Wirdefeldt K.
Journal: Neurology. 2017 Apr 26. pii: 10.1212/WNL.0000000000003961.
PMID: 28446653 (This article is OPEN ACCESS if you would like to read it)

In this report, the researchers suggest that “there was a suggestion of lower risk among patients with truncal vagotomy” and they note that the hazard ratio (or HR) is 0.78 for this group (ranging between 0.55-1.09), compared to the HR of 0.96 (ranging between 0.78-1.17) for all of the vagotomy group combined. And they not that this trend is further apparent when the truncal vagotomy was conducted at least 5 years before Parkinson’s disease diagnosis (HR = 0.59, ranging between 0.37-0.93). These numbers are not statistically significant, so the investigators could only suggest that there was a trend towards truncal vagotomy lowering the risk of Parkinson’s disease.

What are the differences between the studies?

The Danish researcher analysed medical records between 1975 and 1995 from 5339 individuals had a truncal vagotomy and 5870 had superselective vagotomy. The Sweds on the other hand, looked over a longer period (1964 – 2010) but at a smaller sample size for the truncal group (3,245 truncal and 5,029 selective). Perhaps if the truncal group in the Swedish study was higher, the trend may have become significant.

So should we all rush out and ask our doctors for a vagotomy?

No.

That would not be advised (though I’d love to be a fly on the wall for that conversation!).

It is important to understand that a vagotomy can have very negative side-effects, such as vomiting and diarrhoea (Click here to read more on this).

Plus, while the results are interesting, we really need a much larger study for definitive conclusions to be made. You see, in the Danish study (the first report above) the number of people that received a truncal vagotomy (total = 5339) who then went on develop Parkinson’s disease 20 years later was just 10 (compared with 29 in the superselective group). And while that may seem like a big difference between those two numbers, the numbers are still too low to be truly conclusive. We really need the numbers to be in the hundreds.

Plus, it is important to determine whether this result can be replicated in other countries. Or is it simply a Scandinavian trend?

Mmm, interesting. So what does it all mean?

No, stop. We’re not summing up yet. This is one of those ‘but wait there’s more!’ moments.

It has been a very busy week for Parkinson’s gut research.

A German research group published a report about their analysis of the microbes in the gut and how they differ in Parkinson’s disease (when compared to normal healthy controls).

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Microbes. Source: Youtube

Regular readers of this blog will realise that we have discussed this kind of study before in a previous post (Click here for that post).

This type of study – analysing the bacteria of the gut – has now been done not just once:

biota-title

Title: Gut microbiota are related to Parkinson’s disease and clinical phenotype.
Authors: Scheperjans F, Aho V, Pereira PA, Koskinen K, Paulin L, Pekkonen E, Haapaniemi E, Kaakkola S, Eerola-Rautio J, Pohja M, Kinnunen E, Murros K, Auvinen P.
Journal: Mov Disord. 2015 Mar;30(3):350-8.
PMID: 25476529

Nor twice:

Fecal3

Title: Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease andage-matched controls.
Authors: Unger MM, Spiegel J, Dillmann KU, Grundmann D, Philippeit H, Bürmann J, Faßbender K, Schwiertz A, Schäfer KH.
Journal: Parkinsonism Relat Disord. 2016 Nov;32:66-72.
PMID: 27591074

Not three times:

Kesh1

Title: Colonic bacterial composition in Parkinson’s disease
Authors: Keshavarzian A, Green SJ, Engen PA, Voigt RM, Naqib A, Forsyth CB, Mutlu E, Shannon KM.
Journal: Mov Disord (2015) 30, 1351-1360.
PMID: 26179554

Not even four times:

Plos1

Title: Intestinal Dysbiosis and Lowered Serum Lipopolysaccharide-Binding Protein in Parkinson’s Disease.
Authors: Hasegawa S, Goto S, Tsuji H, Okuno T, Asahara T, Nomoto K, Shibata A, Fujisawa Y, Minato T, Okamoto A, Ohno K, Hirayama M.
Journal: PLoS One. 2015 Nov 5;10(11):e0142164.
PMID: 26539989 (This article is OPEN ACCESS if you would like to read it)

But FIVE times now (all the results published in the 2 years):

gut-title

Title: Parkinson’s disease and Parkinson’s disease medications have distinct signatures of the gut microbiome.
Authors: Hill-Burns EM, Debelius JW, Morton JT, Wissemann WT, Lewis MR, Wallen ZD, Peddada SD, Factor SA, Molho E, Zabetian CP, Knight R, Payami H.
Journal: Mov Disord. 2017 Feb 14. [Epub ahead of print]
PMID: 28195358

(And we apologies to any researchers not mentioned here – these are simply the studies we are aware of).

The researchers in the study published this week, however, did something different to these previous studies:

Gut1
Title: Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson’s disease patients
Authors: Bedarf JR, Hildebrand F, Coelho LP, Sunagawa S, Bahram M, Goeser F, Bork P, Wüllner U.
Journal: Genome Med. 2017 Apr 28;9(1):39.
PMID: 28449715 (This article is OPEN ACCESS if you would like to read it)

The researchers in this study focused their analysis on 31 people with early stage Parkinson’s disease. In addition, all of those subjects were not taking any L-DOPA. The fecal samples collected from these subjects was compared with samples from 28 age-matched controls.

And what did they find?

In the early-stage, L-dopa-naïve Parkinson’s disease fecal samples, the researchers found increased levels of two families of microbes (Verrucomicrobiaceae and unclassified Firmicutes) and lower levels of two other familes (Prevotellaceae and Erysipelotrichaceae). And these differences could be used to reliably differentiate between the two groups (PD and control) to an accuracy of 84%.

In addition, the investigators found that the total virus abundance was decreased in the Parkinsonian participants. The researchers concluded that their study provides evidence of differences in the microbiome of the gut in Parkinson’s disease at a very early stage in the course of the condition, and that exploration of the Parkinson’s viral populations “is a promising avenue to follow up with more specific research” (we here at SoPD are particularly intrigued with this statement!).

So is there a a lot of consensus between the studies? Any new biomarkers?

(Big sigh) Yes….. and no on the consensus question.

The good news is that all of the studies agree that there is a difference between the abundance of different groups of bacteria in the Parkinsonian gut.

BUT only three of the six studies studies demonstrate any agreement as to which groups of bacteria. And those three studies could only agree on one family of bacteria. The recent study (Bedarf et al) agreed with the Scheperjans et al and Unger et al studies in that they all observed found reduced levels of Prevotellaceae bacteria in the gut of people with Parkinson’s disease.

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The Prevotellaceae family of bacteria. Source: MindsofMalady

Unfortunately, the reduction in abundance of this particular bacteria does not appear to be specific to Parkinson’s disease, as similar reduced levels have been observed in Japanese multiple sclerosis patients and in autistic children (Click here and here to read more about those studies).

This lack of agreement between the studies with regards to the difference in the abundance of the families of bacteria may reflect the complexity of the gut microbiome. Alternatively, it could also reflect regional differences (the Keshavarzian et al. study was conducted in Chicago, the Bedarf et al and Unger et al studies were in Germany, Scheperjans et al was in Finland, Hill-Burn et al in Alabama, and the Hasegawa et al study was in conducted in Japan).

Either way, it leaves the field lacking agreement as to which families of bacteria should be followed up in future research.

So what does it all mean?

Right, so summing up, researchers are trying to determine what role the gut may play the course of Parkinson’s disease. There is evidence that the nerves connecting the digestive organ to the brain may act as some kind of gate way for an unknown agent or simply a provocative element in the condition. Severing those nerves to the gut appears to reduce the risk of developing Parkinson’s disease.

And the bacteria populating the gut appears to be different in people with Parkinson’s disease, but there does not seem to be consistency between studies, leaving the search for biomarkers in this organ sadly lacking. Maybe it reflects regional differences, perhaps it reflects the complexity of Parkinson’s disease. Hopefully as follow up research into this particular field continues, a consensus will begin to appear. Admittedly, most of these studies are based on single fecal samples collected from individuals at just one time point. A better experimental design would be to collect multiple samples over time, allowing for variability within and between individuals to be ironed out.

Despite all of these cautionary comments, there does appear to be some smoke here. And we will be watching the gut with great interest as more research comes forward.

The banner for today’s post was sourced from the HuffingtonPost

Stress and Parkinson’s disease

April 26, 2017April 26, 2017 ~ Simon ~ 1 Comment

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Stress.

We all suffer it. Whether it is work related, relationship related, or simply self-induced, we humans foolishly put a great deal of pressure on our bodies.

Many pieces of research suggest that this pressure takes a toll on our health, which could lead to long-term conditions like Parkinson’s disease.

Recently some Korean researchers have identified a stress-related hormone that could have beneficial effects for Parkinson’s disease.

In today’s post, we will review their recently published research and look at what it means for people with Parkinson’s disease.

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Source: Islamicity

Shortly before leaving the role of President of the United States of America, ex-President Barrack Obama was asked about the stress that comes with the job, and his answer was interesting. He suggested that it is important to take a ‘long view’ of events and not to get bogged down by the weight of everything going on around you:

Despite these sage words, it is difficult not to notice the impact that his previous job has had on the man:

What a stress can do to a person. Source: Reddit

Stress seems to be a major part of modern life for many people – some people even indicate that they need it and that they thrive on it. But this pressure that we put on our bodies tends to have a damaging effect on our general health. And there is evidence that that stress may even lead to long term consequences such as cancer and neurodegenerative conditions such as Parkinson’s disease.

Causality, however, is very difficult to determine in science.

The best we can do is suggest that a particular variable (such as stress) may increase one’s risk of developing a particular condition (such as Parkinson’s disease).

So what do we know about stress and Parkinson’s disease?

This is Professor Bas Bloem.

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Prof Bloem – no stress here. Source: NRC

He’s awesome.

Professor Bloem is a consultant neurologist at the Department of Neurology, Radboud University Nijmegen Medical Centre (the Netherlands). He is also one of the researchers behind ParkinsonNet – an innovative healthcare concept that now consists of 64 professional networks for people with Parkinson’s disease covering all of the Netherlands.

In 2010, his research group noticed something interesting:

Bloem

Title: Artistic occupations are associated with a reduced risk of Parkinson’s disease.
Authors: Haaxma CA, Borm GF, van der Linden D, Kappelle AC, Bloem BR.
Journal: J Neurol. 2015 Sep;262(9):2171-6.
PMID: 26138540 (This article is OPEN ACCESS if you would like to read it)

In their study, Prof Bloem and his colleagues conducted a case–controlled analysis of 750 men with Parkinson’s disease (onset ≥40 years) and 1300 healthy men, which involved the participants completing a questionnaire about their occupational history. As expected (based on previous reports), they found that farming was associated with an increased risk of developing Parkinson’s disease (click here for more on this).

Interestingly, artistic occupations late in life were associated with a reduced risk of subsequent Parkinson’s disease. Another interesting observation from the study was that no initial occupation (early in life) predicted Parkinson’s disease, which the researchers proposed indicated that the premotor phase of the disease starts later in life.

One interpretation of this finding is that creative people are less likely to develop Parkinson’s disease. An alternative theory, however, may be that artist jobs are associated with a less stressful, more relaxed lifestyle.

Could it be that the lower levels of stress associated with artistic occupations may be having an impact on the risk of developing Parkinson’s disease?

This idea is not as crazy as it sounds.

Consider different kinds of stress. Research suggests that people who undergo tremendous emotional stress have a higher risk of developing Parkinson’s disease. For example, there is the case of ex-prisoners of war:

Prisoner

Title:Neurological disease in ex-Far-East prisoners of war
Authors: Gibberd FB, Simmonds JP.
Journal: Lancet. 1980 Jul 19;2(8186):135-7.
PMID: 6105303

At the end of World war II, a neurological unit was set up at Queen Mary’s Hospital (Roehampton) to treat Ex-Far East prisoners of war. 4684 individuals were referred to the unit, of these 679 were found to have neurological disease (most of these – 593 cases – were loss of sight and peripheral nerve damage).

In follow up work in the 1970s, however, it was found that many of these individuals had gone on to develop other neurological conditions (dementia, multiple sclerosis, etc). Of interest to us, though was the finding that across the entire group of ex-prisoners investigated (4684 individuals), Parkinson’s disease was apparent in 24 of them – this is a frequency 5x that of the general population!

Even in animal models of Parkinson’s disease, emotional stress seems to exaccerbate the neurodegeneration that is being modelled:

Canada
Title: Stress accelerates neural degeneration and exaggerates motor symptoms in a rat model ofParkinson’s disease.
Authors: Smith LK, Jadavji NM, Colwell KL, Katrina Perehudoff S, Metz GA.
Journal: Eur J Neurosci. 2008 Apr;27(8):2133-46.
PMID: 18412632 (This article is OPEN ACCESS if you would like to read it)

The investigators in this study demonstrated that chronic stress exaggerates the motor/behavioural deficits in a rat model of Parkinson’s disease. In addition, the stress resulted in a greater loss of dopamine neurons in the brains of these rats.

For an interesting review of the effect of stress in Parkinson’s disease – Click here.

Interesting. So what did the Korean researchers – you mentioned above – find this week?

Something interesting.

This is Dr Yoon-Il Lee.

Lee

Source: Dgist

He’s a dude.

He is a senior research scientists at the Daegu Gyeongbuk Institute of Science and Technology (DGIST) in Daegu Metropolitan City, South Korea.

Recently, his group has collaborated with Professor Yunjong Lee’s research team published this research report:

Lee

Title: Hydrocortisone-induced parkin prevents dopaminergic cell death via CREB pathway inParkinson’s disease model
Authors: Ham S, Lee YI, Jo M, Kim H, Kang H, Jo A, Lee GH, Mo YJ, Park SC, Lee YS, Shin JH, Lee Y.
Journal: Sci Rep. 2017 Apr 3;7(1):525. doi: 10.1038/s41598-017-00614-w.
PMID: 28366931 (This article is OPEN ACCESS if you would like to read it)

Dr Lee and his colleagues began this study with cells were engineered to produce a bioluminescent signal when a gene called Parkin was activated. Parkin is a Parkinson’s associated gene as genetic mutations in this gene can result in carriers developing a juvenile-onset/early-onset form of Parkinson’s disease.

The researchers then conducted an enormous screening experiment to find agents that turn on the Parkin gene. They applied a library of 1172 FDA-approved drugs (from Selleck Chemicals) to these cells – one drug per cell culture – and looked at which cell cultures began to produce a bioluminescent signal. They found 5 drugs that not only made the cells bioluminescent, but also resulted in Parkin protein being produced at levels 2-3 times higher than normal. Those drugs were:

Deferasirox – an iron chelator (interesting considering our previous post)
Vorinostat – a cancer drug (for treating lymphoma)
Metformin – a diabetes medication
Clindamycin – an antibiotic
Hydrocortisone

Hydrocortisone produced the highest levels of Parkin (Interestingly, hydrocortisone also did not increase the activity of PERK, an indicator of endoplasmic reticulum stress, while the other drugs did).

What is Hydrocortisone?

Hydrocortisone is the name for the hormone ‘cortisol’ when supplied as a medication.

Ok, so what is cortisol?

Cortisol is a glucocorticoid (a type of hormone) produced from cholesterol by enzymes in the cortex of the adrenal gland, which sits on top of the kidneys. It is produced in response to stress (physical or emotional)

CDR739009

The location of the adrenal glands. Source: Cancer

Cortisol helps us to deal with physical or emotional stress by reducing the activity of certain bodily functions – such as the immune system – so that the body can focus all of it’s energies toward dealing with the stress at hand.

Now generally, the functions of cortisol are supposed to be short-lived – long enough for the body to deal with the offending stressor and then levels go back to normal. But the normal levels of cortisol also fluctuate across the span of the day, with levels peaking around 8-9am:

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A graph of cortisol levels over the day. Source: HealthTap

Ok, so what did the Korean researchers do next?

Dr Lee and his colleagues gave the hydrocortisone drug to cell cultures which they then stressed (causing cell death). Hydrocortisone protected the cells from dying, and (importantly) it achieved this feat in a manner that was dependent on parkin activation. In cells that do not naturally have parkin, hydrocortisone was found to have no effect on cell survival.

Next the researchers treated mice with hydrocortisone before they then modelled Parkinson’s disease using the neurotoxin 6-OHDA. Hydrocortisone treatment resulted in approximate a two-fold increase in levels of parkin within particular areas of the brain. Without hydrocortisone treatment, the mice suffered the loss of approximately 45% of their dopamine neurons. Mice pre-treated with hydrocortisone, however, demonstrated enhanced dopamine neuron survival.

The researchers concluded that a sufficient physiological supply of hydrocortisone was required for protection of the brain, and that hydrocortisone treatment could be further tested as a means of maintaining high levels of parkin in the brain.

So what do we know about cortisol in Parkinson’s disease?

So this is where the story gets interesting;

Dobbs

Title: Cortisol is higher in parkinsonism and associated with gait deficit.
Authors: Charlett A, Dobbs RJ, Purkiss AG, Wright DJ, Peterson DW, Weller C, Dobbs SM.
Journal: Acta Neurol Scand. 1998 Feb;97(2):77-85.
PMID: 9517856

The researchers who conducted this study were interested in the role of cortisol in Parkinson’s disease. They measured cortisol levels in the blood of 96 subjects with Parkinson’s disease and 170 control subjects. They found that cortisol levels were 20% higher in the subjects with Parkinson’s disease, and that MAO-B inhibitor treatment for Parkinson’s (Selegiline) reduced cortisol levels.

And MAO-B inhibitors are not the only Parkinson’s medication associated with reduced levels of cortisol:

Muller

Title: Acute levodopa administration reduces cortisol release in patients with Parkinson’s disease.
Authors: Müller T, Welnic J, Muhlack S.
Journal: J Neural Transm (Vienna). 2007 Mar;114(3):347-50.
PMID: 16932991

In this study the researchers found that cortisol levels started to decrease significantly just 30 minutes after L-dopa was taken.

Whether this lowering of cortisol levels may have any kind of detrimental effect on Parkinson’s disease is yet to be determined and required further investigation.

Is hydrocortisone or cortisol used in the clinic?

Yes it is.

Hydrocortisone is used to treat rheumatism, skin diseases, and allergies.

white-tablet-pills-on-reflective-surface

Hydrocortisone tablets. Source: Wisegeeks

Thus, there is the potential for another example of drug repurposing here. But the drug is not without side effects, which include:

Sleep problems (insomnia)
Mood changes
Acne, dry skin, thinning skin, bruising or discoloration;
Slow wound healing
Increased sweating
Headache, dizziness, spinning sensation;
nausea, stomach pain

For the full list of potential side effects – click here.

So what does it all mean?

Researchers in Korea have recently found that hydrocortisone (cortisol) can increase levels of Parkinson’s associated protein Parkin in cells, which in turn has a positive, neuroprotective effect on models of Parkinson’s disease.

We will now wait to see if the results can be independently replicated before attempting to take this drug to clinical trials for Parkinson’s disease. Any replication of the study should involve a range of treatment regimes so that we can determine if delayed administration can also be beneficial (this would involve delaying hydrocortisone treatment until after the neurotoxin has been given). Those studies could also look at the inflammatory effect in the brains as hydrocortisone has previously been demonstrated to have anti-inflammatory effects.

Interesting times. Stay tuned.

EDITOR’S NOTE: Under absolutely no circumstances should anyone reading this material consider it medical advice. The material provided here is for educational purposes only. Before considering or attempting any change in your treatment regime, PLEASE consult with your doctor or neurologist. While some of the drugs discussed on this website are clinically available, they may have serious side effects. We urge caution and professional consultation before altering any treatment regime. SoPD can not be held responsible for any actions taken based on the information provided here.

The banner for today’s post was sourced from ZetaYarwood

Iron, life force, and Parkinson’s disease

April 19, 2017July 3, 2017 ~ Simon ~ 5 Comments

pranaLogo

‘Prana’ is a Hindu Sanskrit word meaning “life force”.

An Australian biotech company has chosen this word for their name.

Recently Prana Biotechnology Ltd announced some exciting results from their Parkinson’s disease research programme.

In today’s post we will look at what the company is doing, the science underlying the business plan, and review the results they have so far.

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Source: ADPD2017

At the end of March, over 3000 researchers in the field of neurodegeneration gathered in the Austrian capital of Vienna for the 13th International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders (also known as ADPD2017).

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The Vienna city hall. Source: EUtourists

A lot of interesting new research in the field of Parkinson’s disease was presented at the conference (we will look at some other presentation in future posts), but one was of particular interest to us here at SoPD HQ.

The poster entitled: ‘Abstract: 104 – PBT434 prevents neuronal loss, motor function and cognitive impairment in preclinical models of movement disorders by modulation of intracellular iron’, was presented by Associate Professor David Finkelstein, of the Florey Institute of Neuroscience and Mental Health (Melbourne, Australia).

Unfortunately the ADPD2017 conference’s scientific programme search engine does not allow for individual abstracts to be linked to on the web so if you would like to read the abstract, you will need to click here for the search engine page and search for ‘PBT434’ or ‘Finkelstein’ in the appropriate boxes.

Prof Finkelstein was presenting preclinical research that had been conducted by an Australian biotech company called Prana Biotechnology Ltd.

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Source: Prana Biotechnology Ltd

What does the company do?

Prana Biotechnology Ltd has a large portfolio of over 1000 small chemical agents that they have termed ‘MPACs’ (or Metal Protein Attenuating Compounds). These compounds are designed to interrupt the interactions between particular metals and target proteins in the brain. The goal of this interruption is to prevent deterioration of brain cells in neurodegenerative conditions.

For Parkinson’s disease, the company is proposing a particular iron chelator they have called PBT434.

What is an iron chelator?

Iron chelator therapy involves the removal of excess iron from the body with special drugs. Chelate is from the Greek word ‘chela’ meaning “claw”.

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Chelator therapy. Source: Stanford

Iron overload in the body is a common medical problem, sometimes arising from disorders of increased iron absorption such as hereditary haemochromatosis. Iron chelator therapy represents one method of reducing the levels of iron in the body.

But why is iron overload a problem?

iron

Iron. Source: GlobalSpec

Good question. It involves the basic properties of iron.

Iron is a chemical element (symbol Fe). It has the atomic number 26 and by mass it is the most common element on Earth (it makes up much of Earth’s outer and inner core). It is absolutely essential for cellular life on this planet as it is involved with the interactions between proteins and enzymes, critical in the transport of oxygen, and required for the regulation of cell growth and differentiation.

So why then – as Rosalind asked in Shakespeare’s As You Like It – “can one desire too much of a good thing?”

Well, if you think back to high school chemistry class you may recall that there are these things called electrons. And if you have a really good memory, you will recall that the chemical hydrogen has one electron, while iron has 26 (hence the atomic number 26).

atoms

The electrons of iron and hydrogen. Source: Hypertonicblog

Iron has a really interesting property: it has the ability to either donate or take electrons. And this ability to mediate electron transfer is one of the reasons why iron is so important in the body.

Iron’s ability to donate and accept electrons means that when there is a lot of iron present it can inadvertently cause the production of free radicals. We have previously discussed free radicals (Click here for that post), but basically a free radical is an unstable molecule – unstable because they are missing electrons.

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How free radicals and antioxidants work. Source: h2miraclewater

In an unstable format, free radicals bounce all over the place, reacting quickly with other molecules, trying to capture the much needed electron to re-gain stability. Free radicals will literally attack the nearest stable molecule, to steal an electron. This leads to the “attacked” molecule becoming a free radical itself, and thus a chain reaction is started. Inside a living cell this can cause terrible damage, ultimately killing the cell.

Antioxidants can help try and restore the balance, but in the case of iron overload iron doctors will prescribe chelator treatment to deal with the situation more efficiently. By soaking up excess iron, we can limit the amount of damage caused by the surplus of iron.

So what research has been done regarding iron content and the Parkinsonian brain?

Actually, quite a lot.

In 1968, Dr Kenneth Earle used an X-ray based technique to examine the amount of iron in the substantia nigra of people with Parkinson’s disease (Source). The substantial nigra is one of the regions in the brain most badly damaged by the condition – it is where most of the brain’s dopamine neurones resided.

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The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source:Memorangapp

Earle examined 11 samples and compared them to unknown number of control samples and his results were a little startling:

The concentration of iron in Parkinsonian samples was two times higher than that of the control samples.

Since that first study, approximately 30 investigations have been made into levels of iron in the Parkinsonian brain. Eleven of those studies have replicated the Earle study by looking at postmortem tissue. They have used different techniques and the results have varied somewhat:

Sofic et al. (1988) 1.8x increase in iron levels
Dexter et al. (1989) 1.3x increase in iron levels
Uitti et al. (1989) 1.1x increase in iron levels
Riederer et al 1989 1.3x increase in iron levels
Griffiths and Crossman (1993) 2.0x increase in iron levels
Mann et al. (1994) 1.6x increase in iron levels
Loeffler et al. (1995) 0.9 (lower)
Galazka-Friedman et al., 1996 1.0 (no difference)
Wypijewska et al. (2010) 1.0 (no difference)
Visanji et al, 2013 1.7x increase in iron levels

Overall, however, there does appear to be a trend in the direction of higher levels of iron in the Parkinsonian brains. A recent meta-analysis of all this data confirmed this assessment as well as noting an increase in the caudate putamen (the region of the brain where the dopamine neuron branches release their dopamine – Click here for that study).

Brain imaging of iron (using transcranial sonography and magnetic resonance imaging (MRI)) has also demonstrated a strong correlation between iron levels in the substantia nigra region and Parkinson’s disease severity/duration (Click here and here to read more on this).

Thus, there appears to be an increase of iron in the regions most affected by Parkinson’s disease and this finding has lead researchers to ask whether reducing this increase in iron may help in the treatment of Parkinson’s disease.

How could iron overload be bad in Parkinson’s disease?

Well in addition to causing the production of free radicals, there are many possible ways in which iron accumulation could be aggravating cell loss in Parkinson’s disease.

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Possible causes and consequences of iron overload in Parkinson’s disease. Source: Hindawi

High levels of iron can cause the oxidation of dopamine, which results in the production of hydrogen peroxide (H₂O₂– a reactive oxygen species – the stuff that is used to bleach hair and is also used as a propellant in rocketry!). This reaction can cause further oxidative stress that can then lead to a range of consequences including protein misfolding, lipid peroxidation (which can cause the accumulation of the Parkinson’s associated protein alpha synuclein), mitochondrial dysfunction, and activation of immune cells in the brain.

And this is just a taster of the consequences.

For further reading on this topic we recommend two very good reviews – click here and here.

Ok, so iron overload is bad, but what was the research presented in Austria?

The abstract:

Title: PBT434 prevents neuronal loss, motor function and cognitive impairment in preclinical models of movement disorders by modulation of intracellular iron
Authors: D. Finkelstein, P. Adlard, E. Gautier, J. Parsons, P. Huggins, K. Barnham, R. Cherny
Location: C01.a Posters – Theme C – Alpha-Synucleinopathies

The researchers at Prana Biotechnology Ltd assessed the potential of one of their candidate drugs, PBT434, in both cell culture and animal models of Parkinson’s disease. The PBT434 drug was selected for further investigation based on its performance in cell culture assays designed to test the inhibition of oxidative stress and iron-mediated aggregation of Parkinson’s associated proteins like alpha synuclein.

PBT434 significantly reduced the accumulation of alpha synuclein and markers of oxidative stress, and prevented neuronal loss.

The investigators also demonstrated that orally administered PBT434 readily crossed the blood brain barrier and entered the brain. In addition the drug was well-tolerated in the experimental animals and improved motor function in toxin-induced (MPTP and 6-hydroxydopamine) and transgenic mouse models of Parkinson’s disease (alpha synuclein -A53T and tau – rTg4510).

These results are in agreement with previous studies that have looked at iron chelator therapy in models of Parkinson’s disease (Click here, here and here for some examples)

Interestingly, PBT434 also demonstrated neuroprotective properties in animal models of multiple systems atrophy (or MSA). Suggesting that perhaps iron chelation could be a broad neuroprotective approach.

The researchers concluded that this preclinical data demonstrates the efficacy of PBT434 as a clinical candidate for Parkinson’s disease. PBT434 shows a strong toxicology profile and favourable therapeutic activity. Prana is preparing its pre-clinical development package for PBT434 to initiate human clinical trials.

Does Prana have any other drugs in clinical trials?

Yes, they do.

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Source: Prana

Prana Biotechnology has another product called PBT2.

The company currently has two clinical trial programs for PBT2 focused on two other neurodegenerative diseases: Alzheimer’s disease and Huntington’s disease.

The Alzheimer’s study was called the IMAGINE Trial, but (there is always a ‘but’) recently PBT2 failed to meet its primary endpoint (significantly reducing levels of beta-amyloid – the perceived bad guy in Alzheimer’s disease) in a phase III trial of mild Alzheimer’s disease. PBT2 was, however, shown to be safe and very well tolerated over the 52 week trial, with no difference in the occurrence of adverse events between the placebo and treated groups.

In addition, there was less atrophy (shrinkage) in the brains of those patients treated with PBT2 when compared to control brains, 2.6% and 4.0%, respectively (based on brain imaging). The company is tracking measures of brain volume and cognition in a 12 month extension study. It could be interesting to continue that follow up long term to evaluate the consequences of long term use of this drug on Alzheimer’s disease – even if the effect is minimal, any drug that can slow the disease down is useful and could be used in conjunction with other neuroprotective medications.

For Huntington’s disease, the company is also using the PBT2 drug and this study has had a bit more success. The study, called Reach2HD, was a six month phase II clinical trial in 109 patients with early to mid-stage Huntington’s disease, across 20 sites in the US and Australia. The company was aiming to assess the safety profile of this drug in this particular condition, as well as determining the motor and behavioural benefits.

In the ReachHD study, PBT2 showed signs of improving some aspects of cognitive function in the study, which potentially represents a major event for a disease for which there is very little in the way of medical treatments.

For a full description of the PBT2 trials, see this wikipedia page on the topic.

Is Prana the only research group working on iron chelators technology for Parkinson’s disease?

No.

There is a large EU-based consortium called FAIR PARK II, which is running a five year trial (2015 – 2020) of the iron chelator deferiprone (also known as Ferriprox). The study is a multi-centre, placebo-controlled, randomised clinical trial involving 338 people with recently diagnosed Parkinson’s disease.

LOGO_FAIR_PARK_TIME1

The population will be divided into two group (169 subjects each). They will then be assigned either deferiprone (15 mg/kg twice a day) or a placebo. Each subject will be given 9-months of treatment followed by a 1-month post-treatment monitoring period, in order to assess the disease-modifying effect of deferiprone (versus placebo).

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Deferiprone. Source: SGPharma

As far as we are aware, this FAIR PARK II clinical trial is still recruiting participants – please click here to read more about this – thus it will most likely be some time before we hear the results of this study.

Are there natural sources of chelators?

Yes there are. In fact, many natural antioxidants exert some chelating activities.

Prominent among the natural sources of chelators: Green tea has components of plant extracts, such as epigallocatechin gallate (EGCG – which we have previously discussed in regards to Parkinson’s disease, click here to read that post) which possess structures which infer metal chelating properties.

As we have said before people, drink more green tea!

cup and teapot of linden tea and flowers isolated on white

Anyone fancy a cuppa? Source: Expertrain

So what does it all mean?

Summing up: We do not know what causes Parkinson’s disease. Most of our experimental treatments are focused on the biological events that occur in the brain around and after the time of diagnosis. These include an apparent accumulation of iron in affected brain regions.

Research groups are currently experimenting with drugs that reduce the levels of iron in the brain as a potential treatment for Parkinson’s disease. Preclinical data certainly look positive. We will now have to wait and see if those results translate into the human.

Previous clinical trials of metal chelators in neurodegeneration have had mixed success in demonstrating positive benefits. It may well be, however, that this treatment approach should be used in conjunction with other neuroprotective approaches – as a supplement. It will be interesting to see how Prana Biotechnology’s drug PBT434 fares in human clinical trials for Parkinson’s disease.

Stay tuned for more on this.

UPDATE – 3rd May 2017

Today the results of a double-blind, phase II clinical trial of iron chelator deferiprone in Parkinson’s disease were published. The results of the study indicate a mildly positive effect (though not statistically significant) after 6 months of daily treatment.

Iron1
Title: Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease
Authors: Martin-Bastida A, Ward RJ, Newbould R, Piccini P, Sharp D, Kabba C, Patel MC, Spino M, Connelly J, Tricta F, Crichton RR & Dexter DT
Journal: Scientific Reports (2017), 7, 1398.
PMID: 28469157 (This article is OPEN ACCESS if you would like to read it)

In this Phase 2 randomised, double-blinded, placebo controlled clinical trial, the researchers recruited 22 people with early stage Parkinson’s disease (disease duration of less than 5 years; 12 males and 10 females; aged 50–75 years). They were randomly assigned to either a placebo group (8 participants), or one of two deferiprone treated groups: 20 mg/kg per day (7 participants) or 30 mg/kg per day (7 participants). The treatment was two daily oral doses (taken morning and evening), and administered for 6 months with neurological examinations, brain imaging and blood sample collections being conducted at 0, 3 and 6 months.

Deferiprone therapy was well tolerated and brain imaging indicated clearance of iron from various parts of the brain in the treatment group compared to the placebo group. Interestingly, the 30 mg/kg deferiprone treated group demonstrated a trend for improvement in motor-UPDRS scores and quality of life (although this was not statistically significance). The researchers concluded that “more extensive clinical trials into the potential benefits of iron chelation in PD”.

Given the size of the groups (7 people) and the length of the treatment period (only 6 months) in this study it is not really a surprise that the researchers did not see a major effect. That said, it is very intriguing that they did see a trend towards motor score benefits in the 30 mg/kg deferiprone group – remembering that this is a double blind study (so even the investigators were blind as to which group the subjects were in).

We will now wait to see what the FAIR PARK II clinical trial finds.

UPDATE: 28th June 2017

Today, the research that Prana biotechnology Ltd was presenting in Vienna earlier this year was published:

Prana

Title: The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease.
Authors: Finkelstein DI, Billings JL, Adlard PA, Ayton S, Sedjahtera A, Masters CL, Wilkins S, Shackleford DM, Charman SA, Bal W, Zawisza IA, Kurowska E, Gundlach AL, Ma S, Bush AI, Hare DJ, Doble PA, Crawford S, Gautier EC, Parsons J, Huggins P, Barnham KJ, Cherny RA.
Journal: Acta Neuropathol Commun. 2017 Jun 28;5(1):53.
PMID: 28659169 (This article is OPEN ACCESS if you would like to read it)

The results suggest that PBT434 is far less potent than deferiprone or deferoxamine at lowering cellular iron levels, but this weakness is compensated by the reduced levels of alpha synuclein accumulation in models of Parkinson’s disease. PBT434 certainly appears to be neuroprotective demonstrating improvements in motor function, neuropathology and biochemical markers of disease state in three different animal models of Parkinson’s disease.

The researchers provide little information as to when the company will be exploring clinical trials for this drug, but in the press release associated with the publication, Dr David Stamler (Prana’s Chief Medical Officer and Senior Vice President, Clinical Development) was quoted saying that they “are eager to begin clinical testing of PBT434”. We’ll keep an eye to the ground for any further news.

FULL DISCLOSURE: Prana Biotechnology Ltd is an Australasian biotechnology company that is publicly listed on the ASX. The information presented here is for educational purposes. Under no circumstances should investment decisions be made based on the information provided here. The SoPD website has no financial or beneficial connection to either company. We have not been approached/contacted by the company to produce this post, nor have we alerted them to its production. We are simply presenting this information here as we thought the science of what the company is doing might be of interest to other readers.

In addition, under absolutely no circumstances should anyone reading this material consider it medical advice. The material provided here is for educational purposes only. Before considering or attempting any change in your treatment regime, PLEASE consult with your doctor or neurologist. Metal chelators are clinically available medications, but it is not without side effects (for more on this, see this website). We urge caution and professional consultation before altering a treatment regime. SoPD can not be held responsible for any actions taken based on the information provided here.

The banner for today’s post was sourced from Prana

On astrocytes and neurons – reprogramming for Parkinson’s

April 18, 2017April 19, 2017 ~ Simon ~ 13 Comments

NG2+-flare

Last week scientists in Sweden published research demonstrating a method by which the supportive cells of the brain (called astrocytes) can be re-programmed into dopamine neurons… in the brain of a live animal!

It was a really impressive trick and it could have major implications for Parkinson’s disease.

In today’s post is a long read, but in it we will review the research leading up to the study, explain the science behind the impressive feat, and discuss where things go from here.

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Different types of cells in the body. Source: Dreamstime

In your body at this present moment in time, there is approximately 40 trillion cells (Source).

The vast majority of those cells have developed into mature types of cell and they are undertaking very specific functions. Muscle cells, heart cells, brain cells – all working together in order to keep you vertical and ticking.

Now, once upon a time we believed that the maturation (or the more technical term: differentiation) of a cell was a one-way street. That is to say, once a cell became what it was destined to become, there was no going back. This was biological dogma.

Then a guy in Japan did something rather amazing.

Who is he and what did he do?

This is Prof Shinya Yamanaka:

yamanaka-s

Prof Shinya Yamanaka. Source: Glastone Institute

He’s a rockstar in the scientific research community.

Prof Yamanaka is the director of Center for induced Pluripotent Stem Cell Research and Application (CiRA); and a professor at the Institute for Frontier Medical Sciences at Kyoto University.

But more importantly, in 2006 he published a research report demonstrating how someone could take a skin cell and re-program it so that was now a stem cell – capable of becoming any kind of cell in the body.

Here’s the study:

IPS2

Title: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.
Authors: Takahashi K, Yamanaka S.
Journal: Cell. 2006 Aug 25;126(4):663-76.
PMID: 16904174 (This article is OPEN ACCESS if you would like to read it)

Shinya Yamanaka‘s team started with the hypothesis that genes which are important to the maintenance of embryonic stem cells (the cells that give rise to all cells in the body) might also be able to cause an embryonic state in mature adult cells. They selected twenty-four genes that had been previously identified as important in embryonic stem cells to test this idea. They used re-engineered retroviruses to deliver these genes to mouse skin cells. The retroviruses were emptied of all their disease causing properties, and could thus function as very efficient biological delivery systems.

The skin cells were engineered so that only cells in which reactivation of the embryonic stem cells-associated gene, Fbx15, would survive the testing process. If Fbx15 was not turned on in the cells, they would die. When the researchers infected the cells with all twenty-four embryonic stem cells genes, remarkably some of the cells survived and began to divide like stem cells.

In order to identify the genes necessary for the reprogramming, the researchers began removing one gene at a time from the pool of twenty-four. Through this process, they were able to narrow down the most effective genes to just four: Oct4, Sox2, cMyc, and Klf4, which became known as the Yamanaka factors.

This new type of cell is called an induced pluripotent stem (IPS) cell – ‘pluripotent’ meaning capable of any fate.

The discovery of IPS cells turned biological dogma on it’s head.

And in acknowledgement of this amazing bit of research, in 2012 Prof Yamanaka and Prof John Gurdon (University of Cambridge) were awarded the Nobel prize for Physiology and Medicine for the discovery that mature cells can be converted back to stem cells.

Prof Yamanaka and Prof Gurdon. Source: UCSF

Prof Gurdon achieved the feat in 1962 when he removed the nucleus of a fertilised frog egg cell and replaced it with the nucleus of a cell taken from a tadpole’s intestine. The modified egg cell then grew into an adult frog! This fascinating research proved that the mature cell still contained the genetic information needed to form all types of cells.

EDITOR’S NOTE: We do not want to be accused of taking anything away from Prof Gurdon’s contribution to this field (which was great!) by not mentioning his efforts here. For the sake of saving time and space, we are focusing on Prof Yamanaka’s research as it is more directly related to today’s post.

ips-cells

Making IPS cells. Source: learn.genetics

This amazing discovery has opened new doors for biological research and provided us with incredible opportunities for therapeutic treatments. For example, we can now take skins cells from a person with Parkinson’s disease and turn those cells into dopamine neurons which can then be tested with various drugs to see which treatment is most effective for that particular person (personalised medicine in it’s purest form).

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Some of the option available to Parkinson’s disease. Source: Nature

Imagination is literally the only limiting factor with regards to the possible uses of IPS cell technology.

Shortly after Yamanaka’s research was published in 2006, however, the question was asked ‘rather than going back to a primitive state, can we simply change the fate of a mature cell directly?’ For example, turn a skin cell into a neuron.

This question was raised mainly to address the issue of ‘age’ in the modelling disease using IPS cells. Researchers questioned whether an aged mature cell reprogrammed into an immature IPS cell still carried the characteristics of an aged cell (and can be used to model diseases of the aged), or would we have to wait for the new cell to age before we can run experiments on it. Skin biopsies taken from aged people with neurodegenerative conditions may lose the ‘age’ element of the cell and thus an important part of the personalised medicine concept would be lost.

So researchers began trying to ‘re-program’ mature cells. Taking a skin cell and turning it directly into a heart cell or a brain cell.

And this is probably the craziest part of this whole post because they actually did it!

Different methods of inducing skin cells to become something else. Source: Neuron

In 2010, scientists from Stanford University published this report:

Nature2

Title: Direct conversion of fibroblasts to functional neurons by defined factors
Authors: Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M.
Journal: Nature. 2010 Feb 25;463(7284):1035-41.
PMID: 20107439

In this study, the researchers demonstrated that the activation of three genes (Ascl1, Brn2 and Myt1l) was sufficient to rapidly and efficiently convert skin cells into functional neurons in cell culture. They called them ‘iN’ cells’ or induced neuron cells. The ‘re-programmed’ skin cells made neurons that produced many neuron-specific proteins, generated action potentials (the electrical signal that transmits a signal across a neuron), and formed functional connection (or synapses) with neighbouring cells. It was a pretty impressive achievement, which they beat one year later by converting mature liver cells into neurons – Click here to read more on this – Wow!

The next step – with regards to our Parkinson’s-related interests – was to convert skin cells directly into dopamine neurons (the cells most severely affected in the condition).

And guess what:

PSNA

Title: Direct conversion of human fibroblasts to dopaminergic neurons.
Authors: Pfisterer U, Kirkeby A, Torper O, Wood J, Nelander J, Dufour A, Björklund A, Lindvall O, Jakobsson J, Parmar M
Journal: Proc Natl Acad Sci U S A (2011) 108:10343-10348.
PMID: 21646515 (This article is OPEN ACCESS if you would like to read it)

In this study, Swedish researchers confirmed that activation of Ascl1, Brn2, and Myt1l re-programmed human skin cells directly into functional neurons. But then if they added the activation of two additional genes, Lmx1a andFoxA2 (which are both involved in dopamine neuron generation), they could convert skin cells directly into dopamine neurons. And those dopamine neurons displayed all of the correct features of normal dopamine neurons.

With the publication of this research, it suddenly seemed like anything was possible and people began make all kinds of cell types out of skin cells. For a good review on making neurons out of skin cells – Click here.

Given that all of this was possible in a cell culture dish, some researchers started wondering if direct reprogramming was possible in the body. So they tried.

And again, guess what:

Nature1

Title: In vivo reprogramming of adult pancreatic exocrine cells to beta-cells.
Authors: Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA.
Journal: Nature. 2008 Oct 2;455(7213):627-32.
PMID: 18754011

Using the activation of three genes (Ngn3, Pdx1 and Mafa), the investigators behind this study re-programmed differentiated pancreatic exocrine cells in adult mice into cells that closely resemble b-cells. And all of this occurred inside the animals, while the animals were wandering around & doing their thing!

Now naturally, researchers in the Parkinson’s disease community began wondering if this could also be achieved in the brain, with dopamine neurons being produced from re-programmed cells.

And (yet again) guess what:

in-vivo

Title: Generation of induced neurons via direct conversion in vivo
Authors: Torper O, Pfisterer U, Wolf DA, Pereira M, Lau S, Jakobsson J, Björklund A, Grealish S, Parmar M.
Journal: Proc Natl Acad Sci U S A. 2013 Apr 23;110(17):7038-43.
PMID: 23530235 (This article is OPEN ACCESS if you would like to read it)

In this study, the Swedish scientists (behind the previous direct re-programming of skin cells into dopamine neurons) wanted to determine if they could re-program cells inside the brain. Firstly, they engineered skin cells with the three genes (Ascl1, Brn2a, & Myt1l) under the control of a special chemical – only in the presence of the chemical, the genes would be activated. They next transplanted these skin cells into the brains of mice and began adding the chemical to the drinking water of the mice. At 1 & 3 months after transplantation, the investigators found re-programmed cells inside the brains of the mice.

Next, the researchers improved on their recipe for producing dopamine neurons by adding the activation of two further genes: Otx2 and Lmx1b (also important in the development of dopamine neurons). So they were now activating a lot of genes: Ascl1, Brn2a, Myt1l, Lmx1a, FoxA2, Otx2 and Lmx1b. Unfortunately, when these reprogrammed cells were transplanted into the brain, few of them survived to become mature dopamine neurons.

The investigators then ask themselves ‘do we really need to transplant cells? Can’t we just reprogram cells inside the brain?’ And this is exactly what they did! They injected the viruses that allow for reprogramming directly into the brains of mice. The experiment was designed so that the cargo of the viruses would only become active in the astrocyte cells, not neurons. And when the researchers looked in the brains of these mice 6 weeks later, they found numerous re-programmed neurons, indicating that direct reprogramming is possible in the intact brain.

So what was so special about the research published last week about? Why the media hype?

The research published last week, by another Swedish group, took this whole process one step further: Not only did they re-program astrocytes in the brain to become dopamine neurons, but they also did this on a large enough scale to correct the motor issues in a mouse model of Parkinson’s disease.

Here is the study:

Title: Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson’s disease model
Authors: di Val Cervo PR, Romanov RA, Spigolon G, Masini D, Martín-Montañez E, Toledo EM, La Manno G, Feyder M, Pifl C, Ng YH, Sánchez SP, Linnarsson S, Wernig M, Harkany T, Fisone G, Arenas E.
Journal: Nature Biotechnology (2017) doi:10.1038/nbt.3835
PMID: 28398344

These researchers began this project 6 years ago with a new cocktail of genes for reprogramming cells to become dopamine neurons. They used the activation of NEUROD1, ASCL1 and LMX1A, and a microRNA miR218 (microRNAs are genes that produce RNA, but not protein – click here for more on this). These genes improved the reprogramming efficiency of human astrocytes to 16% (that is the percentage of astrocytes that were infected with the viruses and went on to became dopamine neurons). The researchers then added some chemicals to the reprogramming process that helps dopamine neurons to develop in normal conditions, and they observed an increase in the level of reprogramming to approx. 30%. And these reprogrammed cells display many of the correct properties of dopamine neurons.

Next the investigators decided to try this conversion inside the brains of mice that had Parkinson’s disease modelled in them (using a neurotoxin). The delivery of the viruses into the brains of these mice resulted in reprogrammed dopamine neurons beginning to appear, and 13 weeks after the viruses were delivered, the researchers observed improvements in the Parkinson’s disease related motor symptoms of the mice. The scientists concluded that with further optimisation, this reprogramming approach may enable clinical therapies for Parkinson’s disease, by the delivery of genes rather than transplanted cells.

How does this reprogramming work?

As we have indicated above, the re-programming utilises re-engineered viruses. They have been emptied of their disease causing elements, allowing us to use them as very efficient biological delivery systems. Importantly, retroviruses infect dividing cells and integrate their ‘cargo’ into the host cell’s DNA.

RetroviralIntegration

Retroviral infection and intergration into DNA. Source: Evolution-Biology

The ‘cargo’ in the case of IPS cells, is a copy of the genes that allow reprogramming (such as the Yamanaka genes), which the cell will then start to activate, resulting in the production of protein for those genes. These proteins subsequently go on to activate a variety of genes required for the maintenance of embryonic stem cells (and re-programming of mature cells).

And viruses were also used for the re-programming work in the brain as well.

There is the possibility that one day we will be able to do this without viruses – in 2013, researchers made IPS cells using a specific combination of chemicals (Click here to read more about this) – but at the moment, viruses are the most efficient biological targeting tool we have.

So what does it all mean?

Last week researchers is Sweden published research explaining how they reprogrammed some of the helper cells in the brains of Parkinsonian mice so that they turned into dopamine neurons and helped to alleviate the symptoms the mice were feeling.

This result and the trail of additional results outlined above may one day be looked back upon as the starting point for a whole new way of treating disease and injury to particular organs in the body. Suddenly we have the possibility of re-programming cells in our body to under take a new functions to help combat many of the conditions we suffer.

It is important to appreciate, however, that the application of this technology is still a long way from entering the clinic (a great deal of optimisation is required). But the fact that it is possible and that we can do it, raises hope of more powerful medical therapies for future generations.

As the researchers themselves admit, this technology is still a long way from the clinic. Improving the efficiency of the technique (both the infection of the cells and the reprogramming) will be required as we move down this new road. In addition, we will need to evaluate the long-term consequences of removing support cells (astrocytes) from the carefully balanced system that is the brain. Future innovations, however, may allow us to re-program stronger, more disease-resistant dopamine neurons which could correct the motor symptoms of Parkinson’s disease without being affected by the disease itself (as may be the case in transplanted cells – click here to read more about this).

Watch for a lot more research coming from this topic.

The banner for today’s post was sourced from Greg Dunn (we love his work!)

An Ambroxol update – active in the brain

April 16, 2017 ~ Simon ~ 5 Comments

Ambroxol-800x400

This week pre-clinical data was published demonstrating that the Ambroxol is active in the brain.

This is important data given that there is currently a clinical trial being conducted for Ambroxol in Parkinson’s disease.

Today’s post will review the new data and discuss what is happening regarding the clinical trial.

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Ambroxol. Source: Skinflint

We have previously discussed the potential use of Ambroxol in the treatment of Parkinson’s disease (Click here to read that post). Today we follow up that post with new data that provides further support for an on-going clinical trial.

Firstly, what is Ambroxol?

Ambroxol is a commonly used treatment for respiratory diseases (the respiratory system being the lungs and related components required for breathing). Ambroxol promotes the clearance of mucus and eases coughing. It also has anti-inflammatory properties, reducing redness in a sore throat. It is the active ingredient of products like Mucosolvan, Mucobrox, and Mucol.

What is the connection between Ambroxol and Parkinson’s disease?

So this is where a gene called GBA comes into the picture.

Genetic mutations in the GBA (full name: Glucosylceramidase Beta) gene are the most common genetic anomaly associated with Parkinson’s disease. People with a mutation in their GBA gene have a higher risk of developing Parkinson’s disease than the general population. And interestingly, people with Parkinson’s disease are approximately five times more likely to carry a GBA mutation than healthy control subjects.

What does GBA do?

The GBA gene provides the instructions for making an enzyme (called glucocerebrosidase) that helps with the digestion and recycling of waste inside cells. The enzyme is located and active inside ‘lysosomes‘.

What are Lysosomes?

Lysosomes are small bags of digestive enzymes that can be found inside cells. They help to break down proteins that have either been brought into the cell or that have served their function and need to be digested and disposed of (or recycled).

Lysosomes

How lysosomes work. Source: Prezi

Inside the lysosomes are enzymes like glucocerebrosidase which help to break material down into useful parts. The lysosome will fuse with other small bags (called vacuole) that act as storage vessels of material inside a cell. The enzymes from the lysosome will mix with the material in the vacuole and digest it (or it break down into more manageable components).

Now people with a genetic mutation in their GBA gene will often have an abnormally short, non-functioning version of the glucocerebrosidase enzyme. In those cases the breaking down of waste inside the lysosome becomes inhibited. And if waste can’t be disposed of or recycled properly, things start to go wrong in the cell.

How does Ambroxol correct this?

It was recently shown that Ambroxol triggers exocytosis of lysosomes (Source). Exocytosis is the process by which waste is exported out of the cell.

exocytosis

Exocytosis. Source: Socratic

Thus by encouraging lysosomes to undergo exocytosis and spit their contents out of the cell – digested or not – Ambroxol allows the cell to remove waste effectively and therefore function in a more normal fashion. This mechanism of treatment seemingly bi-passes the faulty glucocerebrosidase digestion enzyme entirely.

Until recently, two important questions, however, have remained unanswered:

Does Ambroxol enter the brain and have this function there?
What are the consequences of long term Ambroxol use?

We now have an answer for question no. 1:

Amb2

Title: Ambroxol effects in glucocerebrosidase and α-synuclein transgenic mice.
Authors: Migdalska-Richards A, Daly L, Bezard E, Schapira AH.
Journal: Ann Neurol. 2016 Nov;80(5):766-775.
PMID: 27859541 (This article is OPEN ACCESS if you would like to read it)

In this study, the researchers treated mice with Ambroxol for 12 days and then measured the level of glucocerebrosidase activity in the brain. They gave Ambroxol to three different groups of mice:

a group of normal mice,
a group of mice which had been genetically engineered with a specific mutation in their GBA gene (the heterozygous L444P mutation)
a group of mice that produced human alpha synuclein (the protein closely associated with Parkinson’s disease).

When they looked at the level of glucocerebrosidase enzyme activity in normal mice, they found an increase of approximately 20% (in mice treated with 4mM Ambroxol). One curious finding was that this dose was the only dose that increase glucocerebrosidase activity (1, 3, and 5mM of Ambroxol had no effect). The investigators noted, however, a reduction in water drinking of mice receiving 5mM in their drinking water (maybe they didn’t like the taste of it!), suggesting that they were not getting as much Ambroxol as the 4mM group.

The 4mM level of of Ambroxol also increased glucocerebrosidase activity in the L444P mutation mice and the alpha-synuclein mice (which interestingly also has reduced levels of glucocerebrosidase activity). One important observation in the alpha synuclein mice was the finding that Ambroxol was able to reduce the levels of alpha synuclein in the cells, indicating better clearance of un-wanted excess of proteins.

These combined results suggested to the investigators that Ambroxol is entering the brain of mice (passing through the protective blood brain barrier) and able to be effective there. In addition, they did not witness any serious adverse effects of ambroxol administration in the mice – an observation made in other studies of Ambroxol in normal mice (Click here to read more about this).

These studies have been followed up by a dosing study in primates which was just published:

Ambrox

Title: Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate.
Authors: Migdalska-Richards A, Ko WK, Li Q, Bezard E, Schapira AH.
Journal: Synapse. 2017 Mar 12. doi: 10.1002/syn.21967.
PMID: 28295625 (This article is OPEN ACCESS if you would like to read it)

In this study, the investigators analysed the effect of Ambroxol treatment on glucocerebrosidase activity in three healthy non-human primates. One subject was given an ineffective control solution vehicle, another subject received 22.5 mg/day of Ambroxol and the third subject received 100 mg/day of Ambroxol. They showed that daily administration 100 mg/day of Ambroxol results in increased levels of glucocerebrosidase activity in the brain (approximately 20% increase on average across different areas of the brain). Importantly, the 22.5 mg treatment did not result in any increase.

The investigators wanted to determine if the effect of Ambroxol was specific to glucocerebrosidase, and so they analysed the activity of another lysosome enzyme called beta-hexosaminidase (HEXB). They found that 100 mg/day of Ambroxol also increased HEXB activity (again by approximately 20%), suggesting that Ambroxol may be having an effect on other lysosome enzymes and not just glucocerebrosidase.

The researches concluded that these results provide the first data of the effect of Ambroxol treatment on glucocerebrosidase activity in the brain of non-human primates. In addition, the results indicate that Ambroxol is active and as the researchers wrote “should be further investigated in the context of clinical trials as a potential treatment for Parkinson’s disease”.

And there is a clinical trial currently underway?

Yes indeed.

Funded by the Cure Parkinson’s Trust and the Van Andel Research Institute (USA), there is currently a phase I clinical trial with 20 people with Parkinson’s disease receiving Ambroxol over 24 months. Importantly, the participants being enrolled in the study have both Parkinson’s disease and a mutation in their GBA gene. The study is being led by Professor Anthony Schapira at the Royal Free Hospital (London).

EDITORS NOTE HERE: Readers may be interested to know that Prof Schapira is also involved with another clinical trial for GBA-associated Parkinson’s disease. The work is being conducted in collaboration with the biotech company Sanofi Genzyme, and involves a phase II trial, called MOVE-PD, which is testing the efficacy, and safety of a drug called GZ/SAR402671 (Click here to read more about this clinical trial). GZ/SAR402671 is a glucosylceramide synthase inhibitor, which will hopefully reduce the production and consequent accumulation of glycosphingolipids in people with a mutation in the GBA gene. This approach is trying to reduce the amount of protein that can not be broken down by the faulty glucocerebrosidase enzyme. The MOVE-PD study will enroll more than 200 patients worldwide (Click here and here to read more on this).

The current Phase 1 trial at the Royal Free Hospital will be primarily testing the safety of Ambroxol in GBA-associated Parkinson’s disease. The researchers will, however, be looking to see if Ambroxol can increase levels of glucocerebrosidase and also assess whether this has any beneficial effects on the Parkinson’s features.

So what does it all mean?

There is a major effort from many of the Parkinson’s disease related charitable groups to clinically test available medications for their ability to slow this condition. Big drug companies are not interested in this ‘re-purposing effort’ as many of these drugs are no longer patent protected and thus providing limited profit opportunities for them. This is one of the unfortunate realities of the pharmaceutical industry business model.

One of the most interesting drugs being tested in this re-purposing effort is the respiratory disease-associated treatment, Ambroxol. Recently new research has been published that indicates Ambroxol is able to enter the brain and have an impact by increasing the level of protein disposal activity.

A clinical trial testing Ambroxol in Parkinson’s disease is underway and we will be watching for the results when they are released (most likely late 2019/early 2020, though preliminary results may be released earlier).

This trial is worth watching.

Stay tuned.

EDITOR’S NOTE: Under absolutely no circumstances should anyone reading this material consider it medical advice. The material provided here is for educational purposes only. Before considering or attempting any change in your treatment regime, PLEASE consult with your doctor or neurologist. Amboxol is a commercially available medication, but it is not without side effects (for more on this, see this website). We urge caution and professional consultation before altering a treatment regime. SoPD can not be held responsible for any actions taken based on the information provided here.

The banner for today’s post was sourced from Pharmacybook

Stimulating research in London (Canada)

April 14, 2017April 15, 2017 ~ Simon ~ 2 Comments

Spinal-Cord-final

Recently the SoPD has been contacted by readers asking about this video:

http://london.ctvnews.ca/video?clipId=1080895

The video presents a news article from Canada describing a clinical study of spinal cord stimulation for Parkinson’s disease.

In today’s post we review what spinal cord stimulation is and what research has been done in Parkinson’s disease.

should-say-50th-birthday-speech_67e6879f1e6fbd7

50 years celebration. Source: Reference

As many readers will be aware from 2017 represents the 200 year anniversary of the first description of Parkinson’s disease by one Mr James Parkinson.

Many readers will not be aware, however, that 2017 is also represents the 50th anniversary of the first use of a technique called spinal cord stimulation:

What is spinal cord stimulation?

Anterior_thoracic_SCS

An x-ray of the spine with a stimulator implanted (towards the top of the image, and cords leading off to the bottom left). Source: Wikipedia

A spinal cord stimulator involves a small device being used to apply pulsed electrical signals to the spinal cord. It is generally used for pain relief, but it has recently been tested in a variety of other medical conditions.

The device is a column of stimulating electrodes that is surgically implanted in the epidural space of the spine. And before you ask: the epidural space is the area between the outer protective skin of the spinal cord (called the dura mater) and the surrounding vertebrae. So the device lies against the spinal cord, and is protected by the bones that make up the spine (as shown in the image below).

stimimplanttrial_1280

The stimulating electrodes within the epidural space. Source: SpineOne

An electrical pulse generator is implanted in the lower abdomen and conducting wires are connected between the electrodes to the generator. Much like deep brain stimulation, the system is entirely enclosed in the body and operated with a remote control.

How does spinal cord stimulation work?

The stimulation basically interrupts the feeling of pain – blocking it from reaching the brain – substituting it with a more pleasing sensation called paresthesia (a kind of tingling or numbness).

PE-SCS Fig1

Source: MayoClinic

The stimulation does not eliminate the source of pain, it simply masks it by interfering with the signal going to the brain. As a result the amount of relief from pain varies from person to person. In general, spinal cord stimulation resulting in a 50-70% reduction in pain.

But Parkinson’s results from inability to move, how would spinal cord stimulation work in Parkinson’s disease?

Yeah, this is a good question and the answer is not entirely clear, but the researchers (behind the research we discuss below) suggest that beneficial effects from spinal cord stimulation in Parkinson’s disease could be coming from direct activation of ascending pathways reaching thalamic nuclei and the cerebral cortex. That is to say (in plain English): activation of the spinal cord results in a signal going up into the brain where it alters the interaction between two of the regions involved in the initiation of movement (the thalamus and the cortex). And as we shall discuss below, there is evidence backing this idea.

Ok, so how much research has been done on spinal cord stimulation for Parkinson’s disease?

Actually quite a bit (in fact, for a good early review on the topic – click here).

The first real attempt at spinal cord stimulation for Parkinson’s disease was this report here:

Spinal1

Title: Spinal Cord Stimulation Restores Locomotion in Animal Models of Parkinson’s Disease
Authors: Fuentes, R., Petersson, P., Siesser, W. B., Caron, M. G., & Nicolelis, M. A. L.
Journal: Science (2009) 323(5921), 1578-1582.
PMID: 19299613 (This article is OPEN ACCESS if you would like to read it)

It was conducted by Prof Miguel Nicolelis and his colleagues at Duke University. Duke were kind enough to make this short video about the research:

https://www.youtube.com/watch?v=0b6OElzJlMg

In their research report, the scientists injected mice with a drug that reduced the level of dopamine in the brain (the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine or AMPT). Similar to Parkinson’s disease, this resulted in a significant reduction in the movements of those mice. It also resulted in changes in the neuronal activity patterns of cells in an area of the brain called the motor cortex (we have talked about the motor cortex in a previous post). When the researchers then conducted spinal cord stimulation on these mice, they found that stimulation corrected both the loss of movement and the altered activity in the motor cortex.

The researchers then tested spinal cord stimulation in rats which had their dopamine system severely depleted (using the neurotoxin 6-OHDA), and they again found that the treatment could rescue the loss of locomotor ability. Curiously, spinal cord stimulation in the rats also caused an increase in locomotion activity after the stimulation period had stopped. On top of this, the researchers found that spinal cord stimulation aided the effect of L-dopa, allowing lower doses of L-dopa to achieve the same behavioural results as higher doses in animals not receiving spinal cord stimulation.

These initial results were then replicated in primates:

Monkey

Title: Spinal cord stimulation alleviates motor deficits in a primate model of Parkinson disease.
Authors: Santana MB, Halje P, Simplício H, Richter U, Freire MA, Petersson P, Fuentes R, Nicolelis MA.
Journal: Neuron. 2014 Nov 19;84(4):716-22.
PMID: 25447740 (This article is OPEN ACCESS if you would like to read it)

In this study, the researchers modelled Parkinson’s disease in five adult marmosets using the neurotoxin 6-OHDA, which resulted in a reduction in spontaneous behaviour and a significant loss of dopamine neurons in the brain. They then implanted a spinal cord stimulator in each of the animals, which once activated resulted in a 200% improvement in some aspects of behavioural activity. Improvements observed in Parkinson’s-like features included freezing (31%), hypokinesia (23%), posture (23%), and bradykinesia (21%) as calculated by investigators blind to the treatment conditions of each subject.

In the brain, the researchers found that spinal cord stimulation resulted in similar improvements in neural activity as that seen with L-dopa treatment. Given all of these results, the investigators concluded that spinal cord stimulation “should be further tested in clinical studies aimed at measuring its long-term efficacy as a less invasive, long-term therapy for” people with Parkinson’s disease.

And it was not just Prof Nicolelis’ group that has achieved these results. Japanese researchers have also reported spinal cord stimulation having beneficial effects in models of Parkinson’s disease:

NeuoroProtect

Title: Spinal cord stimulation exerts neuroprotective effects against experimental Parkinson’s disease.
Authors: Shinko A, Agari T, Kameda M, Yasuhara T, Kondo A, Tayra JT, Sato K, Sasaki T, Sasada S, Takeuchi H, Wakamori T, Borlongan CV, Date I.
Journal: PLoS One. 2014 Jul 10;9(7):e101468.
PMID: 25009993 (This article is OPEN ACCESS if you would like to read it)

In this report, the researchers actually found that spinal cord stimulation resulted in neuroprotection in a classical model of Parkinson’s disease (rodent 6-OHDA striatal delivery). Across three different levels of stimulation, the researchers reported better rescue of motor deficits and protection of dopamine neurons (particularly for 50Hz stimulation). The researchers also provided evidence suggesting that the neuroprotective effect might have something to do with a protein called Vascular endothelial growth factor (or VEGF). Interestingly, they found that the neuroprotective protein GDNF (that we have discussed before – click here for that post) was not involved.

So has this spinal stimulation procedure ever been conducted in humans with Parkinson’s disease before?

Yes, it has. But the results were a bit disappointing.

Stim1

Title: Spinal cord stimulation failed to relieve akinesia or restore locomotion in Parkinson disease.
Authors: Thevathasan W, Mazzone P, Jha A, Djamshidian A, Dileone M, Di Lazzaro V, Brown P.
Journal: Neurology. 2010 Apr 20;74(16):1325-7.
PMID: 20404313 (This article is OPEN ACCESS if you would like to read it)

In this very small clinical study, just two people (both 75+ years of age) with Parkinson’s disease were fitted with spinal cord stimulators. Ten days after the surgery, the subjects participated in a blind analysis of the motor effects of spinal stimulation (blind analysis meaning that the assessors were not aware of their surgical treatment). The assessors, however, found no improvements as a result of the stimulation treatment.

This report lead to a letter to the journal from Prof Nicolelis and his colleagues:

Neurol

In their letter, Prof Nicolelis and co point out several issues with the clinical study that may impact the final results (such as the tiny size of the study (only two participants) and the fact that the electrodes were located at a high cervical level, while in the rodent study they were located at a high thoracic level). In addition, the commercially available electrodes used in the human clinical study did not match the relative size or orientation of the electrodes used in the rodent study.

The researchers of the clinical study suggested that the beneficial motor effect described in the rodent study may be due to an increase in arousal (as a result of higher stimulation). But Prof Nicolelis and colleagues pointed out in their letter that their rodent study included three control experiments (including air puffs, trigeminal stimulation at the highest intensity tolerated by the animals, and direct measurements of changes in heart rate following spinal stimulation) which did not find a strong connection between arousal response and recovery seen in the level of locomotion.

The letter concluded that the results of the small clinical trial were inconclusive, and that further research in nonhuman primate models of Parkinson’s are required to determine the effects of electrode design and stimulation parameters. The doctors behind the clinical study agreed that more research is required.

And what do we know about this new clinical study?

Unfortunately, not very much.

The study is being conducted by Prof. Mandar Jog of Western University. Recently the Parkinson’s Society Southwestern Ontario provided some funding towards the study (Click here for more on this), but that is about as much as we could find on the work.

So what does it all mean?

Summing up: Spinal cord stimulation is a technique that is used to alleviate severe back pain. It has recently been proposed for Parkinson’s disease, resulting in several clinical trials. Here at the SoPD we are not sure what our opinion on spinal cord stimulation is at present, except that more research is obviously required.

If the results from the new clinical study (being conducted in Canada) indicate that spinal cord stimulation has beneficial effects for people with Parkinson’s disease, it would certainly represent a significant step forward for the community which relies heavily on symptom masking drugs at present. Before proceeding to wider clinical availability, however, larger clinical studies will be required to truly demonstrate safety and efficacy.

We’ll let you know if we hear anything else about this developing area of research.

The banner for today’s post was sourced from Greg Dunn