New drug approved for ALS


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.


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.


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:


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:


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:


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:


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:


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:


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

Blood transfusions and Parkinson’s disease


Donating blood helps to save lives. And an awful lot of blood is needed on a daily basis: In the England alone, over 6,000 blood donations are required every day to treat patients.

There has been concerns over the years about what can be transmitted via blood donation (from donor to recipient). The good news is that we now know that Parkinson’s disease is not.

Today’s post looks at recent research investigating this issue and discusses the implications of the findings.


Blood transfusions save lifes. Source: New York Times

The average adult human carries approx. 10 pints (about 6 litres) of blood in his body. So much blood, that we actually have an excess – we can survive with a little less. And this allows us to donate blood to blood banks on a regular basis (approx. every 8 weeks). Roughly 1 pint can be given during each blood donation and our bodies will have no trouble replacing it all.

These donations can be used in blood transfusions, replacing blood that has been lost via accident or during surgical procedures. It may surprise you that blood transfusion (from human to human) has been practised for some time. The very first blood transfusion was performed by an obstetrician named Dr. James Blundell in the late 1820’s.


Dr. James Blundell. Source: Wikpedia

The exact date of that first procedure is the subject of debate, but Blundell wrote up his experience in the journal Lancet in 1829:


Blundell’s article in the journal Lancet. Source: Wikipedia

Since that time, blood transfusions have gradually become an everyday occurrence at hospitals all over the world. And as we suggested above a lot of blood is used on a daily basis, keeping people alive. Determining whether each donation of blood is safe to use is obviously a critical step in this process, and all donated blood is tested for HIV, hepatitis B and C, syphilis and other infectious diseases before it is released to hospitals. But for a long time there has been a lingering concern that not everything is being detected and filtered out.

In fact there has been a serious concern that some neurodegenerative conditions like Alzheimer’s and Parkinson’s disease may be transmissible. If these diseases are being caused by ‘prion-like behaviour’ from the particular proteins involved with these conditions (eg. beta amyloid and alpha synuclein, respectively), then there is a very real possibility that such rogue proteins could be transferred via blood transfusions.

This was a concern (note the past tense) until July of this year when this research report was published (with a rather mis-leading title):


Title: Transmission of neurodegenerative disorders through blood transfusion. A cohort study
Authors: Edgren G, Hjalgrim H, Rostgaard K, Lambert P, Wikman A, Norda R, Titlestad KE, Erikstrup C, Ullum H, Melbye M, Busch MP, Nyrén O.
Journal: Ann Intern Med. 2016 Sep 6;165(5):316-24.
PMID: 27368068

The researchers in this study took all of the data from the enormous nationwide registers of blood transfusions in Sweden and Denmark – collectively almost 1.5 million people have received transfusions in these two countries between 1968 and 2012 – and compared the medical records of the recipients to those of the donors (you have to love the Scandinavians for the medical databases!). Approximately 3% of the recipients received a blood transfusion from a donor who was diagnosed with one of the neurodegenerative diseases included in this study (Alzheimer’s, Parkinson’s and Motor neurone disease (or Amyotrophic lateral sclerosis – ALS). There was absolutely no evidence of transmission of any of these diseases.

For the statistic lovers amongst you, the hazard ratio for dementia in recipients of blood from donors with dementia versus recipients of blood from healthy donors was 1.04 (95% CI, 0.99 to 1.09). Estimates for individual diseases, Alzheimer disease and Parkinson disease were 0.99 (CI, 0.85 to 1.15) and 0.94 (CI, 0.78 to 1.14), respectively.

These statistics mean that if Parkinson’s disease is being transmitted via a blood transfusion, it is an extremely rare event.

So what does this mean for our understanding of Parkinson’s disease?

Well, we already know that you can’t catch Parkinson’s disease from your spouse (Click here to read more on this) and there is a lot of other evidence to suggest that Parkinson’s disease is not contagious (Click here to read more on this). So this is one less thing for carers, family members and friends to worry about.

But if Parkinson’s disease is not caused by some contagious agent, this knowledge has major implications for our understanding of the disease. Previous lab-based research has pointed toward a ‘Prion’-like nature to alpha synuclein (the protein most associated with Parkinson’s disease. Prions being small infectious agents made up entirely of protein material, that can lead to disease that is similar to viral infection. And researchers actually found that if you inject specific types of alpha synuclein into the muscles of mice, those animals would start to develop cell loss in the brain (Click here to read more about this).

If Parkinson’s disease is a ‘prion’ condition, then we have to ask one important question: why isn’t it being transmitted via blood transfusion? Alpha synuclein is certainly found in the blood of people with Parkinson’s disease.

It could be that an infectious agent initiated the condition many years ago and it has very slowly been developing (similar to chronic infections resulting from Hepatitis – click here to read more on this).

Research like we have reviewed today may result in a serious re-think of our theory of Parkinson’s disease.

The banner for today’s post was sourced from CampusCluj

Older siblings and Parkinson’s disease

Curious new research results out of Sweden this weekend…

To all of our readers who have older siblings that you grew up fighting with – you should  go and give them a hug today, because apparently they have lowered your risk of Parkinson’s disease.

Like I said ‘curious’.


Source: Buzzfeed

Older siblings. Nothing but trouble (a bit like younger siblings now that I think about it).

Who needs them.

Well, according to a massive new epidemiological study from the Karolinska Institutet, Stockholm (Sweden), we all do!


Title: Early-Life Factors and Risk of Parkinson’s Disease: A Register-Based Cohort Study.
Authors: Liu B, Chen H, Fang F, Tillander A, Wirdefeldt K.
Journal: PLoS One. 2016 Apr 15;11(4):e0152841.
PMID: 27082111      (This article is OPEN ACCESS if you would like to read it)

This is a fascinating study, not only in its size and scale, but for the interesting details in the results.

The investigators collected a huge amount of information from multiple nationwide Swedish registers that are cross-linked thanks to the national personal identification number system that is used in Sweden (each Swedish resident is assigned a unique number).


Stockholm, the capital of Sweden. Source: Budgetyourtrip

The information was collected from:

  • The Swedish Multi-Generation Register (MGR) – which holds information about the biological and adoptive parents for all residents born in 1932 or later, and were alive or lived in Sweden in 1961. This database covers over 95% of Swedish-born residents, plus more than 22% of foreign-born residents in Sweden.
  • The Swedish Patient Register – established in 1964/1965, this databases collects inpatient discharge records. It became nationwide in 1987, and since 2001, the Patient Register has recorded information on every inpatient visit and vast majority of the outpatient visits for all Swedish residents. 
  • They also linked their data to the Migration Register and Swedish Population and Housing Censuses from 1960, 1970, 1980, and 1990 for information on socio-economic status.

Like I said, ‘a huge amount of information’. They next set up a selection criteria. Within their pool of people for analysis, individuals had to:

  • be born in Sweden between 1932 and 1970
  • have information available regarding maternal links in the MGR
  • be alive and free of Parkinson’s disease on January 1, 2002,
  • 40 years or older on January 1, 2002 or turned 40 years during the study period

3 545 612 people fulfilled this criteria. 8779 cases of Parkinson’s disease were identified within that population of people (a further 2658 people were identified as having Parkinson’s disease, but since they were diagnosed before 2002, they were excluded). When looking at the findings of the analysis of this study:


  • the average age of diagnosis was 65.1 years of age
  • males had a higher risk than females (1.5 times more men than women)
  • parental occupation as farmers increased risk of Parkinson’s
  • a family history of the condition results in a higher risk of Parkinson’s disease.
  • No difference between blue or white collar occupations, or self employed roles
  • No difference between month/season of birth
  • No association with early life factors, including flu burden in the year of birth.


Compared to those without older siblings, the risk of developing Parkinson’s disease was 7% lower among participants with older siblings (HR = 0.93, 95% CI: 0.89, 0.98). The number of people with no older siblings was 1.68 million, of which 5384 had Parkinson’s disease. But of those with older siblings (1.86 million) only 3395 had Parkinson’s disease. Curiously, however, there was no further associations (eg. the number of older siblings or the interval length between the individual and their older siblings).

The effect (7%) is small, but the number of cases is very large, so we can assume that the finding is real. But how to explain it?!?

Even more surprisingly:

This is not the first time we’ve seen something like this:


Title: Maternal age, exposure to siblings, and risk of amyotrophic lateral sclerosis.
Authors: Fang F, Kamel F, Sandler DP, Sparén P, Ye W.
Journal: Am J Epidemiol. 2008 Jun 1;167(11):1281-6.
PMID: 18367467

In a similar sort of study published in 2008 (also from researchers at the Karolinska Institute in Sweden), it was reported that the risk of amyotrophic lateral sclerosis (ALS, also called Lou Gehrig’s disease; another neurodegenerative condition) increased with the number of younger siblings, and children whose first younger sibling was born after the age of 6 years had the highest risk of ALS. In contrast to the Parkinson’s research above, however, exposure to older siblings was not associated with an increased risk of ALS.

And a similar sort of result has also been observed in cases of Schizophrenia:


Title: Exposure to prenatal and childhood infections and the risk of schizophrenia: suggestions from a study of sibship characteristics and influenza prevalence.
Authors: Westergaard T, Mortensen PB, Pedersen CB, Wohlfahrt J, Melbye M.
Journal: Arch Gen Psychiatry. 1999 Nov;56(11):993-8.
PMID: 10565498

This research came from a different Scandinavian capital (Copenhagen), and involved only 1.74 million people, but it suggested that larger sibships were associated with an increased risk of developing schizophrenia. This result was independent of birth order or interval length between siblings. 

Why these effects exist is a question yet to be answered. In each of these studies, the authors propose elaborate possibilities (eg. developmental theories involving the immune system, etc), but there is no evidence (yet) to support them. Given that the effects are small (just a 7% reduction in risk in the case of Parkinson’s), it would be interesting to investigate differences between subjects within the Parkinson’s population, to determine if there is a subset of individuals more affected than others by this sibling phenomenon. By comparing which commonalities they may share (genetic, environmental or otherwise) we could identify patterns of risk factors for specific individuals.

So while the Parkinson’s connection is an interesting finding, obviously more research is required to better understand what is going on.

Curious result though, right?