On Saturday 7th January, 2018, one of the world’s largest pharmaceutical companies – Pfizer – announced that it was abandoning research efforts focused on finding new drugs for Alzheimer’s and Parkinson’s.
Naturally, the Parkinson’s and Alzheimer’s communities reacted with disappointment to the news, viewing it as a demoralising tragedy. And there was genuine concern that other pharmaceutical companies would follow suit in the wake of this decision.
Those fears, however, are unfounded.
In today’s post we will look at some of the reasons underlying Pfizer’s decision, why our approach to failure is wrong, why Pfizer will definitely be back, and what the Parkinson’s community can do about it all.
1. Our approach to failure
Matthew Syed. Source: Amazon
In the first chapter of his book, Syed makes comparisons between the way the aviation industry and the medical profession approach failure, pointing out the processes that follow situations when a disasters occur. In the aviation industry, when any event occurs there is a major investigative process that starts with the recovery of the black boxes. The aviation industry uses this system of investigation to learn from every single incident. It makes the information available to all and this helps with re-thinking everything from cockpit ergonomics and design to air traffic controller procedures. Even the airline companies are keen to be seen to be involved in this process of investigation. Failure, while unfortunate, is not shameful or stigmatising, but rather embraced and enlightening.
In addition, Syed points out that when an airline pilot sits down in his/her cockpit, their neck is also on the line if something goes wrong. Thus, it is in their best interest that the flight should be successful. And this is another reason why the aviation industry takes the reporting of failure so seriously. Everyone benefits from learning from previous situations. And all of this comes together with the observation that 2017 was the safest year on record for flying (based on deaths/flights – Source).
Here at the SoPD, we regularly talk about the ‘bad boy’ of Parkinson’s disease – a protein called Alpha Synuclein.
Twenty years ago this year, genetic variations were identified in the alpha synuclein gene that increase one’s risk of developing Parkinson’s. In addition, alpha synuclein protein was found to be present in the Lewy bodies that are found in the brains of people with Parkinson’s. Subsequently, alpha synuclein has been widely considered to be the villain in this neurodegenerative condition and it has received a lot of attention from the Parkinson’s research community.
But it is not the only protein that may be playing a role in Parkinson’s.
Today’s post is all about TAU.
I recently informed my wife that I was thinking of converting to Taoism.
She met this declaration with more of a smile than a look of shock. And I was expecting the latter, as shifting from apatheism to any form of religious belief is a bit of a leap you will appreciate.
When asked to explain myself, I suggested to her that I wanted to explore the mindfulness of what was being proposed by Lao Tzu (the supposed author of the Tao Te Ching – the founding document of Taoism).
This answer also drew a smile from her (no doubt she was thinking that Simon has done a bit of homework to make himself sound like he knows what he was talking about).
But I am genuinely curious about Taoism.
Most religions teach a philosophy and dogma which in effect defines a person. Taoism – which dates from the 4th century BCE – flips this concept on its head. It starts by teaching a single idea: The Tao (or “the way”) is indefinable. And then it follows up by suggesting that each person should discover the Tao on their own terms. Given that most people would prefer more concrete definitions in their own lives, I can appreciate that a lot of folks won’t go in for this approach.
Personally speaking, I quite like the idea that the Tao is the only principle and everything else is a just manifestation of it.
According to Taoism, salvation comes from just one source: Following the Tao.
Oh and don’t worry, I’m not going to force any more philosophical mumbo jumbo on you – Taoism is just an idea I am exploring as part of a terribly clichéd middle-life crisis I’m working my way through (my wife’s actual response to all of this was “why can’t you just be normal and go buy a motor bike or something?”).
My reason for sharing this, however, is that this introduction provides a convenient segway to what we are actually going to talk about in this post.
You see, some Parkinson’s researchers are thinking that salvation from neurodegenerative conditions like Parkinson’s will come from just one source: Following the TAU.
What is TAU?
Last year – two years after actor Robin Williams died – his wife Susan Schneider Williams wrote an essay entitled The terrorist inside my husband’s head, published in the journal Neurology.
It is a heartfelt/heartbreaking insight into the actor’s final years. It also highlights the plight of many who are diagnosed with Parkinson’s disease, but experience an array of additional symptoms that leave them feeling that something else is actually wrong.
Today’s post is all about Dementia with Lewy bodies (or DLB). In particular, we will review the latest refinements and recommendations of the Dementia with Lewy Bodies Consortium, regarding the clinical and pathologic diagnosis of DLB.
Robin Williams. Source: Quotesgram
On the 28th May of 2014, the actor Robin Williams was diagnosed with Parkinson’s disease.
At the time, he had a slight tremor in his left hand, a slow shuffling gait and mask-like face – some of the classical features of Parkinson’s disease.
According to his wife, the diagnosis gave the symptoms Robin had been experiencing a name. And this brought her a sense of relief and comfort. Now they could do something about the problem. Better to know what you are dealing with rather than be left unsure and asking questions.
But Mr Williams sensed that something else was wrong, and he was left unsure and asking questions. While filming the movie Night at the Museum 3, Williams experienced panic attacks and regularly forgot his lines. He kept asking the doctors “Do I have Alzheimer’s? Dementia? Am I schizophrenic?”
Williams took his own life on the 11th August 2014, and the world mourned the tragic loss of a uniquely talented performer.
When the autopsy report came back from the coroner, however, it indicated that the actor had been misdiagnosed.
He didn’t have Parkinson’s disease.
What he actually had was Dementia with Lewy bodies (or DLB).
What is Dementia with Lewy bodies?
In Silicon valley (California), everyone is always looking for the “next killer app” – the piece of software (or application) that is going to change the world. The revolutionary next step that will solve all of our problems.
The title of today’s post is a play on the words ‘killer app’, but the ‘app’ part doesn’t refer to the word application. Rather it relates to the Alzheimer’s disease-related protein Amyloid Precursor Protein (or APP). Recently new research has been published suggesting that APP is interacting with a Parkinson’s disease-related protein called Leucine-rich repeat kinase 2 (or LRRK2).
The outcome of that interaction can have negative consequences though.
In today’s post we will discuss what is known about both proteins, what the new research suggests and what it could mean for Parkinson’s disease.
Seattle. Source: Thousandwonders
In the mid 1980’s James Leverenz and Mark Sumi of the University of Washington School of Medicine (Seattle) made a curious observation.
After noting the high number of people with Alzheimer’s disease that often displayed some of the clinical features of Parkinson’s disease, they decided to examined the postmortem brains of 40 people who had passed away with pathologically confirmed Alzheimer’s disease – that is, an analysis of their brains confirmed that they had Alzheimer’s.
What the two researchers found shocked them:
Title: Parkinson’s disease in patients with Alzheimer’s disease.
Authors: Leverenz J, Sumi SM.
Journal: Arch Neurol. 1986 Jul;43(7):662-4.
Of the 40 Alzheimer’s disease brains that they looked at nearly half of them (18 cases) had either dopamine cell loss or Lewy bodies – the characteristic features of Parkinsonian brain – in a region called the substantia nigra (where the dopamine neurons are located). They next went back and reviewed the clinical records of these cases and found that rigidity, with or without tremor, had been reported in 13 of those patients. According to their analysis 11 of those patients had the pathologic changes that warranted a diagnosis of Parkinson’s disease.
And the most surprising aspect of this research report: Almost all of the follow up studies, conducted by independent investigators found exactly the same thing!
It is now generally agreed by neuropathologists (the folks who analyse sections of brain for a living) that 20% to 50% of cases of Alzheimer’s disease have the characteristic round, cellular inclusions that we call Lewy bodies which are typically associated with Parkinson disease. In fact, in one analysis of 145 Alzheimer’s brains, 88 (that is 60%!) had chemically verified Lewy bodies (Click here to read more about that study).
A lewy body (brown with a black arrow) inside a cell. Source: Cure Dementia
Oh, and if you are wondering whether this is just a one way street, the answer is “No sir, this phenomenon works both ways”: the features of the Alzheimer’s brain (such as the clustering of a protein called beta-amyloid) are also found in many cases of pathologically confirmed Parkinson’s disease (Click here and here to read more about this).
So what are you saying? Alzheimer’s and Parkinson’s disease are the same thing???
People with high socioeconomic status jobs are believed to be better off in life.
New research published last week by the Centre for Disease Control, however, suggests that this may not be the case with regards to one’s risk of developing Parkinson’s disease.
In today’s post we will review the research and discuss what it means for our understanding of Parkinson’s disease.
The impact of socioeconomic status. Source: Medicalxpress
In 2013, a group of researchers at Carnegie Mellon University found a rather astonishing but very interesting association:
Children from lower socioeconomic status have shorter telomeres as adults.
Yeah, wow, strange… sorry, but what are telomeres?
Do you remember how all of your DNA is wound up tightly into 23 pairs of chromosomes? Well, telomeres are at the very ends of each of those chromosomes. They are literally the cap on each end. The name is derived from the Greek words ‘telos‘ meaning “end”, and ‘merοs‘ meaning “part”.
Telomeres are regions of repetitive nucleotide sequences (think the As, Gs, Ts, & Cs that make up your DNA) at each end of a chromosome. Their purpose seems to involve protecting the end of each chromosome from deteriorating or fusing with neighbouring chromosomes. Researchers also use their length is a marker of ageing because every time a cell divides, the telomeres on each chromosome gradually get shorter.
Our apologies to anyone who is squeamish about needles, but this is generally how most people get their seasonal flu vaccination.
Why are we talking about flu vaccines?
Because new research, published last week, suggests everyone should be going out and getting them in the hope of reducing our risk of Parkinson’s disease.
In today’s post we will review the research, exactly what a flu vaccine is, and how it relates to Parkinson’s disease.
Electron micro photograph of Influenza viruses. Source: Neuro-hemin
Long time readers of the SoPD blog will know that I have a particular fascination with theories regarding a viral or microbial role in the development of Parkinson’s disease (the ‘idiopathic’ – or arising spontaneously – variety at least).
Numerous reasons. For example:
- The targeted nature of the condition (why are only selective groups of cells are lost in the brain during the early stages of the condition?)
- The unexplained protein aggregation (eg. Lewy bodies; could they be a cellular defensive mechanism against viruses/microbes – Click here to read more on this idea)
- The asymmetry of the onset (why do tremors start on only one side of the body in most cases?)
And we have previously discussed research here on the website regarding possible associations between Parkinson’s disease and and various types of viruses (including Hepatitis C, Herpes Simplex, and Influenza).
Today we re-visit influenza as new research has been published on this topic.
What is influenza?
Influenza is a single-stranded, RNA virus of the orthomyxovirus family of viruses.
A schematic of the influenza virus. Source: CDC
It is the virus that causes ‘the flu’ – (runny nose, sore throat, coughing, and fatigue) – with the symptom arising two days after exposure and lasting for about a week. In humans, there are three types of influenza viruses, called Type A, Type B, and Type C. Type A are the most virulent in humans. The influenza virus behind both of the outbreaks in the 1918 pandemic was a Type A.
Schematic of Influenza virus. Source: Bcm
As the image above indicates, the influenza virus has a rounded shape, with “HA” (hemagglutinin) and “NA” (neuraminidases) proteins on the outer surface of the virus. The HA protein allows the virus to stick to the outer membrane of a cell. The virus can then infect the host cell and start the process of reproduction – making more copies of itself. The NA protein is required for the virus to exit the host cell and go on to infect other cells. Different influenza viruses have different combinations of hemagglutinin and neuraminidase proteins, hence the numbering. For example, the Type A virus that caused the outbreaks in the 1918 pandemic was called H1N1.
Inside the influenza virus, there are there are eight pieces (segments) of RNA, hence the fact that influenza is an RNA virus. Some viruses have DNA while others have RNA. The 8 segments of RNA provide the information that is required for making new copies of the virus. Each of these segments provides the instructions for making one or more proteins of the virus (eg. segment 4 contains the instructions to make the HA protein).
The 8 segments of RNA in influenza. Source: URMC
The Influenza virus is one of the most changeable viruses we are aware of, which makes it such a tricky beast to deal with. Influenza uses two techniques to change over time. They are called shift and drift.
Shifting is an sudden change in the virus, which produces a completely new combination of the HA and NA proteins. Virus shift can take place when a person or animal is infected with two different subtypes of influenza. When new viral particles are generated inside the cell, there is a mix of both subtypes of virus which gives rise to an all new type of virus.
An example of viral shift. Source: Bcm
Drifting is the process of random genetic mutation. Gradual, continuous, spontaneous changes that occur when the virus makes small “mistakes” during the replication of its RNA. These mistakes can results in a slight difference in the HA or NA proteins, and although those changes are small, they can be significant enough that the human immune system will no longer recognise and attack the virus. This is why you can repeatedly get the flu and why flu vaccines must be administered each year to combat new forms of circulating influenza virus.
What is a flu jab exactly?
Seasonal flu vaccination is a treatment that is given each year to minimise the risk of being infected by an influenza virus.
The ‘seasonal’ part of the label refers to the fact that the flu vaccine changes each year. Most flu vaccines target three strains of the viruses (and are thus called ‘Trivalent flu vaccines’) which are selected each year based on data collected by various health organisations around the world.
The three chosen viruses for a particular year are traditionally injected into and grown in hens’ eggs, then harvested and purified before the viral particles are chemically deactivated. The three dead viruses are then pooled together and packaged as a vaccine. As you can see in the image below, the process of vaccine production is laborious and takes a full year:
The process of vaccine production. Source: Linkedin
By injecting people with the dead viruses from three different strains of the influenza virus, however, the immune system has the chance to build up a defence against those viruses without the risk of the individual becoming infected (the dead viruses in the vaccine can not infect cells).
Flu vaccines cause the immune system to produce antibodies which are used by the immune system to help defend the body against future attacks from viruses. These antibodies generally take about two weeks to develop in the body after vaccination.
As we have said most injected flu vaccines protect against three types of flu virus. Generally each of the three viruses is taken from the following strains:
- Influenza A (H1N1) – the strain of flu that caused the swine flu pandemic in 2009.
- Influenza A (H3N2) – a strain of flu that mainly affects the elderly and people at risk with long term health conditions. In 2016/17 the vaccine contains an A/Hong Kong/4801/2014 H3N2-like virus.
- Influenza B – a strain of flu that particularly affects children. In 2016/17 the vaccine contains B/Brisbane/60/2008-like virus.
How effective are the vaccines?
Well, it really depends on which strains of influenza are going to affect the most people each year, and this can vary greatly. Overall, however, research from the Centers for Disease Control and Prevention (or CDC) suggests that the seasonal flu vaccine reduces the chance of getting sick by approximately 50% (Source). Not bad when you think about it.
Ok, so are there actually any connections between influenza and Parkinson’s disease?
This question is up for debate.
There are certainly some tentative associations between influenza and Parkinson’s disease. Early on, those connections were coincidental, but more recently research is suggesting that there could be a closer relationship.
Between January 1918 and December 1920 there were two outbreaks of an influenza virus during an event that became known as the 1918 flu pandemic. Approximately 500 million people across the globe were infected by the H1N1 influenza virus, and this resulted in 50 to 100 million deaths (basically 3-5% of the world’s population). Given that is occurred during World War 1, censors limited the media coverage of the pandemic in many countries in order to maintain morale. The Spanish media were not censored, however, and this is why the 1918 pandemic is often referred to as the ‘Spanish flu’.
1918 Spanish flu. Source: Chronicle
At the same time that H1N1 was causing havoc, a Romanian born neurologist named Constantin von Economo reported a number of unusual symptoms which were referred to as encephalitis lethargica (EL). This disease left victims in a statue-like condition, speechless and motionless.
Constantin von Economo. Source: Wikipedia
By 1926, EL had spread around the world, with nearly five million people being affected. Many of those who survived never returned to their pre-existing state of health. They were left frozen in an immobile state.
An individual with encephalitis lethargica. Source: Baillement
Historically, it was believed that EL was caused by the influenza virus from the 1918 Spanish influenza pandemic. This was largely due to a temporal association (things happening at approximately the same time) and the finding of influenza antigens in some of the suffers of EL (Click here to read more about this).
And then there were also the observations of Dr Oliver Sacks:
Amazing guy! Dr Oliver Sacks. Source: Pensologosou
During the late 1960s, while employed as a neurologist at Beth Abraham Hospital’s chronic-care facility in New York, Dr Sacks began working with a group of survivors of EL, who had been left immobile by the condition. He treated these individuals with L-dopa (the standard treatment for Parkinson’s disease now, but it was still experimental at the time) and he observed them become miraculously reanimated. The sufferers went from being completely motionless to suddenly active and mobile. Unfortunately the beneficial effects were very short lived.
You may be familiar with Dr Sack’s book about his experience of treating these patients. It is called ‘Awakenings’ and it was turned into a film starring actors Robin Williams and Robert De Niro.
Robin Williams and Robert De Niro in Awakenings. Source: Pinterest
More recent, postmortem analysis of the brains of EL patients found an absence of influenza RNA – click here for more on this), which has led many researchers to simply reject the association between influenza and EL. The evidence supporting this rejection, however, has also been questioned (click here to read more on this), leaving the question of an association between influenza and EL still open for debate.
I think it’s fair to say that we genuinely do not know what caused EL. Whether it was influenza or not is still be undecided.
Ok, so that was the coincidental evidence. Has there been a more direct connection between influenza and Parkinson’s disease?
This is Dr Richard J Smeyne:
He is a research faculty member in the Department of Developmental Neurobiology at St. Jude Children’s Research Hospital (Memphis, Tennessee).
He has had a strong interest in what role viruses like influenza could be playing in the development of Parkinson’s disease, and his research group has published several interesting research reports on this topic, including:
Title: Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration.
Author: Jang H, Boltz D, Sturm-Ramirez K, Shepherd KR, Jiao Y, Webster R, Smeyne RJ.
Journal: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14063-8.
PMID: 19667183 (This article is OPEN ACCESS if you would like to read it)
Dr Smeyne and his colleagues found in this study that when they injected the highly infectious A/Vietnam/1203/04 (H5N1) influenza virus into mice, the virus progressed from the periphery (outside the brain) into the brain itself, where it induced Parkinson’s disease-like symptoms.
The virus also caused a significant increase in the accumulation of the Parkinson’s disease-associated protein Alpha Synuclein. In addition, they witnessed the loss of dopamine neurons in the midbrain of the mice at 60 days after the infection – that cell loss resembling what is observed in the brains of people with Parkinson’s disease.
Naturally this got the researchers rather excited!
In a follow up study on H5N1, however, these same researchers found that the Parkinson’s disease-like symptoms that they observed were actually only temporary:
Title: Inflammatory effects of highly pathogenic H5N1 influenza virus infection in the CNS of mice.
Authors: Jang H, Boltz D, McClaren J, Pani AK, Smeyne M, Korff A, Webster R, Smeyne RJ.
Journal: Journal for Neuroscience, 2012 Feb 1;32(5):1545-59.
PMID: 22302798 (This article is OPEN ACCESS if you would like to read it)
Dr Smeyne and colleagues repeated the 2009 study and had a closer look at what was happening to the dopamine neurons that were disappearing at 60 days post infection with the virus. When they looked at mice at 90 days post infection, they found that the number of dopamine neurons had returned to their normal number. This pattern was also observed in a region of the brain called the striatum, where the dopamine neurons release their dopamine. The levels of dopamine dropped soon after infection, but rose back to normal by 90 days post infection.
How does that work?
The results suggest that rather than developing new dopamine neurons in some kind of miraculous regenerative process, the dopamine neurons that were infected by the virus simply stopped producing dopamine while they dealt with the viral infection. Once the crisis was over, the dopamine neurons went back to life as normal. And because the researcher use chemicals in the production of dopamine to identify the dopamine neurons, they mistakenly thought that the cells had died when they couldn’t see those chemicals.
One interesting observation from the study was that H5N1 infection in mice induced a long-lasting inflammatory response in brain. The resident helper cells, called microglia, became activated by the infection, but remained active long after the dopamine neurons returned to normal service. The investigators speculated as to whether this activation may be a contributing factor in the development of neurodegenerative disorders.
And this is an interesting idea.
In a follow up study, they investigated this further by looking another influenza viruse that doesn’t actually infect cells in the brain:
Title: Induction of microglia activation after infection with the non-neurotropic A/CA/04/2009 H1N1 influenza virus.
Author: Sadasivan S, Zanin M, O’Brien K, Schultz-Cherry S, Smeyne RJ.
Journal: PLoS One. 2015 Apr 10;10(4):e0124047.
PMID: 25861024 (This article is OPEN ACCESS if you would like to read it)
In this study, a different type of influenza (H1N1) was tested, and while it did not infect the brain, it did cause the microglia cells to flare up and become activated. And again, this activation was sustained for a long period after the infection (at least 90 days).
This is a really interesting finding and relates to the idea of a “double hit” theory of Parkinson’s disease, in which the virus doesn’t necessarily cause Parkinson’s disease but may play a supplemental or distractionary role, grabbing the attention of the immune system while some other toxic agent is also attacking the body. Or perhaps simply weakening the immune system by forcing it to fight on multiple fronts. Alone the two would not cause as much damage, but in combination they could deal a terrible blow.
So what was the flu vaccine research published last week?
Again, from Dr Smeyne’s research group, this report looked whether the combination of an influenza virus infection plus a toxic agent gave a worse outcome than just the toxic agent by itself. An interesting idea for a study, but then the investigators threw in another component: what effect would a influenza vaccine have in such an experiment. And the results are interesting:
Title: Synergistic effects of influenza and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can be eliminated by the use of influenza therapeutics: experimental evidence for the multi-hit hypothesis
Authors: Sadasivan S, Sharp B, Schultz-Cherry S, & Smeyne RJ
Journal: npj Parkinson’s Disease 3, 18
PMID: N/A (This article is OPEN ACCESS if you would like to read it)
What the researchers found was that H1N1-infected mice that were treated with a neurotoxin (called MPTP – a toxin that specifically kills dopamine neurons) exhibit a 20% greater loss of dopamine neurons than mice that were treated with MPTP alone.
And this increase in dopamine neuron loss was completely eliminated by giving the mice the influenza vaccination. The researchers concluded that the results demonstrate that multiple insults (such as a viral infection and a toxin) can enhance the impact, and may even be significant in allowing an individual to cross a particular threshold for developing a disease.
It’s an intriguing idea.
Have epidemiologists (population data researchers) ever investigated a connection between Parkinson’s disease and influenza?
And yes they have:
Title: Parkinson’s disease or Parkinson symptoms following seasonal influenza.
Authors: Toovey S, Jick SS, Meier CR.
Journal: Influenza Other Respir Viruses. 2011 Sep;5(5):328-33.
PMID: 21668692 (This article is OPEN ACCESS if you would like to read it)
In this first study, the researcher used the UK‐based General Practice Research Database to perform a case–control analysis (that means they compare an affected population with an unaffected ‘control’ population. They identified individual cases who had developed an ‘incident diagnosis’ of Parkinson’s disease or Parkinson’s like symptoms between 1994 and March 2007. For each of those case files identified, they matched them with at least four age matched control case files for comparative sake.
Their analysis found that the risk of developing Parkinson’s disease was not associated with previous influenza infections. BUT, they did find that Influenza was associated with Parkinson’s‐like symptoms such as tremor, particularly in the month after an infection. One can’t help but wonder if the dopamine neurons stopped producing dopamine during that period while they dealt with the viral infection.
But of course, I’m only speculating here… and it’s not like there was a second study suggesting that there is actually an association between Parkinson’s disease and influenza.
A year after that first study, a second study was published:
Journal: Association of Parkinson’s disease with infections and occupational exposure to possible vectors.
Authors: Harris MA, Tsui JK, Marion SA, Shen H, Teschke K.
Journal: Movement Disorder. 2012 Aug;27(9):1111-7.
This second study reported that there is actually an association between Parkinson’s disease and influenza.
This investigation was also a case-control study, but it was based in British Columbia, Canada. The researchers recruited 403 individuals detected by their use of antiparkinsonian medications and matched them with 405 control subjects selected from the universal health insurance plan. Severe influenza was associated with Parkinson’s disease at an odds ratio of 2.01 (1 being no difference) and the range of the odds was 1.16-3.48. That’s pretty significant.
Interestingly, the effect is reduced when the reports of infection were restricted to those occurring within 10 years before diagnosis. This observation would suggest that early life infections may have more impact than previously thought.
Curiously, the researchers also found that exposure to certain animals (cats odds ration of 2.06; range 1.09-3.92) and cattle (2.23; range 1.22-4.09) was also associated with developing Parkinson’s disease.
Time to get rid of the pet cow.
Do any other neurodegenerative condition have associations with influenza?
In the limited literature search that we conducted, we only found reports dealing with influenza and Alzheimer’s disease.
Large studies suggest that Alzheimer’s is not associated with influenza (click here to read more on this). Interestingly, the Alzheimer’s associated protein beta amyloid has been shown to inhibit influenza A viruses (Click here to read that report), which may partly explain the lack of any association.
Influenza does have a mild association, however, with depression (Click here to see that report).
So what does it all mean?
A viral theory for Parkinson’s disease has existed since the great epidemic of 1918. Recent evidence points towards several viruses potentially having some involvement in the development of this neurodegenerative condition. And recent evidence suggests that influenza in particular could be particularly influential.
In 1938, Jonas Salk and Thomas Francis developed the first vaccine against flu viruses. It could be interesting for epidemiologists to go back and see if regular flu vaccination usage (if such data exists) reduces the risk of developing Parkinson’s disease.
But until such data is published, however, perhaps it would be wise to go and get a flu vaccine shot.
The banner for today’s post was sourced from the HuntingtonPost
The title of this post is a play on a Thomas Jefferson quote (“the olive tree is surely the richest gift of heaven“). Jefferson, the third President of the United States (1801 to 1809), was apparently quite the lover of food. During the Revolutionary War, while he was a U.S. envoy to France, Jefferson travelled the country. In Aix-en-Provence, he developed an admiration for olive trees, calling them “the most interesting plant in existence”.
Being huge food lovers ourselves, we here at the SoPD wholeheartedly agree with Jefferson. But we also think that olives are interesting for another reason:
They contain a chemical called Oleuropein.
In today’s post we’ll explore what is known about this chemical and discuss what it could mean for Parkinson’s disease.
Olives. Source: Gardeningknowhow
The olive, also known by the botanical name ‘Olea europaea,’ is an evergreen tree that is native to the Mediterranean, Asia and Africa, but now found around the world. It has a rich history of economic and symbolic importance within western civilisation. And the fruit of the tree also tastes good, either by themselves or in a salad or pasta dish.
Traditional diets of people living around the Mediterranean sea are very rich in extra-virgin olive oil. Olives are an excellent source of ‘good’ fatty acids (monounsaturated and di-unsaturated), antioxidants and vitamins. Indeed, research has shown that the traditional Mediterranean diet reduces the risk of heart disease (Click here to read more on this).
Olive oil. Source: Bonzonosvilla
There are also chemicals within the olive fruit that may have very positive benefits for Parkinson’s disease.
But before you rush out and gorge yourself on olives, we have one small piece of advice:
The chemical is called Oleuropein, and it is usually removed from olives due to its bitterness.
What is Oleuropein?
Oleuropein is a ‘phenylethanoid’ – a type of phenolic compound that is found in the leaf and the fruit of the olive. Phenolic compounds are produced by plants as a protective measure against different kinds of stress.
Oleuropein. Source: Wikipedia
The main phenolic compounds found in olives are hydroxytyrosol and oleuropein – both of which give extra-virgin olive oil its bitter taste and both have demonstrated neuroprotective effects.
More research has been done on oleuropein so we will focus on it here (for more on hydroxytyrosol – please click here).
Oleuropein has been found to have many interesting properties, such as:
The many properties of oleuropein. Source: Mdpi
What neuroprotective research has been done on Oleuropein?
Thus far, most of the research addressing this question has been conducted on models of Alzheimer’s disease. The first study
Title: Oleuropein aglycone protects transgenic C. elegans strains expressing Aβ42 by reducing plaque load and motor deficit.
Authors: Diomede L, Rigacci S, Romeo M, Stefani M, Salmona M.
Journal: PLoS One. 2013;8(3):e58893.
PMID: 23520540 (This article is OPEN ACCESS if you would like to read it)
The Italian researchers who conducted this study treated a microscopic worm model of Alzheimer’s disease with oleuropein aglycone. We should not that oleuropein aglycone is a hydrolysis product of oleuropein (a hydrolysis product is a chemical compound that is broken apart by the addition of water). The microscopic worm used in the study are called Caenorhabditis elegans:
Caenorhabditis elegans – cute huh? Source: Nematode
Caenorhabditis elegans (or simply C. Elegans) are tiny creatures that are widely used in biology because they can be easily genetically manipulated and their nervous system is very simple and well mapped out (they have just 302 neurons and 56 glial cells!). The particular strain of C. elegans used in this first study produced enormous amounts of a protein called Aβ42.
Amyloid beta (or Aβ) is the bad boy/trouble maker of Alzheimer’s disease; considered to be critically involved in the condition. A fragment of this protein (called Aβ42) begins clustering in the brains of people with Alzheimer’s disease. This clustering of Aβ42 goes on to form the plaques that are so characteristic of the Alzheimer’s affected brain.
The Italian researchers conducting this study had previously shown that oleuropein can inhibit the ability of Aβ42 to aggregate in cells growing in culture dishes (Click here to read more about that study), and they wanted to see if oleuropein had the same properties in actual live animals. So they chose the C. Elegans that had been genetically engineered to produce a lot of Aβ42 to test this idea.
In the C. Elegans that produce a lot of Aβ42 gradually become paralysed and their lives are shortened. By treating these worms with oleuropein, however, the Italian researchers found that there was less aggregation of Aβ42 (though the levels of the protein stayed the same), resulting in less plaque formation, and improved mobility (>50% reduction in paralysis) and survival compared to untreated Aβ42 producing C. Elegans.
Encouraged by this result, the researchers next moved on to studies in mice:
Title: The polyphenol oleuropein aglycone protects TgCRND8 mice against Aß plaque pathology.
Authors: Grossi C, Rigacci S, Ambrosini S, Ed Dami T, Luccarini I, Traini C, Failli P, Berti A, Casamenti F, Stefani M.
Journal: PLoS One. 2013 Aug 8;8(8):e71702.
PMID: 23951225 (This article is OPEN ACCESS if you would like to read it)
For this study, the Italian researchers used the genetically engineered TgCRND8 mice. These mice have a mutant form of amyloid precursor protein (which, similar to Aβ42, is associated with Alzheimer’s disease). In the brains of these mice, amyloid clustering begins at 3 months of age, and dense plaques are evident from 5 months of age. The mice also exhibit a clear learning impairment from 3 months of age.
By treating these mice with oleuropein aglycone, the researchers observed a remarkable reduction in plaques in the brain, and those that were present appeared less compact and “fluffy” (their very technical description, not ours). In addition, there was a reduction in the activation of astrocytes and microglia (the helper cells in the brain), indicating a healthier environment.
These same researchers have observed the same results in a rat model of Alzheimer’s disease in a report published the next year (Click here to read more about this).
Interestingly, the oleuropein treated TgCRND8 mice also displayed a major increase in autophagy activity. As we discussed in our previous post (Click here to read that post), autophagy is the rubbish disposal/recycling system of each cell, and increasing the activity of this system can help to keep cells health (particularly if there is a lot of a genetically engineered protein present!).
The Italian researchers repeated this study, and published the results this year, with an interesting twist:
Title: Oleuropein aglycone and polyphenols from olive mill waste water ameliorate cognitive deficits and neuropathology.
Authors: Pantano D, Luccarini I, Nardiello P, Servili M, Stefani M, Casamenti F.
Journal: Br J Clin Pharmacol. 2017 Jan;83(1):54-62.
In this study, the researchers tested the same genetically engineered mice, but with two different treatments:
- Two much lower doses of oleuropein (4 and 100 times lower)
- A mixture of polyphenols from olive mill concentrated waste water
The lowest dose of oleuropein (100 times less oleuropein than the previous study) did not provide any significant improvements for the mice, but the intermediate dose (only 4 times less oleuropein than the previous study) did provide significant benefits. These result indicate that there is a dose-dependent range to the beneficial properties of oleuropein.
The researchers also observed very similar beneficial effects from the mice drinking a mixture of polyphenols from olive mill concentrated waste water. Given these results, the investigators are now seeking to design appropriate conditions to perform a clinical trial to assess better the possible use of oleuropein (or a mix of olive polyphenols) against Alzheimer’s disease.
Ok, but what research has been done with oleuropein and Parkinson’s disease?
Unfortunately, not much.
A research group in Iran has looked at the effect of oleuropein in aged rodents and found an interesting result:
Title: Antioxidant role of oleuropein on midbrain and dopaminergic neurons of substantia nigra in aged rats.
Authors: Sarbishegi M, Mehraein F, Soleimani M.
Journal: Iran Biomed J. 2014;18(1):16-22.
PMID: 24375158 (This article is OPEN ACCESS if you would like to read it)
In this study, the investigators took twenty aged rats (18-month-old) and randomly assigned them to two groups: a treatment group (which received a daily dose of 50 mg/kg of oleuropein for 6 months) and a control group (which received just water). Following these treatments, the investigators found an increase in the activity of anti-oxidant agents (such as superoxide dismutase, catalase and glutathione) in the treatment group compared to control group. The treated rats also had significantly more dopamine neurons in the region of the brain affected by Parkinson’s disease (the substantia nigra). The investigators concluded that oleuropein consumption in a daily diet may be useful in reducing oxidative stress damage by increasing the antioxidant activity in the brain.
This first study was followed more recently by a report from a group in Quebec (Canada) who investigated oleuropein use in a cell culture model of Parkinson’s disease:
Title: Oleuropein Prevents Neuronal Death, Mitigates Mitochondrial Superoxide Production and Modulates Autophagy in a Dopaminergic Cellular Model.
Authors: Achour I, Arel-Dubeau AM, Renaud J, Legrand M, Attard E, Germain M, Martinoli MG.
Journal: Int J Mol Sci. 2016 Aug 9;17(8).
PMID: 27517912 (This article is OPEN ACCESS if you would like to read it)
The researcher conducting this study wanted to determine if oleuropein could prevent neuronal degeneration in a cellular model of Parkinson’s disease. They exposed cells to the neurotoxin 6-hydroxydopamine (6-OHDA) and then investigated mitochondrial oxidative stress and autophagy.
What is mitochondrial oxidative stress?
Mitochondria are the power house of each cell. They keep the lights on. Without them, the lights go out and the cell dies.
Mitochondria and their location in the cell. Source: NCBI
Oxidative stress results from too much oxidation. Oxidation is the loss of electrons from a molecule, which in turn destabilises the molecule. Think of iron rusting. Rust is the oxidation of iron – in the presence of oxygen and water, iron molecules will lose electrons over time. Given enough time, this results in the complete break down of objects made of iron.
Rust, the oxidation of metal. Source: TravelwithKevinandRuth
The exact same thing happens in biology. Molecules in your body go through a similar process of oxidation – losing electrons and becoming unstable. This chemical reaction leads to the production of what we call free radicals, which can then go on to damage cells. A free radical is an unstable molecule – unstable because they are missing electrons.
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.
Now if this oxidative process starts in the mitochondria, it can be very bad for a cell.
And what is autophagy?
Yes, the researchers also looked at autophagy levels in their cells. Autophagy is an absolutely essential function in a cell. Without autophagy, old proteins and mitochondria will pile up making the cell sick and eventually it dies. Through the process of autophagy, the cell can break down the old protein, clearing the way for fresh new proteins to do their job.
Think of autophagy as the waste disposal/recycling process of the cell.
The process of autophagy. Source: Wormbook
Waste material inside a cell is collected in membranes that form sacs (called vesicles). These vesicles then bind to another sac (called a lysosome) which contains enzymes that will breakdown and degrade the waste material. The degraded waste material can then be recycled or disposed of by spitting it out of the cell.
Ok, so what did the researchers find?
Well, by pretreating the their cells with oleuropein 3 hours before exposing them to the neurotoxin, the investigators found a significant neuroprotective effect. There was a significant reduction in mitochondrial production of free radicals, and the investigators found an important role for oleuropein in the regulation of autophagy.
And the good news is that other research groups have observed similar beneficial effects of oleuropein in cell culture models of Parkinson’s disease (Click here to read more about that).
The bad news is: that is all the published research on oleuropein and Parkinson’s disease we could find (and we would be happy to be corrected on this if people are aware of other reports!).
So what does Oleuropein do in the brain?
This is a good question, but with so little research done in this area, it is hard to answer.
We know that oleuropein is well absorbed by the human body and that it is relatively stable (Click here to read more on this). In addition, it can cross the blood-brain-barrier – in rodents at least (Click here to read more on that).
Obviously (based on the research we described above), we know that oleuropein has anti-oxidant promoting activities. In addition, it appears to be doing something with regards to autophagy. And it may be regulating autophagy by acting as an inhibitor of mammalian target of rapamycin (mTOR) activation.
What is mTOR?
mTOR is a protein that binds with other proteins to form the nexus of a signalling pathway which integrates both intracellular and extracellular signals (such asnutrients, growth factors, and cellular energy status) and then serves as one of the central instructors of how the cell should respond.
For example, insulin can signal to mTOR the status of glucose levels in the body. mTOR also deals with infectious or cellular stress-causing agents, thus it could be involved in a cells response to conditions like Parkinson’s disease.
Factors that activate mTOR. Source: Selfhacked
One important property of mTOR is its ability to block autophagy (the recycling process of the cell that we discussed above). Recently, the Italian researchers whose work we reviewed above, found that oleuropein can activate autophagy by blocking the mTOR pathway:
Title: Oleuropein aglycone induces autophagy via the AMPK/mTOR signalling pathway: a mechanistic insight.
Authors: Rigacci S, Miceli C, Nediani C, Berti A, Cascella R, Pantano D, Nardiello P, Luccarini I, Casamenti F, Stefani M.
Journal: Oncotarget. 2015 Nov 3;6(34):35344-57.
PMID: 26474288 (This article is OPEN ACCESS if you would like to read it)
The researchers conducting this study found that treatment with oleuropein caused an increase in autophagy in both cell culture and in a mouse model of Alzheimer’s disease, and they demonstrated that it achieved this by blocking the mTOR pathway.
Has anyone ever looked at oleuropein in the clinic?
No, not to our knowledge (and we are happy to be corrected on this).
There have been six clinical trials of olive leaf extract (the majority of which is oleuropien), but none of them have been focused on any neurological conditions.
So oleuropein is safe then?
It is a widely available supplement that a lot of people use to help lower bad cholesterol and blood pressure, so yes it can be considered safe. But any decision to experiment with oleuropein should only be made in consultation with your regular medically trained physician.
Why? Because there are always caveats.
Importantly, individuals with low blood pressure and diabetes may suffer even lower blood pressure and blood glucose levels as a result of consumption of oleuropein. Oleuropein may also interact with other pharmaceutical drugs that are designed to lower blood pressure or regulate diabetes. Such interactions could be dangerous.
And this is a particularly important factor for Parkinson’s disease as up to 30% of people with Parkinson’s may be glucose intolerant (Click here to see our post on Parkinson’s & diabetes).
Those who experience symptoms such as headache, nausea, flu-like symptoms, fainting, dizziness, and other life threatening symptoms should medical attention immediately.
What does it all mean?
We are grateful to regular reader (Don) who brought oleuropein to our attention. It is a very interesting chemical and we are definitely intrigued by it. We would certainly like to see more research on oleuropein in models of Parkinson’s disease.
Attentive readers will have noticed that most of the research discussed above have been conducted in the last 5-10 years. This suggests that oleuropein research is still in its infancy, particularly with regards to research on neurological conditions. And we hope that by reporting on it here, we will be bringing it to the attention of researchers.
Oleuropein is extracted from all parts of the olive tree (the leaves, bark, root, and fruit). It forms part of the defence system of the olive tree against stress or infection. Perhaps we could apply some of its interesting properties to Parkinson’s disease.
EDITORIAL NOTE: Under absolutely no circumstances should anyone reading the material on this website consider it medical advice. The information 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 and supplements 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 this post was sourced from jrbenjamin
Exciting news this week from the world of neurodegenerative research. Researchers have identified two clinically available drugs that display neuroprotective properties.
The drugs – Dibenzoylmethane and Trazodone – are currently used to treat cancer and depression, respectively.
In this post, we will review the research and discuss what it could mean for folks with Parkinson’s disease.
Old drugs – new tricks? Source: Repurposingdrugs101
As you may have heard from media reports (for examples, click here, here and here), researchers have identified two clinically available drugs that may help in the fight against neurodegenerative conditions, like Parkinson’s disease.
The re-purposing of clinically available drugs is the focus of much attention within the Parkinson’s community as it represents a means of bringing treatments to the clinic faster. The traditional lengthy clinical trial process that is required in the development of new medications means getting a new drug to market for neurodegeneration can take up to 15 years, as the trials run over several years each (and there are three phases to pass through).
Shortening the wait. Source: Austinpublishing
In an age of smart phones and instant gratification, who has that kind of patience? ( #Wewontwait ).
Thus, re-purposing of available drugs represents a more rapid means of bringing new treatments/therapies to the Parkinson’s community.
So what is the new research all about?
This is Professor Giovanna Mallucci.
Prof Giovanna Mallucci. Source: MRC
Her area of research interest is understanding mechanisms of neurodegeneration, with a particular focus on prion and Alzheimer’s disease.
A few years ago, her group published this report:
Title: Sustained translational repression by eIF2α-P mediates prion neurodegeneration.
Authors: Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Martin MG, Halliday M, Morgan J, Dinsdale D, Ortori CA, Barrett DA, Tsaytler P, Bertolotti A, Willis AE, Bushell M, Mallucci GR.
Journal: Nature. 2012 May 6;485(7399):507-11.
PMID: 22622579 (This article is OPEN ACCESS if you would like to read it)
In this study, Prof Mallucci’s group were interested in the biological events that were occurring in the brain following infection of mice with prion disease – another neurodegenerative condition. They found that a sudden loss of protein associated with the connections between neurons (those connections being called synapses) occurred at 9 weeks post infection. This led them to investigate the production of protein and they found that an increase in the levels of phosphorylation of a protein called eIF2alpha was associated with the reduction in protein synthesis occurring at 9 weeks post infection.
What is Phosphorylation?
Phosphorylation of a protein is basically the process of turning it on or off – making it active or inactive – for a particular function.
Phosphorylation of a kinase protein. Source: Nature
And what is eIF2alpha?
Eukaryotic Translation Initiation Factor 2 Alpha is (as the label on the can suggests) a translation initiation factor. This means that this particular protein functions in the early steps of the production of protein. That is to say, eIF2alpha has important roles in the first steps – the initiation – of making other proteins.
eIF2alpha’s role in neurodegeneration. Source: Frontiers
The increased phosphorylation of eIF2alpha results in the inactivation of eIF2alpha and therefore the transient shutdown of protein production.
This shutdown in protein production can serve as an important ‘checkpoint’ when a cell is stressed. By blocking general protein production, a damaged or stressed cell can have the opportunity to either recuperate or be eliminated (if the damage is beyond repair).
The shutdown can also be caused by the unfolded protein response (or UPR). The unfolded protein response is a protective mechanism triggered by rising levels of misfolded proteins.
What are misfolded proteins?
When proteins are being produced, they need to be folded into the correct shape to do their job. Things can turn ugly very quickly for a cell if protein are being misfolded or only partially folded.
Two proteins. Guess which is the misfolded protein. Source: Biogeekery
In fact, misfolded proteins are suspected of being responsible for many of the neurodegenerative conditions we know of (including Parkinson’s, Alzheimer’s, etc). Thus the unfolded protein response gives a cell time to stop protein production, degrade & dispose of any misfolded proteins, and then re-activate proteins involved with increasing the production again.
And Prof Mallucci’s group found an increase in the phosphorylation of eIF2alpha?
Yes. At 9 weeks post infection with prions, there is a decrease in the proteins required for maintaining the connections between neurons and an increase in the phosphorylation of eIF2alpha.
The interesting thing is that the researchers found that levels of phosphorylated eIF2alpha increased throughout the course of study.
So, the researchers asked themselves if promoting a recovery in protein production in the cells in neuroprotective. To test this they used a protein called GADD34, which is a specific eIF2alpha phosphatase (a phosphatase is a protein that dephosphates a protein). By introducing a lot of GADD34 in the cells, the researchers were able to re-activate eIF2alpha, rescue the connectivity between neurons and protect the cells from dying.
A cool trick, huh?
This report established the importance of eIF2alpha in the early stages of neurodegeneration, and Prof Mallucci and her group next decided to conduct a massive screening study of currently available medications to see which could be used to target eIF2alpha levels.
And that research gave rise to the report that caused so much excitement this week. This report here:
Title: Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice
Authors: Halliday M, Radford H, Zents KAM, Molloy C, Moreno JA, Verity NC, Smith E, Ortori CA, Barrett DA, Bushell M, Mallucci GR.
Journal: Brain, 2017 Epub early online publication
PMID: N/A (This article is OPEN ACCESS if you would like to read it)
The investigators began by testing 1,040 compounds (that represent many of the clinically available drugs we have) on tiny microscopic worms (called C.elegans). These worms represent a useful experimental model for screening drugs as many aspects of biology can be examined. These worms were exposed to both a chemical (called tunicamycin, which induces the unfolded protein response we were talking about above) and one of the 1040 compounds.
Of the 1040 compounds tested, the investigators selected the 20 that provided the best protection to the worms. They next analysed those top 20 compounds for their ability to reduce levels of phosphorylated eIF2alpha in cells. Cells were engineered to produce a bioluminescent signal when eIF2alpha was phosphorylated. The researchers used a potent blocker of the unfolded protein response (called GSK2606414) and a drug called ISRIB (which is an experimental drug which reverses the effects of eIF2alpha phosphorylation) as controls for the experiment.
Their results were interesting:
The results of the top 20 drugs screened. Source: Brain
As you can see from the graph above, there were five compounds (highlighted with ***) that provided a similar level of reduction as the ISRIB (control) drug:
- Azadirachtin – which is the active ingredient in many pesticides.
- Dibenzoylmethane – a cancer treatment.
- Proguanil – a medication used to treat and prevent malaria.
- Trazodone – an antidepressant used to treat depression and anxiety disorders.
- Trifluoperazine – an antipsychotic of the phenothiazine chemical class.
The investigators decided not to further investigate Azadirachtin as it is a pesticide and displays a poor ability to penetrant the blood-brain-barrier – the protective layer surrounding the brain. They also rejected Proguanil because while it is safe to use in humans, it is toxic in mice. This detail limited the amount of preclinical testing for neurodegeneration that the researchers could do. And finally Trifluoperazine was eliminated as it should not be used in the elderly populations (apparently it ‘increases the risk of death’!), which obviously limited it’s further utility given that age is a major determinant of neurodegeneration.
This selection process left the researchers with Dibenzoylmethane and Trazodone.
The researchers found that both of these drugs can cross the blood-brain-barrier and were able to prevent neurodegeneration and rescue behavioural deficits in prion-infected mice. And they observed no toxic effects of these treatments in other organs (such as the pancreas). The drugs restore correct protein production and increased the survival of the prion-infected mice.
Taking the study one step further, Prof Mallucci and her group asked if the drugs could be effective in a model of another neurodegenerative condition, such as Alzheimer’s disease. To investigated this, they treated rTg4510 mice with both of the drugs. rTg4510 mice produce a lot of a human protein (called tau) that has a particular mutation (known as P301L), which results in the onset of Alzheimer’s like pathology at an early age. The rTg4510 mice received either trazodone or Dibenzoylmethane on a daily basis from 4 months of age and were examined at 8 months of age. The researchers found significantly less cell loss and shrinkage in the brains of the mice treated with one of the two drugs when compared to rTg4510 mice that received no treatment.
The researchers concluded that “these compounds therefore represent potential new disease-modifying treatments for dementia. Trazodone in particular, a licensed drug, should now be tested in clinical trials in patients”.
As Professor Mallucci suggested to the press: “We know that trazodone is safe to use in humans, so a clinical trial is now possible to test whether the protective effects of the drug we see on brain cells in mice with neurodegeneration also applies to people in the early stages of Alzheimer’s disease and other dementias. We could know in 2-3 years whether this approach can slow down disease progression, which would be a very exciting first step in treating these disorders. Interestingly, trazodone has been used to treat the symptoms of patients in later stages of dementia, so we know it is safe for this group. We now need to find out whether giving the drug to patients at an early stage could help arrest or slow down the disease through its effects on this pathway.”
This is great for Alzheimer’s disease, but what about Parkinson’s?
Well, the researchers did not test the drugs in models of Parkinson’s disease. But we can assume that several research groups are going to be testing this drug in the near future… if they aren’t already!
But have increased levels of eIF2alpha been seen in Parkinson’s disease?
Great question. And the answer is: Yes.
Title: Activation of the unfolded protein response in Parkinson’s disease.
Authors: Hoozemans JJ, van Haastert ES, Eikelenboom P, de Vos RA, Rozemuller JM, Scheper W.
Journal: Biochem Biophys Res Commun. 2007 Mar 16;354(3):707-11.
In this study the investigators analysed the levels of Unfolded Protein Response activation in the postmortem brains of people who passed away with or without Parkinson’s disease. Specifically, they focused their analysis on the substantia nigra (the region where the dopamine neurons reside and which is most severely affected in Parkinson’s).
The researchers found that both eIF2alpha and a protein called PERK (also known as protein kinase-like ER kinase – which phosphalates eIF2alpha) are present in the dopamine neurons in the substantia nigra of brains from people with Parkinson’s disease, but not in healthy control brains. And as the graph below shows, the investigators noted that there was a trend towards the levels of these proteins peaking within the first five years after diagnosis.
eIF2alpha & PERK levels in the brain. Source: ScienceDirect
Similar postmortem analysis studies have also highlighted the increased levels of Unfolded Protein Response activation in the Parkinsonian brain (Click here to read more on this).
The increase in Unfolded Protein Response activation could be a common feature across different neurodegenerative conditions, suggesting that trazodone and dibenzoylmethane could be used widely to slow the progress of various conditions.
Another connection to Parkinson’s disease is the finding that high levels of the Parkinson’s associated protein alpha synuclein can cause the Unfolded Protein Response:
Title: Induction of the unfolded protein response by α-synuclein in experimental models of Parkinson’s disease.
Authors: Bellucci A, Navarria L, Zaltieri M, Falarti E, Bodei S, Sigala S, Battistin L, Spillantini M, Missale C, Spano P.
Journal: J Neurochem. 2011 Feb;116(4):588-605.
PMID: 21166675 (This article is OPEN ACCESS if you would like to read it)
The researchers in this study found that introducing large amounts of alpha synuclein into cell cultures results in the initiation of the unfolded protein response. They also observed this phenomenon in genetically engineered mice that produce large amounts of alpha synuclein.
Thus, there is some evidence for eIF2alpha and unfolded protein response-related activities in Parkinson’s disease
So is there are evidence that Dibenzoylmethane might be neuroprotective for Parkinson’s disease?
Yes there is (sort of):
Title: A dibenzoylmethane derivative protects dopaminergic neurons against both oxidative stress and endoplasmic reticulum stress.
Authors: Takano K, Kitao Y, Tabata Y, Miura H, Sato K, Takuma K, Yamada K, Hibino S, Choshi T, Iinuma M, Suzuki H, Murakami R, Yamada M, Ogawa S, Hori O.
Journal: Am J Physiol Cell Physiol. 2007 Dec;293(6):C1884-94. Epub 2007 Oct 3.
PMID: 17913843 (This article is OPEN ACCESS if you would like to read it)
The investigators of this study found a derivative of dibenzoylmethane which they called 14-26 (chemical name 2,2′-dimethoxydibenzoylmethane) displayed neuroprotective functions both in cell culture and animal models of Parkinson’s disease. The researchers did not look at the unfolded protein response or eIF2alpha and PERK levels, nor did they determine if dibenzoylmethane itself exhibits neuroprotective properties.
This may now need to be re-addressed.
And is there any evidence trazodone having neuroprotective effects in other neurodegenerative conditions?
For a review of the neuroprotective effects of trazodone (and other anti-psychotic/anti-depressant drugs) in Huntington’s Disease – Click here.
This sounds very positive for Parkinson’s disease then, no?
Weeeeeell, there is a word of caution to be thrown in here:
There have been reports in the past of trazodone causing motor-related issues in the elderly. Such as this one:
Title: Can trazodone induce parkinsonism?
Authors: Albanese A, Rossi P, Altavista MC.
Journal: Clin Neuropharmacol. 1988 Apr;11(2):180-2.
This report was a single case study of a 74 year old lady who developed depression after losing her sister with whom she lived. She was prescribed trazodone, which was effective in improving her mood. Just several months later, however, she began presenting Parkinsonian symptoms.
Firstly the onset of a resting tremor in the left arm, then a slowing of movement and a masking of the face. The attending physician withdrew the trazodone treatment and within two months the symptoms began to disappear, with no symptoms apparent 12 months later.
And unfortunately this is not an isolated case – other periodic reports of trazodone-induced motor issues have been reported (Click here and here for examples). And this is really strange as Trazodone apparently has no dopaminergic activity that we are aware of. It is a serotonin antagonist and reuptake inhibitor (SARI); it should not affect the re-uptake of norepinephrine or dopamine within the brain.
Thus, we may need to proceed with caution with the use of Trazodone for Parkinson’s disease.
So what does it all mean?
The repurposing of old drugs to treat alternative conditions is a very good idea. It means that we can test treatments that we usually know a great deal about (with regards to human usage) on diseases that they were not initially designed for, in a rapid manner.
Recently, scientists have identified two clinically available drugs that have displayed neuroprotection in two different models of neurodegeneration. Without doubt there will now be follow up investigations, before rapid efforts are made to set up clinical trials to test the efficacy of these drugs in humans suffering from dementia.
Whether these two treatments are useful for Parkinson’s disease still needs to be determined. There is evidence supporting the idea that they may well be, but caution should always be taken in how we proceed. This does not mean that other clinically available drugs can not be tested for Parkinson’s disease, however, and there are numerous clinical trials currently underway testing several of them (Click here to read more on this).
We’ll let you know when we hear anything about these efforts.
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 Linkedin
‘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.
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).
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.
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”.
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. 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).
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.
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.
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.
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.
Ok, so iron overload is bad, but what was the research presented in Austria?
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).
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.
Prana Biotechnology has another product called PBT2.
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?
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.
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).
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!
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.
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:
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
Recently the results of a small clinical study looking at Resveratrol in Alzheimer’s disease were published. Resveratrol has long been touted as a miracle ingredient in red wine, and has shown potential in animal models of Parkinson’s disease, but it has never been clinically tested.
Is it time for a clinical trial?
In today’s post we will review the new clinical results and discuss what they could mean for Parkinson’s disease.
From chemical to wine – Resveratrol. Source: Youtube
In 2006, there was a research article published in the prestigious journal Nature about a chemical called resveratrol that improved the health and survival of mice on a high-calorie diet (Click here for the press release).
Title: Resveratrol improves health and survival of mice on a high-calorie diet.
Authors: Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA.
Journal: Nature. 2006 Nov 16;444(7117):337-42.
PMID: 17086191 (This article is OPEN ACCESS if you would like to read it)
In this study, the investigators placed middle-aged (one-year-old) mice on either a standard diet or a high-calorie diet (with 60% of calories coming from fat). The mice were maintained on this diet for the remainder of their lives. Some of the high-calorie diet mice were also placed on resveratrol (20mg/kg per day).
After 6 months of this treatment, the researchers found that resveratrol increased survival of the mice and insulin sensitivity. Resveratrol treatment also improved mitochondria activity and motor performance in the mice. They saw a clear trend towards increased survival and insulin sensitivity.
The report caused a quite a bit of excitement – suddenly there was the possibility that we could eat anything we wanted and this amazing chemical would safe us from any negative consequences.
That report was proceeded by numerous studies demonstrating that resveratrol could extend the life-span of various micro-organisms, and it was achieving this by activating a family of genes called sirtuins (specifically Sir1 and Sir2) (Click here, here and here for more on this).
Subsequent to these reports, there have been numerous scientific publications suggesting that resveratrol is capable of all manner of biological miracles.
Wow! So what is resveratrol?
Do you prefer your wine in pill form? Source: Patagonia
Resveratrol is a chemical that belongs to a group of compounds called polyphenols. They are believed to act like antioxidants. Numerous plants produce polyphenols in response to injury or when the plant is under attack by pathogens (microbial infections).
Fruit are a particularly good source of resveratrol, particularly the skins of grapes, blueberries, raspberries, mulberries and lingonberries. One issue with fruit as a source of resveratrol, however, is that tests in rodents have shown that less than 5% of the oral dose was observed as free resveratrol in blood plasma (Source). This has lead to the extremely popular idea of taking resveratrol in the form of wine, in the hope that it could have higher bioavailability compared to resveratrol in pill form. Red wines have the highest levels of Resveratrol in their skins (particularly Mabec, Petite Sirah, St. Laurent, and pinot noir). This is because red wine is fermented with grape skins longer than is white wine, thus red wine contains more resveratrol.
EDITOR’S NOTE: Sorry to rain on the parade, but it is important to note here that red wine actually contains only small amounts of resveratrol – less than 3-6 mg per bottle of red wine (750ml). Thus, one would need to drink a great deal of red wine per day to get enough resveratrol (the beneficial effects observed in the mouse study described above required 20mg/kg of resveratrol per day. For a person weighting 80kg, this would equate to 1.6g per day or approximately 250 750ml bottles).
We would like to suggest that consuming red wine would NOT be the most efficient way of absorbing resveratrol. And obviously we DO NOT recommend any readers attempt to drink 250 bottles per day (if that is even possible).
The recommended daily dose of resveratrol should not exceed 250 mg per day over the long term (Source). Resveratrol might increase the risk of bleeding in people with bleeding disorders. And we recommend discussing any change in treatment regimes with your doctor before starting.
So what did they find in the Alzheimer’s clinical study?
Well, the report we will look at today is actually a follow-on to published results from a phase 2/safety clinical trial that were reported in 2015:
Title: A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease.
Authors: Turner RS, Thomas RG, Craft S, van Dyck CH, Mintzer J, Reynolds BA, Brewer JB, Rissman RA, Raman R, Aisen PS; Alzheimer’s Disease Cooperative Study.
Title: Neurology. 2015 Oct 20;85(16):1383-91.
PMID: 26362286 (This article is OPEN ACCESS if you would like to read it)
The researchers behind the study are associated with the Georgetown research group that conducted the initial Nilotinib clinical study in Parkinson’s disease (Click here for our post on this).
The investigators conducted a randomized, placebo-controlled, double-blind, multi-center phase 2 trial of resveratrol in individuals with mild to moderate Alzheimer disease. The study lasted 52 weeks and involved 119 individuals who were randomly assigned to either placebo or resveratrol 500 mg orally daily treatment.
EDITOR’S NOTE: We appreciate that is daily dose exceeds the recommended daily dose mentioned above, but it is important to remember that the participants involved in this study were being closely monitored by the study investigators.
Brain imaging and samples of cerebrospinal fluid (the liquid within which the brain sits) were collected at the start of the study and after completion of treatment.
The most important result of the study was that resveratrol was safe and well-tolerated. The most common side effect was feeling nausea and diarrhea in approximately 42% of individuals taking resveratrol (curiously 33% of the participants blindly taking the placebo reported the same thing). There was also a weight loss effect between the groups, with the placebo group gaining 0.5kg on average, while the resveratrol treated group lost 1kg on average.
The second important take home message is that resveratrol crossed the blood–brain barrier in humans. The blood brain barrier prevents many compounds from having any effect in the brain, but it does not stop resveratrol.
The investigators initially found no effects of resveratrol treatment in various Alzheimer’s markers in the cerebrospinal fluid. Not did they see any effect in brain scans, cognitive testing, or glucose/insulin metabolism. The authors were cautious about their conclusions based on these results, however, as the study was statistically underpowered (that is to say, there were not enough participants in the various groups) to detect clinical benefits. They recommended a larger study to determine whether resveratrol is actually beneficial.
While exploring the idea of a larger study, the researchers have re-analysed some of the data, and that brings us to the report we want to review today:
Title: Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease.
Authors: Moussa C, Hebron M, Huang X, Ahn J, Rissman RA, Aisen PS, Turner RS.
Journal: J Neuroinflammation. 2017 Jan 3;14(1):1. doi: 10.1186/s12974-016-0779-0.
PMID: 28086917 (This article is OPEN ACCESS if you would like to read it)
In this report, the investigators conducted a retrospective study re-examining the cerebrospinal fluid and blood plasma samples from a subset of subjects involved in the clinical study described above. In this study, they only looked at the subjects who started with very low levels in the cerebrospinal fluid of a protein called Aβ42.
Amyloid beta (or Aβ) is the bad boy/trouble maker of Alzheimer’s disease; considered to be critically involved in the disease. A fragment of this protein (called Aβ42) begin clustering in the brains of people with Alzheimer’s disease and as a result, low levels of Aβ42 in cerebrospinal fluid have been associated with increased risk of Alzheimer’s disease and considered a possible biomarker of the condition (Click here to read more on this).
The resveratrol study investigators collected all of the data from subjects with cerebrospinal fluid levels of Aβ42 less than 600 ng/ml at the start of the study. This selection criteria gave them 19 resveratrol-treated and 19 placebo-treated subjects.
In this subset re-analysis study, resveratrol treatment appears to have slowed the decline in cognitive test scores (the mini-mental status examination), as well as benefiting activities of daily living scores and cerebrospinal fluid levels of Aβ42.
One of the most striking results from this study is the significant decrease observed in the cerebrospinal fluid levels of a protein called Matrix metallopeptidase 9 (or MMP9) after resveratrol treatment. MMP9 is slowly emerged as an important player in several neurodegenerative conditions, including Parkinson’s disease (Click here to read more on this). Thus the decline observed is very interesting.
This re-analysis indicates beneficial effects in some cases of Alzheimer’s as a result of taking resveratrol over 52 weeks. The researchers concluded that the findings of this re-analysis support the idea of a larger follow-up study of resveratrol in people with Alzheimer’s disease.
Ok, but what research has been done on resveratrol in Parkinson’s disease?
Yes, good question.
One of the earliest studies looking at resveratrol in Parkinson’s disease was this one:
Title: Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson’s disease in rats.
Authors: Jin F, Wu Q, Lu YF, Gong QH, Shi JS.
Journal: Eur J Pharmacol. 2008 Dec 14;600(1-3):78-82.
In this study, the researchers used a classical rodent model of Parkinson’s disease (using the neurotoxin 6-OHDA). One week after inducing Parkinson’s disease, the investigators gave the animals either a placebo or resveratrol (at doses of 10, 20 or 40 mg/kg). This treatment regime was given daily for 10 weeks and the animals were examined behaviourally during that time.
The researchers found that resveratrol improved motor performance in the treated animals, with them demonstrating significant results as early as 2 weeks after starting treatment. Resveratrol also reduced signs of cell death in the brain. The investigators concluded that resveratrol exerts a neuroprotective effect in this model of Parkinson’s disease.
Subsequent studies have also looked at what effect resveratrol could be having on the Parkinson’s disease associated protein alpha synuclein, such as this report:
Title: Effect of resveratrol on mitochondrial function: implications in parkin-associated familiarParkinson’s disease.
Authors: Ferretta A, Gaballo A, Tanzarella P, Piccoli C, Capitanio N, Nico B, Annese T, Di Paola M, Dell’aquila C, De Mari M, Ferranini E, Bonifati V, Pacelli C, Cocco T.
Journal: Biochim Biophys Acta. 2014 Jul;1842(7):902-15.
PMID: 24582596 (This article is OPEN ACCESS if you would like to read it)
In this study, the investigators collected skin cells from people with PARK2 associated Parkinson’s disease.
What is PARK2 associated Parkinson’s disease?
There are about 20 genes that have been associated with Parkinson’s disease, and they are referred to as the PARK genes. Approximately 10-20% of people with Parkinson’s disease have a genetic variation in one or more of these PARK genes (we have discussed these before – click here to read that post).
PARK2 is a gene called Parkin. Mutations in Parkin can result in an early-onset form of Parkinson’s disease. The Parkin gene produces a protein which plays an important role in removing old or sick mitochondria.
Hang on a second. Remind me again: what are mitochondria?
We have previously written about mitochondria (click here to read that post). Mitochondria are the power house of each cell. They keep the lights on. Without them, the lights go out and the cell dies.
Mitochondria and their location in the cell. Source: NCBI
You may remember from high school biology class that mitochondria are bean-shaped objects within the cell. They convert energy from food into Adenosine Triphosphate (or ATP). ATP is the fuel which cells run on. Given their critical role in energy supply, mitochondria are plentiful and highly organised within the cell, being moved around to wherever they are needed.
Another Parkinson’s associated protein, Pink1 (which we have discussed before – click here to read that post), binds to dysfunctional mitochondria and then grabs Parkin protein which signals for the mitochondria to be disposed of. This process is an essential part of the cell’s garbage disposal system.
Park2 mutations associated with early onset Parkinson disease cause the old/sick mitochondria are not disposed of correctly and they simply pile up making the cell sick. The researchers that collected the skin cells from people with PARK2 associated Parkinson’s disease found that resveratrol treatment partially rescued the mitochondrial defects in the cells. The results obtained from these skin cells derived from people with early-onset Parkinson’s disease suggest that resveratrol may have potential clinical application.
Thus it would be interesting (and perhaps time) to design a clinical study to test resveratrol in people with PARK2 associated Parkinson’s disease.
So why don’t we have a clinical trial?
Resveratrol is a chemical that falls into the basket of un-patentable drugs. This means that big drug companies are not interested in testing it in an expensive series of clinical trials because they can not guarantee that they will make any money on their investment.
There was, however, a company set up in 2004 by the researchers behind the original resveratrol Nature journal report (discussed at the top of this post). That company was called “Sirtris Pharmaceuticals”.
Sirtris identified compounds that could activate the sirtuins family of genes, and they began testing them. They eventually found a compound called SRT501 which they proposed was more stable and 4 times more potent than resveratrol. The company went public in 2007, and was subsequently bought by the pharmaceutical company GlaxoSmithKline in 2008 for $720 million.
From there, however, the story for SRT501… goes a little off track.
In 2010, GlaxoSmithKline stopped any further development of SRT501, and it is believed that this decision was due to renal problems. Earlier that year the company had suspended a Phase 2 trial of SRT501 in a type of cancer (multiple myeloma) because some participants in the trial developed kidney failure (Click here to read more).
Then in 2013, GlaxoSmithKline shut down Sirtris Pharmaceuticals completely, but indicated that they would be following up on many of Sirtris’s other sirtuins-activating compounds (Click here to read more on this).
Whether any of those compounds are going to be tested on Parkinson’s disease is yet to be determined.
We’ll let you know when we hear of anything.
So what does it all mean?
Summing up: Resveratrol is a chemical found in the skin of grapes and berries, which has been shown to display positive properties in models of neurodegeneration. A recent double blind phase II efficacy trial suggests that resveratrol may be having positive benefits in Alzheimer’s disease.
Preclinical research suggests that resveratrol treatment could also have beneficial effects in Parkinson’s disease. It would be interesting to see what effect resveratrol would have on Parkinson’s disease in a clinical study.
Perhaps we should have a chat to the good folks at ‘CliniCrowd‘ who are investigating Mannitol for Parkinson’s disease (Click here to read more about this). Maybe they would be interested in resveratrol for Parkinson’s disease.
ONE LAST 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. SoPD can not be held responsible for actions taken based on the information provided here.
The banner for today’s post was sourced from VisitCalifornia