Shining a light on movement

May 18, 2017May 18, 2017 ~ Simon ~ 9 Comments

10-years-of-optogenetics

Researchers are using a powerful new tool to determine which parts of the brain are involved in movement.

The technology involves shining light on brain cells…and well, a bit of biological magic.

Today we will review some newly published research highlighting how this approach and discuss what it means for Parkinson’s disease.

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The Vienna city hall. Source: EUtourists

Personal story: I was at the Dopamine 2016 conference in September last year in lovely Vienna (Austria). Wonderful city, beautiful weather, and an amazing collection of brilliant researchers focused on all things dopamine-related. The conference really highlighted all the new research being done on this chemical.

There was – of course – a lots of research being presented on Parkinson’s disease, given that dopamine plays such an important role in the condition.

And it was all really interesting.

Anyways, I was sitting in one of the lecture presentation session, listening to all these new results being discussed.

And then, a lady from Carnegie Mellon University stood up and (without exaggeration) completely – blew – my – mind!

Her name is Aryn H. Gittis:

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She is an Assistant Professor in the Department of Biological Sciences at Carnegie Mellon University, where her group investigates the neural circuits underlying the regulation of movement, learning, motivation, and reward.

And the ‘mind blowing‘ research that she presented in Vienna has recently been published in the journal Nature Neuroscience:

Title: Cell-specific pallidal intervention induces long-lasting motor recovery in dopamine-depleted mice
Authors: Mastro KJ, Zitelli KT, Willard AM, Leblanc KH, Kravitz AV & Gittis AH
Journal: Nature Neuroscience (2017) doi:10.1038/nn.4559
PMID: 28481350

In this report, Dr Gittis and her colleagues demonstrated that elevating the activity of one type of cell in an area of the brain called the globus pallidus, could provide long lasting relief from Parkinson’s-like motor features.

Hang on a second. What is the globus pallidus?

The globus pallidus is a structure deep in the brain and before Dr Gittis and her colleagues published their research, we already knew it played an important role in our ability to move.

Movement is largely controlled by the activity in a specific group of brain regions, collectively known as the ‘Basal ganglia‘.

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The basal ganglia structures (blue) in the human brain. Source: iKnowledge

But while the basal ganglia controls movement, it is not the starting point for the movement process.

The prefrontal cortex is where we do most of our ‘thinking’. It is the part of the brain that makes decisions with regards to many of our actions, particularly voluntary movement. It is involved in what we call ‘executive functions’. It is the green area in the image below.

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Areas of the cortex. Source: Rasmussenanders

Now the prefrontal cortex might come up with an idea: ‘the left hand should start to play the piano’. The prefrontal cortex will communicate this idea with the premotor cortex and together they will send a very excited signal down into the basal ganglia for it to be considered. Now in this scenario it might help to think of the cortex as hyperactive, completely out of control toddlers, and the basal ganglia as the parental figure. All of the toddlers are making demands/proposals and sending mixed messages, and it is for the inhibiting basal ganglia to gain control and decide which is the best.

So the basal ganglia receives signals from the cortex, processes that information before sending a signal on to another important participant in the regulation of movement: the thalamus.

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A brain scan illustrating the location of the thalamus in the human brain. Source: Wikipedia

The thalamus is a structure deep inside the brain that acts like the central control unit of the brain. Everything coming into the brain from the spinal cord, passes through the thalamus. And everything leaving the brain, passes through the thalamus. It is aware of most everything that is going on and it plays an important role in the regulation of movement. If the cortex is the toddler and the basal ganglia is the parent, then the thalamus is the ultimate policeman.

Now to complicate things for you, the processing of movement in the basal ganglia involves a direct pathway and an indirect pathway. In the simplest terms, the direct pathway encourages movement, while the indirect pathway does the opposite: inhibits it.

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Source: Studyblue

The thalamus will receive signals from the two pathways and then decide – based on those signals – whether to send an excitatory or inhibitory message to the primary motor cortex, telling it what to do (‘tell the muscles to play the piano’ or ‘don’t start playing the piano’, respectively). The primary motor cortex is the red stripe in the image below.

motor areas

The primary motor cortex then sends this structured order down the spinal cord (via the corticospinal pathway) and all going well the muscles will do as instructed.

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Source: adapted from Pinterest

Now, in Parkinson’s disease, the motor features (slowness of movement and resting tremor) are associated with a breakdown in the processing of those direct and an indirect pathways. This breakdown results in a stronger signal coming from the indirect pathway – thus inhibiting/slowing movement. This situation results from the loss of dopamine in the brain.

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Excitatory signals (green) and inhibitory signals (red) in the basal ganglia, in both a normal brain and one with Parkinson’s disease. Source: Animal Physiology 3rd Edition

Under normal circumstances, dopamine neurons release dopamine in the basal ganglia that helps to mediate the local environment. It acts as a kind of lubricant for movement, the oil in the machine if you like. It helps to reduce the inhibitory bias of the basal ganglia.

Thus, with the loss of dopamine neurons in Parkinson’s disease, there is an increased amount of activity coming out of the indirect pathway.

And as a result, the thalamus is kept in an overly inhibited state. With the thalamus subdued, the signal to the motor cortex is unable to work properly. And this is the reason why people with Parkinson’s disease have trouble initiating movement.

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Source: BJP

Now, as you can see from the basic schematic above, the globus pallidus is one of the main conduits of information into the thalamus. Given this pivotal position in the regulation of movement, the globus pallidus has been a region of major research focus for a long time.

It is also one of the sites targeted in ‘deep brain stimulation’ therapy for Parkinson’s disease (the thalamus being another target). Deep brain stimulation (or DBS) involves placing electrodes deep into the brain to help regulate activity.

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DBS in the globus pallidus. Source: APS

By regulating the level of activity in the globus pallidus, DBS can control the signal being sent to the thalamus, reducing the level of inhibition, and thus alleviating the motor related features of the Parkinson’s disease.

The dramatic effects (and benefits) of deep brain stimulation can be seen in this video (kindly provided by fellow kiwi Andrew Johnson):

Deep brain stimulation is not perfect, however.

The placing of the electrodes can sometimes be off target, resulting in limited beneficial effects. Plus the tuning of the device can be a bit fiddly in some cases.

A more precise method of controlling the globus pallidus would be ideal.

Ok, so the globus Pallidus region of the brain is important for movement. What did Dr Gittis and her colleagues find in their research?

They used an amazing piece of technology called ‘optogenetics‘ to specifically determine which group of cells in the globus pallidus are involved in the inhibitory signals going to the thalamus.

And their results are VERY interesting.

But what is optogenetics?

Good question.

The short answer: ‘Magic’

The long answer: In 1979, Nobel laureate Francis Crick suggested that one of the major challenge facing the study of the brain was the need to control one type of cell in the brain while leaving others unaltered.

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The DNA duo: Francis Crick (left) and James Watson. Source: CNN

Electrical stimulation cannot address this challenge because electrodes stimulate everything in the immediate vicinity without distinction. In addition the signals from electrodes lack precision; they cannot turn on/off neurons as dynamically as we require. The same problems (and more) apply to the use of drugs.

Crick later speculated that the answer might be light.

How on earth would you do that?

Well, in 1971 – eight years before Crick considered the problem – two researchers, Walther Stoeckenius and Dieter Oesterhelt, discovered a protein, bacteriorhodopsin, which acts as an ion pump on the surface of a cell membrane. Amazingly, this protein can briefly become activated by green light.

A rather remarkable property.

Later, other groups found similar proteins. One such protein, called ‘Channelrhodopsin’, was discovered in green algae (click here to read more on this). When stimulated by particular frequencies of light, these channels open up on the cell surface and allow ions to pass through. If enough channels open, this process can stimulate particular activity in the cell.

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Channelrhodopsin. Source: Openoptogenetics

Interesting, but how do you get this into the brain?

This is Karl Diesseroff:

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Source: Ozy

Looks like the mad scientist type, right? Well, remember his name, because this guy is fast heading for a Nobel prize.

He’s awesome!

He is the D. H. Chen Professor of Bioengineering and of Psychiatry and Behavioral Sciences at Stanford University. And he is one of the leading researchers in a field that he basically started.

Back in 2005, he and his collaborators published this research report:

opto
Title: Millisecond-timescale, genetically targeted optical control of neural activity
Authors: Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K.
Journal: Nat Neurosci. 2005 Sep;8(9):1263-8. Epub 2005 Aug 14.
PMID: 16116447

In this research report, Deisseroth and his colleagues (particularly Ed Boyden, lead author and now a professor of Biological Engineering at the McGovern Institute for Brain Research at MIT) took the short section of DNA that provides the instructions for making Channelrhodopsin from green algae and they put that piece of DNA into neurons.

And when they then shined blue light on the neurons, guess what happened? Yes, the neurons became activated – that is to say, they produced an ‘action potential’, which is one of the way information is passed from one neuron to another.

Like I said ‘Magic’!

Optogenetic-infographic

Source: Sqonline

And the best part of this biological manipulation was that Deisseroth and his colleagues could activate the neurons with absolutely amazing precision! By pulsing light on the cells for just millisecond periods, they could elicit instant action potentials:

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Precise control of the firing of a neuron. Source: Frontiers

And of course any surrounding cells that do not have the Channelrhodopsin DNA were not affected by the light, but were activated by the signal coming from the Channelrhodopsin+ cells.

This original research report lead to a gold rush-like search for other proteins that are light activated, and we now have an ever increasing toolbox of new proteins with curious properties. For example, we can now not only turn on neurons, but we also have proteins that can shut their activity down, blocking any action potentials (with proteins called ‘Halorhodopsin’ – click here for more on this). And many of these proteins are activated by different frequencies of light. It is really remarkable biology.

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Source: Harvard

For an excellent first-hand history of the early development of optogenetics (written by Ed Boydon who worked with Diesseroff on the first optogenetics study) – click here.

Two years after the first report of optogenetics, the first research demonstrating the use of this technology in the brain of a live animal was published (Click here and here to read more on this). And these fantastic tools are not just being used in the brain, they are being applied to tissues all over the body (for example, optogenetics can be used to make heart cells beat – click here to read more on this).

This TED talk video of Ed Boyden’s description of optogenetics is worth watching if you want to better understand the technique and to learn more about it:

Ok, so Dr Gittis and her colleagues used optogenetics in their research. What did they find?

Well, from previous research they knew that there were two types of neurons in the globus pallidus that regulate a lot of the activity in this region. The two types were identifiable by two different proteins: Lim homeobox 6 (Lhx6) and Parvalbumin (PV).

The Lhx6 neurons, which do not have any PV protein, are generally concentrated in the medial portion of the globus pallidus (closer to the centre of the brain). These Lhx6 neurons also have strong connections with the striatum and substantia nigra parts of the brain. The PV neurons, on the other hand, are more concentrated in the lateral portions of the globus pallidus (closer to the side of the brain), and they have strong connections with the thalamus (Click here to read this previous research).

In their new research report, Dr Gittis and her colleagues have used optogenetics to determine the functions of these two types of cells in the globus pallidus.

Initially, they stimulated both Lhx6 and PV neurons at the same time to see if they could restore movement in mice that had been treated with a neurotoxin (6-OHDA) that killed all the dopamine neurons. Unfortunately, they saw no rescue of the motor abilities of the mice.

They next shifted their attention to activating the two groups of cells separately to see if one of them was inhibiting the other. And when they stimulated the PV neurons alone, something amazing happened: the mice basically got up and started moving.

But the really mind blowing part: even after they turned off the stimulating light – after the pulse of light stopped – the mice were still able to keep moving around.

And this effect lasted for several hours! (note that the red line – indicating a decrease in immobility – in the image below remains stable after the stimulation of light pulses – blue lines – has stopped. Even between light pulses the mouse doesn’t return to immobility).

nn.4559-F2

Stimulation of the PV neurons. Source: Nature

The investigators then tested the reverse experiment: inhibiting the Lhx6 neurons.

And guess what?

They found that by inhibiting the Lhx6 neurons with pulses of light, they could restore movement in the dopamine-depleted mice (and again for hours beyond stimulation – note the blue line in the image below remains even after the light pulses – green lines – have stopped).

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Inhibiting of the Lhx6 neurons. Source: Nature

This result blew my mind at the conference in Vienna. And even now as I write this, I am still….well, flabbergasted! (there’s a good word).

In addition to being a very elegant experiment and use of this new optogenetic technology, this study opens new doors for us in the Parkinson’s disease research field regarding our understanding of how movement works and how we can now potentially treat PD.

Is optogentics being tested in the clinic?

The incredible answer to this question is: Yes.

Source: Retrosense

A company in Ann Arbor (Michigan) called RetroSense Therapeutics announced in March of 2016 that they had treated their first subject in a Phase I/IIa, open-label, dose-escalation clinical study of the safety and tolerability of their lead product, RST-001 in patients with retinitis pigmentosa (Click here for the press release).

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Source: Michiganvca

Retinitis pigmentosa is an inherited eye disease that causes severe vision impairment due to the progressive degeneration of the rod photoreceptor cells in the retina. The condition starts with patients experiencing progressive “tunnel vision” and eventual leads to blindness.

RetroSense’s lead product, RST-001 is basically a virus that infects cells with the photosensitivity gene, channelrhodopsin-2, that we discussed above. Several studies have demonstrated the ability of this approach to restore the perception of light and even vision in experimental models of blindness (Click here to read more about this).

The therapy involves injecting RST-001 into the retinas of patients who are blind. The infected cells will then fire when stimulated with blue light coming into the eye, and this information will hopefully be passed on to the brain. All going well, RetroSense plans to enroll 15 blind subjects in its trial, and they will follow them for two years. They hope to release some preliminary data, however, later this year. And a lot of people will be watching this trial and waiting for the results.

So, yes, optogenetics is being tested in humans.

Obviously, however, these are the first tentative steps in this new field. And it may be sometime before the medical regulatory bodies allow researchers to start conducting optogentic trials in the brain, let alone on people with Parkinson’s disease.

What does it all mean?

It is always rather wondrous where new discoveries take us.

A little over 10 years ago, some scientists discovered that by inserting a photosensitivity gene into brain cells they could control the firing of those cells with rapid pulses of light. And now other researchers are using that technology not only to better understand the works of our brains and how we move, but also to help make blind people see again.

Whether this technology will be able to replace therapies like deep brain stimulation with a more precise method of controlling the firing of the globus pallidus, is yet yo be seen. But this amazing new technique in our research toolbox will most certainly help to enhance our understanding of Parkinson’s disease. Taking us one step closer to ridding ourselves of it entirely.

The banner for today’s post was sourced from Scientifica

PARK2 and the big C

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

cancer

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

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

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

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

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

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

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The basics of genetics. Source: CompoundChem

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

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Lots of different types of genetic variations. Source: Nature

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

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Somatic vs germ line mutations. Source: AutismScienceFoundation

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

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Autosomal dominant vs recessive. Source: Wikipedia

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

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

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

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

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

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

What are PARK genes?

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

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

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

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

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

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

Here is the research report:

MolCell2

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

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

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

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

Hang on a second, what is PARK2?

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

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

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The location of PARK2. Source: Atlasgeneticsoncology

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

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

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

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

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

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

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

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

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

No.

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

And there are two good reasons why not:

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

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Comparing PARK2 Cancer and PD associated mutations. Source: Nature

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

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

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

So please relax.

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

What does it all mean?

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

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

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

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

The banner for today’s post was sourced from Ilovegrowingmarijuana

Rotten eggs, Rotorua and Parkinson’s disease

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

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

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

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

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The geothermal wonderlands of Rotorua. Source: Audleytravel

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

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

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Maori culture. Source: TamakiMaoriVillage

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

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Lake Rotorua. Source: Teara

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

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Tourist playing with mud. Source: Rotoruanz

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

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

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

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

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

Yusuf

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

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

The second study is the more interesting of the pair:

roto

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

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

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

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

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

Hang on a second, what exactly is hydrogen sulfide?

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

Hydrogen_sulfide

H2S. Source: Wikipedia

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

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

F1.large

Source: Clinsci

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

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

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

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

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

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

SH1

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

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

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

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

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

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

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

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

And this is exactly what researchers did next:

HS5

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

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

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

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

Has anyone ever looked at hydrogen sulfide and alpha synuclein?

Not that we are aware of.

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

But researchers have looked at hydrogen sulfide and amyloid formation:

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

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

jp-2014-08471v_0008

Source: NCBI

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

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

Has hydrogen sulfide ever been tested in the clinic?

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

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

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

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

Blakely_June_Hydrogen-Sulfide

Source: Blakely

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

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

There are many foods that contain hydrogen sulfide.

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

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

What does it all mean?

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

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

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

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

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

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

The banner for today’s post was sourced from Trover

New drug approved for ALS

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

ice-bucket-challenge

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

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

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

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Lou Gehrig. Source: NBC

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

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

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

als-whats-is-ALS-info

ALS in a nutshell. Source: Walkforals

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

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

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

p03dn27d

Source: BBC

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

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

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

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

So what happened this week?

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

It is called Edaravone.

What is Edaravone?

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

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

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

What is a free radical?

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

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

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

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

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

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

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

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

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

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

2008-1

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

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

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

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

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

BMC

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

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

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

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

2013-1

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

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

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

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

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

2015-1

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

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

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

Good question.

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

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

4000716f1

Two-dimensional gel electrophoresis. Source: Nature

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

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

In this experiment, the variable was Edaravone.

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

Now this was a really interesting finding.

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

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

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

Are you convinced?

Regardless, it an interesting drug huh?

Are there any downsides to the drug?

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

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

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

So what does it all mean?

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

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

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

It’s just a thought.

The banner for today’s post was sourced from Forbes

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

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

maxresdefault

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

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

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

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

image-title1

Sir Alexander Fleming. Source: Biography

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

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

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

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

photograph_from_1929_paper_by_fleming

Penicillin in a culture dish of staphylococci. Source: NCBI

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

He named it penicillin and the rest is history.

Fleming himself appreciated the serendipity of the finding:

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

And this gave rise to his famous quote:

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

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

Louis-Pasteur-Quotes-1

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

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

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

Three things:

Serendipity
Prepared minds
Antibiotics.

Huh?

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

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

Then it clicked:

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

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

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

And guess what: both group demonstrated neuroprotection!

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

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

Transformation of the neurotoxin 6-OHDA. Source: NCBI

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

Ok, and question 2. What is doxycycline?

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

doxycycline100-1-1k_1

Remind me again, what is an antibiotic?

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

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The ways antibiotics function. Source: FastBleep

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

Basically, yeah.

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

Glial

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

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

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

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

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

Curiously, No.

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

table1

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

Table2

Source: Glia

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

Is doxycycline the only antibiotic that exhibits neuroprotective properties?

No.

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

MPTP

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

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

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

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

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

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

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

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

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

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

Yes.

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

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

title1

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

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

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

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

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

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

Huh?!?

There’s a good reason why not.

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

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

And he is correct.

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

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

Its the purest form of natural selection.

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How bacteria become resistant to antibiotics. Source: Reactgroup

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

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

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

And he is correct again.

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

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

The structure of doxycycline. Source: Wikipedia

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

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

So what does it all mean?

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

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

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

We’ll let you know when we hear something.

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

The banner for today’s post was sourced from Youtube

Trying to digest gut research

May 3, 2017 ~ Simon ~ 7 Comments

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

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

Source: Qz

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

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

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

And those bacteria have influence!

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

Wow, so what new gut research has been reported?

A little bit of history first:

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

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

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

So what’s a truncal vagotomy?

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

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

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

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

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

And what did the Danish scientists find?

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

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

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

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

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

Vagotomy

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

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

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

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

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

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

What are the differences between the studies?

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

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

No.

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

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

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

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

Mmm, interesting. So what does it all mean?

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

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

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

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Microbes. Source: Youtube

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

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

biota-title

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

Nor twice:

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

Not three times:

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

Not even four times:

Plos1

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

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

gut-title

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

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

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

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

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

And what did they find?

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

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

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

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

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

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

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The Prevotellaceae family of bacteria. Source: MindsofMalady

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

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

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

So what does it all mean?

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

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

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

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

Improving Patient Education – Introducing Eirwen Malin

April 30, 2017 ~ Simon ~ 1 Comment

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Today’s post is something a bit different from our usual fodder.

Here at SoPD HQ, we like to throw our support behind worthy projects. And we were recently contacted by Eirwen Malin regarding an idea that we were genuinely passionate about: Improving patient education

Eirwen is being supported by the Winston Churchill Memorial Trust and in the second half of the year she will travel to the USA and then later to Argentina to find new ideas for Patient Education.

In today’s post, we are handing over the keys to the car to Eirwen and we will let her explain the project that she is about to undertake. The goal of this post is to get feedback, ideas and thoughts about the plans for her project. We also encourage all our readers to follow Eirwen (contact details at the bottom of the post) as she undertakes this exciting endeavour.

Untitled Hello, this is me – Eirwen Malin. I’m not prepared to own up to quite how many years I worked in the Third sector in Wales but take it from me (and my photo) quite a lot. I worked mostly trying to influence policy and practice, advocating on behalf of a range of different groups and issues, researching, running demonstration projects, that type of thing. Trying to get the issues heard above the clamour and competing for funding which would hopefully make a difference.

In 2014 I was diagnosed with Parkinson’s and life changed a lot.

It took me a while to realise it but apart from threatening my physical voice, (it’s suggested that 75-90% of people with Parkinson’s have some sort of voice, speech or communication difficulties, see here for more information) having Parkinson’s gave me a new and more powerful voice. I could now speak with the authority of “lived experience”, which might help me make a difference for me and my fellow Parkies.

My own experience of diagnosis was not good. I’d been referred to a neurologist to “put my mind at rest”, so it was completely unexpected. I was not diagnosed by a PD specialist and had to be referred on to a clinic, I was told what I needed was information and then sent off to wait for an appointment with no phone number, website address, fact sheet, nothing!

While I waited, for nearly 6 months, I found masses of information, some of it well expressed and clear, some incomprehensible, some coming from authoritative sources, some from people who were living with the condition, some contradictory, some pseudo-scientific, some completely off the wall yet plausible, in short a potential minefield! Now I am a reasonably competent person, who quite enjoys and is able to read and make sense of research papers, understand the statistics, weigh up the arguments and generally make sense of what’s available. However lots of people with Parkinson’s will not be like me.

So, now I thought maybe I could use my new voice to shout out for the need for Patient Education.

I signed up as a volunteer facilitator for Parkinson’s UK’s Self-Management Programme.

parkinsonsuk_logolong_4cp

It’s an excellent course, based on work long championed by Dr Kate Lorig at Stanford:

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I have seen it help people to gain confidence and regain a measure of control over their lives. I would thoroughly recommend it, however, 6 half day sessions can’t provide the on-going information about medical, social and lifestyle adjustments that are required to live as well as possible with Parkinson’s. Sometimes one needs almost daily updates to manage the complex and peskily changing symptoms. After all the patient is the only one who is there 24/7/365! They must know where to find information and importantly what questions to ask. I meet far too many people desperately seeking guidance.

The opportunity arose to apply for a Winston Churchill Travel Fellowship, as the strapline says the idea is “Travel to learn – return to inspire”.

Established in 1965, following the death of Sir Winston Churchill, the Winston Churchill Memorial Trust hands out 150 fellowships each year providing a unique opportunity for UK citizens to travel overseas with the goal of bringing back fresh ideas and new solutions to today’s issues, for the benefit of others in the UK.

At the end of a quite lengthy application process which has whittled over 1000 application down to about 150 Fellowships I feel very honoured, “Yippee”, to have been successful in the Medical Practice and Education category alongside a CEO of an NHS Trust, Doctors, Nurses, Researchers etc, Yikes!

My quest is to find new ideas for Patient Education. I am focussing particularly in the field of degenerative neurological conditions. This area is particularly tricky because I think it’s reasonable to say that even the experts still have much to learn and the multi-faceted nature of the conditions and their symptoms result in the need for a team of medical practitioners to support the patient making it even more difficult to provide consistent information. The patient has to know whats going on.

For my fellowship, I will be travelling to USA and Argentina.

map-canada-usa-argentina

Yippee, exciting trips, but once again Yikes, the journeys are long, I’ll get even stiffer, and I don’t do well in crowds or queues. It’s a good job that my partner can come and help with the stressful bits.

I’ve tried to cover as many perspectives as I can think of but I’d welcome ideas from readers. I’ll try to fit them in.

A bit more detail on the US trip July-August 2017.

New York

A meeting with the Michael J Fox Foundation. I found lots of information on their website, it seems like a good place to start.

MJFFLogo

I’m hoping to visit New York University’s Electronic Media Patient Education Initiative but still waiting for confirmation

I’m excited to be going to visit Dance for PD in Brooklyn. They do some fantastic work getting people moving and I’m sure there is much to learn.

DFPDlogo400x129

I’ll be talking with the charismatic David Leventhal and other staff to ask how they see their educational role. Most important I want to get feedback from their participants. I have developed a one-woman storytelling performance Sorting the Sock Drawer which I will use to stimulate discussion.

San Francisco area

I’m going to see Dr Kate Lorig (mentioned above) and hoping to talk to some people who will be at Stanford on a one-week course.

University of California San Francisco Parkinson’s Disease Clinic and Research Centre. Really clearly written information on their website that I wish I had found earlier.

UCSF_sublogo_ParkinsonsDiseaseClinic_navy_RGB

By the way I’ll be packing my cheesecloth tunic and flares – it’s the 50^th anniversary of the “Summer of Love” with apologies to younger readers who don’t remember!

Denver

I will meet Professor Cynthia McRae, a behavioural psychologist who focusses on the impact of non-medical symptoms such as quality of life, depression, loneliness, and other psychological factors that are often associated with Parkinson’s disease, but are not always included within medical research.

cMcRae_000

Professor Cynthia McRae

She said “If there is such a thing as a good place to have Parkinson’s then Denver is it!” and introduced me to the Parkinson’s Association of the Rockies. They have so much going on I shall spend some time with them. Once again I’ll be using my performance to stimulate a discussion.

Dallas

A flying visit to spend a day with the Parkinson’s Voice Project, their mantra about people with Parkinson’s living “with intent” really speaks to me.

logoxx

Pittsburgh and around

University of Pittsburgh Institute for Neurodegenerative Diseases to be confirmed

I will visit the Wheeling Hospital Parkinson’s Education Centre. Also at Wheeling I will be filling a gap in the schedule to speak with general medical practitioners to ask about issues for them in helping patients with neurodegenerative conditions

Finally Health Plan, in St Clairesville Ohio. Health Plan is a not-for profit health insurance provider that calls itself a health maintenance organisation. It will be interesting to get a business perspective on Patient Education.

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Alongside the formal meetings I hope to just talk to people I meet, tell them what I am doing and get their views. In the end that might be as important as the planned programme.

Planning for Argentina in Oct-Nov still to be finalised.

So once again Yippee it’s going to be fascinating and exciting but Yikes I really do hope I can come home with the goods and help influence the provision of a better system of educating patients than I encountered. I feel the sense of responsibility to the Winston Churchill Memorial Trust who have invested faith and funds in my idea and my ability to deliver and even more so to my fellow Parkies diagnosed or not for whom I’d like to make a difference.

I’ll be posting activities, photos, videos of the formal meetings and the more touristy parts of the trips on facebook https://www.facebook.com/EirwenWCTF you can follow my activities, send me messages there os send messages via e-mail eirwenwctf@gmail.com

Wearable Tech 4 Parkinson’s

April 29, 2017May 3, 2017 ~ Simon ~ 6 Comments

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We live in an increasingly interconnected technological world.

One can chose to embrace it or ignore it, but I don’t think anyone can do anything to stop it – the masses seem to desire it.

The benefits of all this technology are many, however, for people with Parkinson’s disease. In today’s post we will look at some of the ways wearable technology can be used to improve the lives of people with Parkinson’s disease.

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Does anyone still talk to each other? Source: Teachingwithipad

The great Albert Einstein once said that he feared “the day that technology will surpass our human interaction. The world will have a generation of idiots”.

While there are certainly many examples of this situation playing out in our modern society today, the quote misses the mark with regards to the application and benefits of such technology.

For example, people with Parkinson’s disease can now communicate with people in the Parkinson’s community (like ourselves) from anywhere the world. They can reach out and share not only their experiences, but also what treatments and remedies have worked for them.

And then there are the other less obvious applications of an interconnected world:

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A schematic illustrating the limited monitoring of Parkinson’s. Source: Riggare

On her fantastic blog, engineer and ‘proud mother’ Sara Riggare posted the image above to illustrate the ridiculous current situation regarding the monitoring of Parkinson’s disease. In 2014, she spent 8,765 hours in self care, applying her own knowledge and experience to managing her Parkinson’s disease (8,765 being the number of hours in a year) and had just 1 hour with her physician.

The schematic perfectly illustrates perfectly how little monitoring people with Parkinson’s receive in the standard healthcare system.

People like Sara, however, are taking matters into their own hands. She has become an enthusiastic proponent of ‘self tracking’:

Self tracking represents a fantastic opportunity not only for people with Parkinson’s disease to track their progress, but also for researchers to build up large databases of information relating to the disease from which new theories/hypotheses/treatment approaches could be generated.

And this is possible on a global scale, only because we are a generation of idiots living in a fully interconnected world.

So what opportunities exist for me to self track?

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Apple Watch. Source: Huffington Post

Recently the technology company Apple announced that it is working on new devices to help track Parkinson’s disease (Click here and here for more on this). The company already offers ResearchKit – a platform available on their iphone.

Apple, however, is actually coming to this party rather late. The Michael J Fox foundation and computer giant Intel formed a partnership back in 2014 to look at wearable technology (Click here to read more about this).

And there are already dozens of applications that can be used on smart phones and tablets. We have previously discussed one such app from a company called uMotif – Click here to read that post.

umotif

umotif. Source: ParkinsonsMovement

In addition, there are other smart phone apps available that readers could try (such as MyTherapyApp) and you can even support new applications as they are being developed (such as Progress Recorder).

What if I don’t have time for entering all the details on the smart phone app?

Not a problem.

Why not just wear a recording sensor? The same way you may wear a piece of jewellery. Simple, easy approach and you can just forget that it is even there.

Would you like an interesting example?

This is Utkarsh Tandon.

He’s a 17 years old student at Cupertino High School. He is also the Founder and CEO of OneRing, an intelligent tool for monitoring Parkinson’s

Yes, you read that correctly – he is just 17 years old. Smart kid, we’ll be watching him.

Why is this technology important?

Until recently out understanding of Parkinson’s has relied entirely on what occurs in the lab and clinic based settings. Now information is being collected 24 hours a day. From sleep quality apps to measuring tremor, all of this technology has several very positive features from the view point of research scientists:

Objective monitoring – rather than subjective measures (eg. clinician’s opinion or subject survey) definitive, replicatable data can be generated.
Continuous monitoring – rather than brief periods of monitoring in an artificial research clinic environment, data can be collected in real world settings on a continuous basis
Data accessibility – rather than pencil and paper collection of results, data can be collected electronically and converted to different formats.
Participant engagement – this included benefits such as getting the community involved with the research, getting feedback about the technology throughout the study, and being able to provide subjects with performance reports on a regular basis.

Is wearable tech only for measuring Parkinson’s disease?

No.

Recently it has also started to aid people with the condition. The best example of this is the story that has most recently captured the attention of the Parkinson’s community here in the UK:

Emma Lawton was diagnosed with Parkinson’s disease at just 29 years of age. Working with Haiyan Zhang (Director of Innovation at Microsoft Research) and colleagues, a bracelet was created that counteracted the tremor in Emma’s wrist.

It’s a good story.

Other tech is helping to make life easier for people with Parkinson’s disease – just have a look at what LiftWare is doing.

liftware560

The Liftware stablising spoon. Source: The Verge

In a clinical study, the Liftware spoons reduced shaking of the spoon bowl by an average of 76 per cent (Click here to read more about this).

meet-anupam-pathak-lift-labs-founder

Anupam Pathak – founder of LiftWare. Source: ET

Liftware has now been aquired by Verily Life Sciences – an independent subsidiary of Alphabet Inc (formerly of Google).

So what does it all mean?

The point of this post was to make readers aware of some of the technological resources that are available to them in this modern age. Using these tools, we can quickly collect a vast amount of information regarding all aspects of life for people with Parkinson’s disease. And it also offers folks the opportunity to get involved with research indirectly (if they have a fear of university hospitals!).

There is also another element to all of this recording of information about Parkinson’s disease that is not immediately apparent: we are potentially (and hopefully) the last generations of human being that will be affected by Parkinson’s disease. If current research efforts allow us to block or dramatically slow the condition in the near future, there may not be a disease for our descendants to worry about. While this is a very worthy goal, there is also a responsibility on the current generation to record, document and learn as much as we can about the condition so that those future generations will have information at hand regarding a forgotten medical condition.

Some folks are already doing this in their own creative ways. For example, we recommend all readers subscribe to PD365 – a fantastic project in which David Sangster and Emma Lawton (her of the bracelet described above) will be making one short video each day about life with Parkinson’s disease. Raising awareness about the condition and providing intimate insight into basic daily life with PD.

Here is Emma’s first video:

And here is David’s first video:

And this idea is really important.

Consider the great fire of London in 1666. It is estimated that the fire destroyed the homes of 70,000 of the City’s 80,000 inhabitants (Source: Wikipedia), and yet our best sources of information regarding the events of that catastrophe are limited to just a few books like the diary of Samuel Pepys.

This may seem like a silly example, but the premise stands. Given all of the technology we have available today, it would be a great failure for our generation not to be able to provide a thorough source of information regarding this disease.

That said, have a think about getting involved.

The banner for today’s post was sourced from Raconteur

Stress and Parkinson’s disease

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

stress_general_shutterstock-ollyy_0

Stress.

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

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

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

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

timthumb

Source: Islamicity

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

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

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

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

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

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

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

This is Professor Bas Bloem.

0903tzbasbloem

Prof Bloem – no stress here. Source: NRC

He’s awesome.

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

In 2010, his research group noticed something interesting:

Bloem

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

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

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

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

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

This idea is not as crazy as it sounds.

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

Prisoner

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

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

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

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

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

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

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

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

Something interesting.

This is Dr Yoon-Il Lee.

Lee

Source: Dgist

He’s a dude.

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

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

Lee

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

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

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

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

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

What is Hydrocortisone?

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

Ok, so what is cortisol?

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

CDR739009

The location of the adrenal glands. Source: Cancer

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

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

open-uri20120801-11642-h5dnby

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

Ok, so what did the Korean researchers do next?

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

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

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

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

So this is where the story gets interesting;

Dobbs

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

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

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

Muller

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

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

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

Is hydrocortisone or cortisol used in the clinic?

Yes it is.

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

white-tablet-pills-on-reflective-surface

Hydrocortisone tablets. Source: Wisegeeks

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

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

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

So what does it all mean?

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

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

Interesting times. Stay tuned.

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

The banner for today’s post was sourced from ZetaYarwood

Old dogs, new tricks – repurposing drugs for Parkinson’s

April 21, 2017April 21, 2017 ~ Simon ~ 3 Comments

Drugrepurpose

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.

Drugs

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).

ajbtbe-v2-id1047-g001

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.

Leicester-2015-05-11-0182_800

Prof Giovanna Mallucci. Source: MRC

She’s awesome.

She led the team from the Medical Research Council’s (MRC) Toxicology Unit (University of Leicester) that conducted the research and she is now based at the University of Cambridge.

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:

Nature

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.

U2CP5-4_Phosphorylation_revised

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.

Roles of eIF2 kinases in the pathogenesis of Alzheimer's disease

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.

prions

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:

Brain
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 rTg4510mice 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.

ParkUPS

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.
PMID: 17254549

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.

graph

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:

Activation
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):

Basic RGB

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?

Yes.

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:

Trazodone

Title: Can trazodone induce parkinsonism?
Authors: Albanese A, Rossi P, Altavista MC.
Journal: Clin Neuropharmacol. 1988 Apr;11(2):180-2.
PMID: 3378227

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.

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