Antidepressants are an important class of drugs in modern medicine, providing people with relief from the crippling effects of depression.
Recently, research has suggested that some of these drugs may also provide benefits to people suffering from Parkinson’s disease. But by saying this we are not talking about the depression that can sometimes be associated with this condition.
This new research suggests anti-depressants are actual providing neuroprotective benefits.
In today’s post we will discuss depression and its treatment, outline the recent research, and look at whether antidepressants could be useful for people with Parkinson’s disease.
It is estimated that 30 to 40% of people with Parkinson’s disease will suffer from some form of depression during the course of the condition, with 17% demonstrating major depression and 22% having minor depression (Click here to read more on this).
This is a very important issue for the Parkinson’s community.
Depression in Parkinson’s disease is associated with a variety of poor outcomes not only for the individuals, but also for their families/carers. These outcomes can include greater disability, less ability to care for oneself, faster disease progression, reduced cognitive performance, reduced adherence to treatment, worsening quality of life, and increased mortality. All of which causes higher levels of caregiver distress for those supporting the affected individual (Click here to read more about the impact of depression in early Parkinson’s).
What is depression?
Wikipedia defines depression as a “state of low mood and aversion to activity that can affect a person’s thoughts, behaviour, feelings, and sense of well-being” (Source). It is a common mental state that causes people to experience loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, low energy, and poor concentration.
Importantly, depression can vary significantly in severity, from simply causing a sense of melancholy to confining people to their beds.
What causes depression?
Trehalose is a small molecule – nutritionally equivalent to glucose – that helps to prevent protein from aggregating (that is, clustering together in a bad way).
Parkinson’s disease is a neurodegenerative condition that is characterised by protein aggregating, or clustering together in a bad way.
Is anyone else thinking what I’m thinking?
In today’s post we will look at what trelahose is, review some of the research has been done in the context of Parkinson’s disease, and discuss how we should be thinking about assessing this molecule clinically.
Neuropathologists examining a section of brain tissue. Source: Imperial
When a neuropathologist makes an examination of the brain of a person who passed away with Parkinson’s, there are two characteristic hallmarks that they will be looking for in order to provide a definitively postmortem diagnosis of the condition:
1. The loss of dopamine producing neurons in a region of the brain called the substantia nigra.
The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source:Memorangapp
2. The clustering (or ‘aggregation’) of a protein called alpha synuclein. Specifically, they will be looking for dense circular aggregates of the protein within cells, which are referred to as Lewy bodies.
A Lewy body inside of a neuron. Source: Neuropathology-web
A cartoon of a neuron, with the Lewy body indicated within the cell body. Source: Alzheimer’s news
In addition to Lewy bodies, the neuropathologist may also see alpha synuclein clustering in other parts of affected cells. For example, aggregated alpha synuclein can be seen in the branches of cells (these clusterings are called ‘Lewy neurites‘ – see the image below where alpha synuclein has been stained brown on a section of brain from a person with Parkinson’s disease.
Examples of Lewy neurites (indicated by arrows). Source: Wikimedia
Given these two distinctive features of the Parkinsonian brain (the loss of dopamine neurons and the aggregation of alpha synuclein), a great deal of research has focused on A.) neuroprotective agents to protect the remaining dopamine-producing neurons in the substantia nigra, and B.) compounds that stop the aggregation of alpha synuclein.
In today’s post, we will look at the research that has been conducted on one particular compounds that appears to stop the aggregation of alpha synuclein.
It is call Trehalose (pronounces ‘tray-hellos’).
Nuclear receptor related 1 protein (or NURR1) is a protein that is critical to the development and survival of dopamine neurons – the cells in the brain that are affected in Parkinson’s disease.
Given the importance of this protein for the survival of these cells, a lot of research has been conducted on finding activators of NURR1.
In today’s post we will look at this research, discuss the results, and consider issues with regards to using these activators in Parkinson’s disease.
Comet Hale–Bopp. Source: Physics.smu.edu
Back in 1997, 10 days after Comet Hale–Bopp passed perihelion (April 1, 1997 – no joke; perihelion being the the point in the orbit of a comet when it is nearest to the sun) and just two days before golfer Tiger Woods won his first Masters Tournament, some researchers in Stockholm (Sweden) published the results of a study that would have a major impact on our understanding of how to keep dopamine neurons alive.
Dopamine neurons are one group of cells in the brain that are severely affected by Parkinson’s disease. By the time a person begins to exhibit the movement symptoms of the condition, they will have lost 40-60% of the dopamine neurons in a region called the substantia nigra. In the image below, there are two sections of brain – cut on a horizontal plane through the midbrain at the level of the substantia nigra – one displaying a normal compliment of dopamine neurons and the other from a person who passed away with Parkinson’s demonstrating a reduction in this cell population.
The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source:Memorangapp
The researchers in Sweden had made an amazing discovery – they had identified a single gene that was critical to the survival of dopamine neurons. When they artificially mutated the section of DNA where this gene lives – an action which resulted in no protein for this gene being produced – they generated genetically engineered mice with no dopamine neurons:
Title: Dopamine neuron agenesis in Nurr1-deficient mice
Authors: Zetterström RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T.
Journal: Science. 1997 Apr 11;276(5310):248-50.
The researchers who conducted this study found that the mice with no NURR1 protein exhibited very little movement and did not survive long after birth. And this result was very quickly replicated by other research groups (Click here and here to see examples)
So what was this amazing gene called?
Recently I discussed my ‘Plan B’ idea, which involves providing a cheap alternative to expensive drugs for folks living in the developing world with Parkinson’s (Click here for that post).
While doing some research for that particular post, I came across another really interesting bit of science that is being funded by Parkinson’s UK.
It involves Beetroot.
In today’s post we will look at how scientists are attempting turn this red root vegetable into a white root vegetable in an effort to solve Parkinson’s in the developing world.
Pompeii and Mount Vesuvius. Source: NationalGeo
During visits to the ancient Roman city of Pompeii (in Italy), tourists are often drawn by their innocent curiosity to the ‘red light’ district of the city. And while they are there, they are usually amused by the ‘descriptive’ murals that still line the walls of the buildings in that quarter.
So amused in fact that they often miss the beetroots.
I’m not suggesting that anyone spends a great deal of time making a close inspection of the walls, but if you look very carefully, you will often see renditions of beetroots.
They are everywhere. For example:
Two beetroots hanging from the ceiling.
The Romans considered beetroot to be quite the aphrodisiac, believing that the juice ‘promoted amorous feelings’. They also ate the red roots for medicinal purposes, consuming it as a laxative or to cure fever.
And this medicinal angle lets me segway nicely into the actual topic of today’s post. You see, in the modern era researcher are hoping to use beetroot for medicinal purposes again. But this time, the beetroot will be used to solve an issue close to my heart: treating people with Parkinson’s in the developing world.
Using beetroot to treat Parkinson’s?
The protein Alpha Synuclein has long been considered the bad-boy of Parkinson’s disease research. Possibly one of the main villains in the whole scheme of things.
New research suggests that it may be interfering with a neuroprotective pathway, leaving the affected cell more vulnerable to stress/toxins. But that same research has highlighted a novel beneficial feature of an old class of drugs: MAO-B inhibitors.
In today’s post we will outline the new research, discuss the results, and look at whether this new Trk warrants a re-think of MAO-B inhibitors.
The great Harry Houdini. Source: Wikipedia
I’m not sure about you, but I enjoy a good magic trick.
That exhilarating moment when you are left wondering just one thing: How do they do that?
(Seriously, at 4:40 a baguette comes out of thin air – how did he do that?)
Widely believed to have been one of the greatest magicians of all time (Source), Harry Houdini is still to this day revered among those who practise the ‘dark arts’.
Born Erik Weisz in Budapest (in 1874), Houdini arrived in the US in 1878. Fascinated with magic, in 1894, he launched his career as a professional magician and drew attention for his daring feats of escape. He renamed himself “Harry Houdini” – the first name being derived from his childhood nickname, “Ehrie,” and the last name paying homage to the great French magician Jean Eugène Robert-Houdin. In 1899, Houdini’s act caught the eye of Martin Beck, an entertainment manager, and from there the rest is history. Constantly upping the ante, his feats became bolder and more death defying.
And the crowds loved him.
From stage, he moved on to film – ultimately starting his own production company, Houdini Picture Corporation. In addition, he was a passionate debunker of psychics and mediums, his training in magic helping him to expose frauds (which turned him against his former friend Sir Arthur Conan Doyle, who believed deeply in spiritualism).
This is all very interesting, but what does any of it have to do with Parkinson’s?
The motor features of Parkinson’s disease can be managed with treatments that replace the chemical dopamine in the brain.
While there are many medically approved dopamine replacement drugs available for people affected by Parkinson’s disease, there also are more natural sources.
In today’s post we will look at the science and discuss the research supporting one of the most potent natural source for dopamine replacement treatment: Mucuna pruriens
When asked by colleagues and friends what is my ‘plan B’ (that is, if the career in academia does not play out – which is highly probable I might add – Click here to read more about the disastrous state of biomedical research careers), I answer that I have often considered throwing it all in and setting up a not-for-profit, non-governmental organisation to grow plantations of a tropical legume in strategic places around the world, which would provide the third-world with a cheap source of levodopa – the main treatment in the fight against Parkinson’s disease.
Plan B: A legume plantation. Source: Tropicalforages
The response to my answer is generally one of silent wonder – that is: me silently wondering if they think I’m crazy, and them silently wondering what on earth I’m talking about.
As romantic as the concept sounds, there is an element of truth to my Plan B idea.
I have read many news stories and journal articles about the lack of treatment options for those people with Parkinson’s disease living in the developing world.
Hospital facilities in the rural Africa. Source: ParkinsonsLife
Some of the research articles on this topic provide a terribly stark image of the contrast between people suffering from Parkinson’s disease in the developing world versus the modernised world. A fantastic example of this research is the work being done by the dedicated researchers at the Parkinson Institute in Milan (Italy), who have been conducting the “Parkinson’s disease in Africa collaboration project”.
The researchers at the Parkinson Institute in Milan. Source: Parkinson Institute
The project is an assessment of the socio-demographic, epidemiological, clinical features and genetic causes of Parkinson’s disease in people attending the neurology out-patients clinic of the Korle Bu Teaching and Comboni hospitals. Their work has resulted in several really interesting research reports, such as this one:
Title: The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa.
Authors: Cilia R, Akpalu A, Sarfo FS, Cham M, Amboni M, Cereda E, Fabbri M, Adjei P, Akassi J, Bonetti A, Pezzoli G.
Journal: Brain. 2014 Oct;137(Pt 10):2731-42.
PMID: 25034897 (This article is OPEN ACCESS if you would like to read it)
In this study, the researchers collected data in Ghana between December 2008 and November 2012, and each subject was followed-up for at least 6 months after the initiation of Levodopa therapy. In total, 91 Ghanaians were diagnosed with Parkinson’s disease (58 males, average age at onset 60 ± 11 years), and they were compared to 2282 Italian people with Parkinson’s disease who were recruited during the same period. In long-term follow up, 32 Ghanaians with Parkinson’s disease were assessed (with an average follow period of 2.6 years).
There are some interesting details in the results of the study, such as:
- Although Levodopa therapy was generally delayed – due to availability and affordability – in Ghana (average disease duration before Levodopa treatment was 4.2 years in Ghana versus just 2.4 years in Italy), the actual disease duration – as determined by the occurrence of motor fluctuations and the onset of dyskinesias – was similar in the two populations.
- The motor fluctuations were similar in the two populations, with a slightly lower risk of dyskinesias in Ghanaians.
- Levodopa daily doses were higher in Italians, but this difference was no longer significant after adjusting for body weight.
- Ghanaian Parkinson’s sufferers who developed dyskinesias were younger at onset than those who did not.
Reading these sorts of research reports, I am often left baffled by the modern business world’s approach to medicine. I am also left wondering how an individual’s experience of Parkinson’s disease in some of these developing nations would be improved if a cheap alternative to the dopamine replacement therapies was available.
Are any cheap alternatives available?
This week a group of scientists have published an article which indicates differences between mice and human beings, calling into question the use of these mice in Parkinson’s disease research.
The results could explain way mice do not get Parkinson’s disease, and they may also partly explain why humans do.
In today’s post we will outline the new research, discuss the results, and look at whether Levodopa treatment may (or may not) be a problem.
The humble lab mouse. Source: PBS
Much of our understanding of modern biology is derived from the “lower organisms”.
From yeast to snails (there is a post coming shortly on a snail model of Parkinson’s disease – I kid you not) and from flies to mice, a great deal of what we know about basic biology comes from experimentation on these creatures. So much in fact that many of our current ideas about neurodegenerative diseases result from modelling those conditions in these creatures.
Now say what you like about the ethics and morality of this approach, these organisms have been useful until now. And I say ‘until now’ because an interesting research report was released this week which may call into question much of the knowledge we have from the modelling of Parkinson’s disease is these creatures.
You see, here’s the thing: Flies don’t naturally develop Parkinson’s disease.
Nor do mice. Or snails.
Or yeast for that matter.
So we are forcing a very un-natural state upon the biology of these creatures and then studying the response/effect. Which could be giving us strange results that don’t necessarily apply to human beings. And this may explain our long history of failed clinical trials.
We work with the best tools we have, but it those tools are flawed…
What did the new research report find?
This is the study:
Title: Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease
Authors: Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC, Jeon S, Santos DP, Blanz J, Obermaier CD, Strojny C, Savas JN, Kiskinis E, Zhuang X, Krüger R, Surmeier DJ, Krainc D
Journal: Science, 07 Sept 2017 – Early online publication
The researchers who conducted this study began by growing dopamine neurons – a type of cell badly affected by Parkinson’s disease – from induced pluripotent stem (IPS) cells.
What are induced pluripotent stem cells?
BE WARNED: THIS POST MIGHT UPSET SOME READERS
A recently published research report has caused a bit of a fuss in the media, and I have been contacted by a lot of concerned readers regarding this particular study.
It deals with some chemicals – which can be found in everyday products – that may be having a negative effect on biological processes that are related to Parkinson’s disease – specifically, the normal functioning of the mitochondria (the power stations of each cell).
In today’s post we will discuss the new research, what the chemicals do, and whether the Parkinson’s community should be concerned.
It is something that most of us take completely for granted in the modern world. A product that sits in our bathroom, by the sink or on a shelf, and 2-3 times per day we stick some of it in our mouth and brush it around a bit. Given the well ingrained habit of repetitively ingesting of the stuff, we have little trouble with the idea of switching brands or trying new variations (“Oooh look, this one will make your teeth whiter. Let’s try it”).
I mean, come on – it’s just toothpaste. It’s safe, right?
It probably won’t surprise many of you to learn that the composition of toothpaste has changed quite a bit over the years, but what might amaze you is just how many years are involved with that statement:
Egyptian toothbrush. Source: Nathanpaarth
The Egyptians recognised the importance of looking after one’s teeth at a very early stage. Apparently they had a lot of trouble with their teeth because their bread had grit in it which wore away their enamel. As far back as 5000BC, they had a form of toothpaste that they used to clean their teeth. It was a mix of powdered ashes of ox hooves, myrrh, powdered and burnt eggshells, and pumice (Source: Wikipedia). The Greeks, followed by the Romans, improved on the recipes (by adding abrasive ingredients such as crushed bones and oyster shells – delightful, huh?), but it wasn’t until after World War I that the modern day pre-mixed toothpastes became popular.
The cavity fighting chemical, Fluoride, was first added to toothpastes in the 1890s, and in 1908 Newell Sill Jenkins (an American dentist) invented the first toothpaste that contained disinfectants. It was called Kolynos (from the Greek words Kolyo nosos (κωλύω νόσος), meaning “disease prevention”).
Following the advent of Kolynos, most toothpaste companies added antiseptic and disinfectant agents to improve the quality and effectiveness of their product. Being offered a tooth cleaning product with magical antibiotic properties seemed to reassure consumers that they were buying something that might actually work. And this led to more and more chemicals being added to toothpaste. Such additions included chemical like triclosan, cetylpyridinium chloride and benzalkonium chloride.
These chemicals are safe though…right?
This week a biotech company called Voyager Therapeutics announced the results of their ongoing phase Ib clinical trial. The trial is investigating a gene therapy approach for people with severe Parkinson’s disease.
Gene therapy is a technique that involves inserting new DNA into a cell using a virus. The DNA can help the cell to produce beneficial proteins that go on help to alleviate the motor features of Parkinson’s disease.
In today’s post we will discuss gene therapy, review the new results and consider what they mean for the Parkinson’s community.
On 25th August 2012, the Voyager 1 space craft became the first human-made object to exit our solar system.
After 35 years and 11 billion miles of travel, this explorer has finally left the heliosphere (which encompasses our solar system) and it has crossed into the a region of space called the heliosheath – the boundary area that separates our solar system from interstellar space. Next stop on the journey of Voyager 1 will be the Oort cloud, which it will reach in approximately 300 years and it will take the tiny craft about 30,000 years to pass through it.
Where is Voyager 1? Source: Tampabay
Where is Voyager actually going? Well, eventually it will pass within 1 light year of a star called AC +79 3888 (also known as Gliese 445), which lies 17.6 light-years from Earth. It will achieve this goal on a Tuesday afternoon in 40,000 years time.
Gliese 445 (circled). Source: Wikipedia
Remarkably, the Gliese 445 star itself is actually coming towards us. Rather rapidly as well. It is approaching with a current velocity of 119 km/sec – nearly 7 times as fast as Voyager 1 is travelling towards it (the current speed of the craft is 38,000 mph (61,000 km/h).
Interesting, but what does any of that have to do with Parkinson’s disease?
Well closer to home, another ‘Voyager’ is also ‘going boldly where no man has gone before’ (sort of).
Dopamine agonist treatments are associated with approximately 90% of hyper-sexuality and compulsive gambling cases that occur in people with Parkinson’s disease.
This issue does not affect everyone being treated with this class of drugs, but it is a problem that keeps popping up, with extremely damaging consequences for the affected people who gamble away their life’s saving or ruin their marriages/family life.
The U.S. Food and Drug Administration (FDA) is yet to issue proper warning for this well recognised side-effect of dopamine agonists, and yet last week they gave clearance for the clinical testing of a new implantable device that will offer continuous delivery of dopamine agonist medication.
In today’s post, we will discuss what dopamine agonists are, the research regarding the impulsive behaviour associated with them, and why the healthcare regulators should acknowledge that there is a problem.
Dopamine. Source: Wikimedia
Before we start talking about dopamine agonists, let’s start at the very beginning:
What is dopamine?
By the time a person is sitting in front of a neurologist and being told that they ‘have Parkinson’s disease’, they will have lost half the dopamine producing cells in an area of the brain called the midbrain.
Dopamine is a chemical is the brain that plays a role in many basic functions of the brain, such as motor co-ordination, reward, and memory. It works as a signalling molecule (or a neurotransmitter) – a way for brain cells to communicate with each other. Dopamine is released from brain cells that produce this chemical (not all brain cells do this), and it binds to target cells, initiating biological processes within those cells.
Dopamine being released by one cell and binding to receptors on another. Source: Truelibido
Dopamine binds to target cells via five different receptors – that is to say, dopamine is released from one cell and can bind to one of five different receptors on the target cell (depending on which receptor is present). The receptor is analogous to a lock and dopamine is the key. When dopamine binds to a particular receptor it will allow something to happen in that cell. And this is how information from a dopamine neuron is passed or transmitted on to another cell.
Dopamine acts like a key. Source: JourneywithParkinsons