It is one of the most frequent non-motor features of Parkinson’s and yet it is one of the least publicly discussed.
The word ‘constipation’ is generally used to describe bowel movements that are infrequent or difficult to pass. The stool is often dry, lumpy and hard, and problematic to expel. Other symptoms can include abdominal pain, bloating, and the feeling that one has not completely passed the bowel movement.
In today’s post we look at what can cause constipation, why it may be so common in Parkinson’s, discuss what can be done to alleviate it, and look at clinical trials focused on this issue.
As many as 1 in 5 people say they have suffered from chronic (long-term) constipation at some point in their lives.
It results in more than 2.5 million hospital and physicians visits per year in the USA.
And Americans spend more than $700 million on treatments for it annually (Source).
More importantly, constipation is considered by many researchers to be a risk factor for developing Parkinson’s, as many people in the affected community claim to have experienced constipation for long periods prior to diagnosis.
Why this is, what is being done to research it, and what can be done about constipation in Parkinson’s is the topic of today’s post. But first, let’s start with the obvious question:
What is constipation?
Researchers at Cambridge University published a new report this week that extends on a very interesting line of Parkinson’s research. The studies focus on a compound (and derivatives of that compound) that has been derived from the dogfish shark.
The protein – called Squalamine – has an amazing ability to prevent the Parkinson’s-associated protein alpha synuclein from clustering (or aggregating) together. The aggregation of alpha synuclein is considered to be a key component of the biology underlying Parkinson’s, and thus any compound that block/reduce this aggregation is viewed with therapeutic applications in mind.
Unfortunately there is a problem with squalamine: it does not cross the blood brain barrier (the protective membrane surrounding the brain).
But a derivative of squalamine – called Trodusquemine – does!
In today’s post, we will look at what Squalamine and Trodusquemine are, we will review the new research, and look at current clinical research efforts involving these compounds.
The effects of aggregated Alpha Synuclein protein in a neuron. Source: R&D
We often talk about one particular protein on this website. It is called alpha synuclein. It is one of the most common proteins in the human brain, and it appears to be centrally involved with Parkinson’s.
In the Parkinsonian brain, alpha synuclein clumps (or aggregates) together, which is believed to lead to the appearance of Lewy bodies.
What are Lewy bodies?
There has been a lot of discussion on this site (and elsewhere on the web) regarding the need for more objective systems of measuring Parkinson’s – particularly in the setting of clinical trials.
Yes, subjective reports of patient experience are important, but they can easily be biased by ‘placebo responses’.
Thus, measures that are beyond the clinical trial participants conscious control – and focused on biological outcomes – are needed.
In today’s post, we will consider one possible approach: Smart pills. We will discuss what they are, how they work, and how they could be applied to Parkinson’s research.
In order to encourage a growing discussion regarding objective measures of Parkinson’s (and to follow up on previous rants – Click here and here for examples), I have decided to regularly (once a month) highlight new technologies that could provide the sort of unbiased methods of data collection that are required for assessing whether a treatment is having an impact on Parkinson’s.
Today, we will look at smart pills.
What is a smart pill?
At the end of each year, it is a useful practise to review the triumphs (and failures) of the past 12 months. It is an exercise of putting everything into perspective.
2017 has been an incredible year for Parkinson’s research.
And while I appreciate that statements like that will not bring much comfort to those living with the condition, it is still important to consider and appreciate what has been achieved over the last 12 months.
In this post, we will try to provide a summary of the Parkinson’s-related research that has taken place in 2017 (Be warned: this is a VERY long post!)
The number of research reports and clinical trial studies per year since 1817
As everyone in the Parkinson’s community is aware, in 2017 we were observing the 200th anniversary of the first description of the condition by James Parkinson (1817). But what a lot of people fail to appreciate is how little research was actually done on the condition during the first 180 years of that period.
The graphs above highlight the number of Parkinson’s-related research reports published (top graph) and the number of clinical study reports published (bottom graph) during each of the last 200 years (according to the online research search engine Pubmed – as determined by searching for the term “Parkinson’s“).
PLEASE NOTE, however, that of the approximately 97,000 “Parkinson’s“-related research reports published during the last 200 years, just under 74,000 of them have been published in the last 20 years.
That means that 3/4 of all the published research on Parkinson’s has been conducted in just the last 2 decades.
And a huge chunk of that (almost 10% – 7321 publications) has been done in 2017 only.
So what happened in 2017? Continue reading
In addition to looking at current Parkinson’s disease research on this website, I like to look at where technological advances are taking us with regards to future therapies.
In July of this year, I wrote about a new class of engineered viruses that could potentially allow us to treat conditions like Parkinson’s disease using a non-invasive, gene therapy approach (Click here to read that post). At the time I considered this technology way off at some point in the distant future. Blue sky research. “Let’s wait and see” – sort of thing.
So imagine my surprise when an Italian research group last weekend published a new research report in which they used this futurist technology to correct a mouse model of Parkinson’s disease. Suddenly the distant future is feeling not so ‘distant’.
In today’s post we will review and discuss the results, and look at what happens next.
Technological progress – looking inside the brain. Source: Digitial Trends
I have said several times in the past that the pace of Parkinson’s disease research at the moment is overwhelming.
So much is happening so quickly that it is quite simply difficult to keep up. Not just here on the blog, but also with regards to the ever increasing number of research articles in the “need to read” pile on my desk. It’s mad. It’s crazy. Just as I manage to digest something new from one area of research, two or three other publications pop up in different areas.
But it is the shear speed with which things are moving now in the field of Parkinson’s research that is really mind boggling!
Take for example the case of Squalamine.
In February of this year, researchers published an article outlining how a drug derived from the spiny dogfish could completely suppress the toxic effect of the Parkinson’s associated protein Alpha Synuclein (Click here to read that post).
The humble dogfish. Source: Discovery
And then in May (JUST 3 MONTHS LATER!!!), a biotech company called Enterin Inc. announced that they had just enrolled their first patient in the RASMET study: a Phase 1/2a randomised, controlled, multi-center clinical study evaluating a synthetic version of squalamine (called MSI-1436) in people with Parkinson’s disease. The study will enrol 50 patients over a 9-to-12-month period (Click here for the press release).
Wow! That is fast.
Yeah, I thought so too, but then this last weekend a group in Italy published new research that completely changed my ideas on the meaning of the word ‘fast’. Regular readers will recall that in July I discussed amazing new technology that may one day allow us to inject a virus into a person’s arm and then that virus will make it’s way up to the brain and only infect the cells that we want to have a treatment delivered to. This represents non-invasive (as no surgery is required), gene therapy (correcting a medical condition with the delivery of DNA rather than medication). This new study used the same virus we discussed in July.
This week an interesting study was published in the scientific journal, Proceedings of the National Academy of Sciences. It involved our old friend, alpha synuclein – the aggregating protein that is associated with Parkinson’s disease – and the dogfish shark.
Not natural dance partners, I agree. But the findings of the study are very interesting.
In today’s post we will review the study and explain the connection between the protein and the shark.
Some people call them spiny dogfish.
Others call them Spurdogs. Or Mud shark. Or even Piked dogfish.
Call them what you will – in the scientific realm they are referred to as Squalus acanthias. They are one of the most common members of the Squalide (dogfish) family of sharks. In the wild, Squalus acanthias are found in shallow waters, but can be seen further offshore in more temperate latitudes. They are relatively harmless to humans, but they do have venom in their rear fin – when under attack, the dogfish shark will arch its back and pierce/poison its attacker (so beware!).
Interesting, but what is the connection with Parkinson’s disease?
So here’s the thing about dogfish sharks: they are extremely hardy when it comes to infection.
They don’t really get sick all that often. And this is despite having a relatively “primitive” immune system (Click here to read more on this). A team led by Prof Michael Zasloff (of Georgetown University) discovered that a chemical called ‘Squalamine’ may be one of the reasons for this robustness.
What is Squalamine?
Squalamine is steroid with a wide range of antimicrobial activity. Steroids are used as a treatment for certain inflammatory conditions, but the research published this week suggests another property for Squalamine.
This is the research article that was published:
Title: A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity
Authors: Perni M, Galvagnion C, Maltsev A, Meisl G, Müller MB, Challa PK, Kirkegaard JB, Flagmeier P, Cohen SI, Cascella R, Chen SW, Limboker R, Sormanni P, Heller GT, Aprile FA, Cremades N, Cecchi C, Chiti F, Nollen EA, Knowles TP, Vendruscolo M, Bax A, Zasloff M, Dobson CM.
Journal: PNAS 2017; doi:10.1073/pnas.1610586114
PMID: 28096355 (this article is OPEN ACCESS if you would like to read it)
In this study, the researchers discovered that squalamine can actually block alpha synuclein from aggregating (that is clumping together). They treated human cells (that produce too much alpha synuclein, which ultimately kills them) in culture with squalamine and they observed an almost complete suppression of the toxic effect of alpha synuclein.
Caenorhabditis elegans – cute huh? Source: Nematode
The researchers next looked at the effects of squalamine in a microscopic worm called Caenorhabditis elegans . These tiny creatures are widely used in biology because they can be easily genetically manipulated and their nervous system is very simple and well mapped out (they have just 302 neurons and 56 glial cells!). The particular strain of Caenorhabditis elegans used in this current study produced enormous amounts of alpha synuclein, which results in muscle paralysis.
By treating the worms with squalamine, the researchers observed a dramatic reduction of alpha synuclein protein aggregating and an almost complete elimination of the muscle paralysis. In addition, they noted a reduction in the cellular damage caused by the aggregation of alpha synuclein. All in all, a pretty impression result! The researchers suggested that their findings indicate that “squalamine could be a means of therapeutic intervention in Parkinson’s disease”.
So is squalamine being tested in the clinic?
The answer is: Yes, but not for Parkinson’s disease.
There is currently a clinical trial for squalamine in people with neovascular age-related macular degeneration – a condition of the eye (click here for more information about that trial). This work is being carried out by a company called Ohr Pharmaceuticals and as far as we are aware all of their work is focused on eye treatments. Squalamine has also been tested in clinical studies of fungal infection of the scalp – tinea capitis – and appeared to be well tolerated (Click here for more information).
Regarding Parkinson’s disease, there is just one small problem:
Squalamine doesn’t cross the blood-brain barrier
(click here to read more on this)
The blood brain barrier is a membrane that covers and protects the brain. It limits what chemicals can enter (or leave) the brain. Squalamine is one chemical that the blood brain barrier won’t let into the brain.
But this is not the end of the world!
Prof Zasloff and colleagues have designed a drug very similar to Squalamine, which they have called MSI-1436 which is currently being tested. And the good news is that it can cross the blood brain barrier (Click here to read more on this). MSI-1436 appears to exhibit potent appetite suppression and anti-diabetic properties when injected in animals. MSI-1436 has been clinically tested (phase 1) for tolerance in diabetes with obesity (Click here to see the details of that trial), but that clinical trial was conducted in 2008-9 and the results are still not available. The company behind the trial, ‘Genaera Corp’, has since been shut down (Click here for more on this), and we are unaware of any follow up clinical work on this drug.
What does it all mean?
Well, the researchers in this study have found a chemical (squalamine) which is able to prevent alpha synuclein from aggregating – which is believed to be one the underlying processes in Parkinson’s disease. This means that we have another experimental therapy to add to the growing arsenal of potential future Parkinson’s disease treatments.
It is important to appreciate, however, that this is the first time this result has been shown and what we need to see now is independent replication of these results. This follow-up work will also need to involve squalamine being tested in a more advanced animal model of Parkinson’s disease (worms are cute and all, but there is only so much data we can get from them!). In addition, if squalamine (or MSI-1436) has a future in treating Parkinson’s disease, we will need to better investigate the weight-loss properties of this chemical as this would not be an ideal side effect for people with Parkinson’s disease.
As this research progresses on squalamine, we’ll report it here.
Watch this space.
UPDATE – 16th May, 2016
Wow! So this is all happening very fast.
Today, Enterin Inc. has just enrolled their first patient in the RASMET study: a Phase 1/2a randomised, controlled, multi-center clinical study evaluating synthetic squalamine in people with PD. The study will enrol 50 patients over a 9-to-12-month period (Click here for the press release).
We’ll continue to watch this space… things appear to be moving very quick here!
The banner for today’s post was sourced from X-ray Mag