This week exciting new research from a collaboration between Chinese researchers and scientists at the University of Iowa has pointed towards a clinically-available, generic drug that could be re-purposed for Parkinson’s.
The researchers found a drug called Terazosin – which is used for the treatment of enlarged prostates and high blood pressure – can boost energy production in neurons, and also rescue multiple preclinical models of Parkinson’s (including human cell cultures).
Most intriguing, however, was their discovery that people taking Terazosin (or similar drugs) have a reduced incidence of Parkinson’s, and people with Parkinson’s who take Terazosin seem to have less disease progression.
In today’s post, we will look at what Terazosin is, how it functions, what this new research suggests, and how the finding is being taken forward.
Reader questions. Source: Yoursalesplaybook
So I have had a few inquiries over the last 24 hours.
Lots of questions.
A wee bit of interest in some recent Parkinson’s associated research.
It seems that there was a bit of excitement generated by press releases regarding new research from a group of researchers in China and the University of Iowa suggesting that a commonly used blood pressure and prostate treatment called Terazosin not only had beneficial effects in multiple models of Parkinson’s, but also reduced the incidence of Parkinson’s in people taking the drug.
Terazosin. Source: Wikipedia
Here is the study in question:
Title: Enhancing glycolysis attenuates Parkinson’s disease progression in models and clinical databases.
Authors: Cai R, Zhang Y, Simmering JE, Schultz JL, Li Y, Fernandez-Carasa I, Consiglio A, Raya A, Polgreen PM, Narayanan NS, Yuan Y, Chen Z, Su W, Han Y, Zhao C, Gao L, Ji X, Welsh MJ, Liu L.
Journal: J Clin Invest. 2019 Sep 16. pii: 129987.
PMID: 31524631 (This report is OPEN ACCESS if you would like to read it)
In this study, the researchers investigated the properties of a drug called terazosin in various models of Parkinson’s.
What is terazosin?
Microglia are the resident immune cells in the brain – they maintain law and order when trouble kicks off. And when things get really bad, these cells change shape, become “activated”, and start to absorb toxins, debris and anything else that they feel should not be there – via a process called phagocytosis.
And they are ruthless in this task.
When we are young, these cells function very well at maintaining a general sense of ‘homeostasis‘ (or stable equilibrium). But as we age,… well, let’s just say things start to slip a little.
Recently a group of researchers at Stanford University have discovered by inhibiting a single protein, called CD22, they can restore microglial homeostasis in the ageing brain, and this had beneficial effects in a model of Parkinson’s.
In today’s post, we will look at what microglia are, what phagocytosis is, and what these new CD22 results could mean for Parkinson’s.
My father often says: Ageing is not for sissies.
And as the birthdays have started to mount up, I’ve come to better understand what he means.
There are days when I feel like an old man trapped in a 27 year old’s body. For the record, I’m 27. And for the record, I’m going to be 27 until I die (27 was a great year!).
An amazing journey. Source: Topsimages
While some are able (and foolishly gleeful) to avoid taxes, until recently no one has been able to escape the rentless march of ageing. Until recently, the vast majority of us have been resigned to our fates. And until recently, the fountain of youth has only existed in the realm of the Hollywood movies.
The force is strong with this one. Source: Reddit
Recently there has been an enormous amount of research focused on stopping ageing and preventing death (both of which are being viewed as “curable diseases” – click here to read more about this). Now to be honest, much of this is still quackery.
But there does seem to be progress being made in the biology of extending ‘healthspan’ (as opposed to lifespan).
And some of that research could have implications for Parkinson’s.
In 2017, a research report suggested that people taking the asthma treatment Salbutamol had a lower risk of developing Parkinson’s. In addition, that same study suggested that another medication called Propranolol – which is used for hypertension/high blood pressure – increased ones risk of developing Parkinson’s.
Both drugs work via a molecule called the Beta2 adrenoreceptor. The study caused a lot of excitement, and clinical studies were even proposed.
Now, however, new research suggests that these associations may not actually exist and those clinical trial plans will be need to be put on standby.
In today’s post we will discuss what the Beta2 adrenoreceptor is, how these two drugs (Salbutamol and Propranolol) affect it, and look at what the new results suggest.
Saul Goodman. Source: Amc
There is a popular show on Netflix called ‘Better call Saul’ (the title of this post is a play on the name).
It chronicles the life of a lawyer – named Saul Goodman – who struggles to make his way in the grey world of the law profession. He fights to survive by taking the information he has, and using it to plead his cases. But sometimes the original pieces of information he is dealing with are not always what they appear to be.
A similar situation faces researchers the world over.
Every day new information is reported. And this process is unrelenting. It simply never stops.
For Parkinson’s research alone, every day there is about 20 new research reports (approximately 120 per week).
But determining what is ‘usable’ information relies on independent replication. And sometimes efforts to validate a new finding fail to reproduce the initially reported results.
An example of this has occurred recently in the world of Parkinson’s research, with some rather large implications.
At 23:30 on the 3rd August 2017, the results of a phase II clinical trial investigating the use of a Glucagon-like peptide-1 receptor (GLP-1R) agonist called Exenatide (Bydureon) in Parkinson’s were published the Lancet journal website.
The findings of the study were very interesting.
And after years of failed trials, the Parkinson’s community finally had a drug that appeared to be ‘doing something’. Naturally these results got many in the Parkinson’s community very excited.
Over the last couple of weeks, further research related to this topic has been published. In today’s post we will review some of this new research and ask some important questions regarding how to move forward with these results.
Dr John Eng. Source: Health.USnews
The Award was created in 2012 to celebrate researchers whose seemingly odd or obscure federally funded research turned out to have a significant and positive impact on society.
This week a research report was published in the journal Nature Medicine that expanded on the work of Dr Eng (some 25 years after his big discovery).
And it could be very important to the Parkinson’s community.
Sounds intriguing. What did Dr Eng do?
A recent study published by French, British and Swiss researchers has grabbed the attention of some readers.
The report suggests that the inert/noble gas, Xenon, has powerful anti-dyskinetic properties in both mouse and primate models of Parkinson’s with L-DOPA-induced dyskinesias.
Dyskinesias are involuntary movements that can develop over time with prolonged used of L-DOPA treatments.
In today’s post, we will discuss what Xenon is, how it may be reducing dyskinesias, and we will consider some of the issues associated with using Xenon.
Dyskinesia. Source: JAMA Neurology
There is a normal course of events following a diagnosis of Parkinson’s.
Yes, I am grossly over-generalising, and no, I’m not talking from personal experience, but just go with me on this for the sake of discussion.
First comes the shock of the actual diagnosis. For many it is devastating news – an event that changes the course of their future. For others, however, the words ‘you have Parkinson’s‘ can provide a strange sense of relief that their current situation has a name and gives them something to focus on.
This initial phase is usually followed by the roller coaster of various emotions (including disbelief, sadness, anger, denial). It depends on each individual.
The emotional rollercoaster. Source: Asklatisha
And then comes the period during which many will try to familiarise themselves with their new situation. They will read books, search online for information, join Facebook groups (Click here for a good one), etc.
That search for information often leads to awareness of some of the realities of the condition.
And one potential reality that causes concern for many people (especially for people with early onset Parkinson’s) is dyskinesias.
What are dyskinesias?
The results of a recent clinical study for Parkinson’s conducted in Georgia (USA) has grabbed the attention of some readers.
The study involved Niacin (also known as nicotinic acid), which is a naturally occurring organic dietary compound and a form of vitamin B3.
The study was very small, but the researchers noticed something interesting in the blood of the participants: Niacin was apparently switching some of the immune cells from an inflammatory state to an anti-inflammatory state.
In today’s post, we will discuss what Niacin is, how it relates to Parkinson’s, and we will consider some of the issues with having too much niacin in your diet.
It is one of the most common requests I get:
“Can you give an opinion on this supplement ____ or that vitamin ____ as a treatment for Parkinson’s?”
And I don’t like giving opinions, because (my standard disclosure) “I am not a clinician, just a research scientist. And even if i was a clinician, it would be unethical for me to comment as I am not familiar with each individual’s medical history. The best person to speak to is your personal doctor“.
But I also don’t like giving opinions because of a terrible fear that if I write anything remotely positive about anything remotely supplemental or vitamintal (is that a word?), a small portion of readers will rush off and gorge themselves on anything that sounds remotely similar to that supplement or vitamin.
So you will hopefully understand why I am hesitant to write this post.
But having said that, the recently published results of a small clinical study conducted in Augusta (Georgia, USA) are rather interesting.
Please do not misread the title of this post!
Compounds targeting the Nociceptin receptor (or NOP) could provide the Parkinson’s community with novel treatment options in the not-too-distant future.
In pre-clinical models of Parkinson’s, compounds designed to block NOP have demonstrated neuroprotective properties, while drugs that stimulate NOP appear to be beneficial in reducing L-dopa induced dyskinesias.
In today’s post we look at exactly what NOP is and what it does, we will review some of the Parkinson’s-based research that have been conducted so far, and we will look at what is happening in the clinic with regards to NOP-based treatments.
On the surface of every cell in your body, there are lots of small proteins that are called receptors.
They are numerous and ubiquitous.
And they function act like a ‘light switch’ – allowing for certain biological processes to be initiated or inhibited. All a receptor requires to be activated (or blocked) is a chemical messenger – called a ligand – to come along and bind to it.
An example of a receptor on a cell. Source: Droualb
Each type of receptor has a particular structure, which is specific to certain shaped ligands (the chemical messenger I mentioned above). These ligands are floating around in the extracellular space (the world outside of the cell), having been released (or secreted) by other cells.
And this process represents one of the main methods by which cells communicate with each other.
By binding to a receptor, the ligand can either activate the receptor or alternatively block it. The activator ligands are called agonists, while the blockers are antagonists.
Agonist vs antagonist. Source: Psychonautwiki
Many of the drugs we currently have available in the clinic function in this manner.
For example, with Parkinson’s medications, some people will be taking Pramipexole (‘Mirapex’ and ‘Sifrol’) or Apomorphine (‘Apokyn’) to treat their symptoms. These drugs are Dopamine agonists because they bind to the dopamine receptors, and help with dopamine-mediated functions (dopamine being one of the chemicals that is severely in the Parkinsonian brain). As you can see in the image below the blue dopamine agonists can bypass the dopamine production process (which is reduced in Parkinson’s) and bind directly to the dopamine receptors on the cells that are the intended targets of dopamine.
There are also dopamine antagonists (such as Olanzapine or ‘Zyprexa’) which blocks dopamine receptors. These drugs are not very helpful to Parkinson’s, but dopamine antagonist are commonly prescribed for people with schizophrenia.
Are there other receptors of interest in Parkinson’s?
An Advanced Glycation Endproduct (or AGE) is a protein or lipid that has become glycated.
Glycation is a haphazard process that impairs the normal functioning of molecules. It occurs as a result of exposure to high amounts of sugar. These AGEs are present at above average levels in people with diabetes and various ageing-related disorders, including neurodegenerative conditions. AGEs have been shown to trigger signalling pathways within cells that are associated with both oxidative stress and inflammation, but also cell death.
RAGE (or receptor of AGEs) is a molecule in a cell membrane that becomes activated when it interacts with various AGEs. And this interaction mediates AGE-associated toxicity issues. Recently researchers found that that neurons carrying the Parkinson’s associated LRRK2 G2019S genetic variant are more sensitive to AGEs than neurons without the genetic variant.
In today’s post we will look at what AGE and RAGE are, review the new LRRK2 research, and discuss how blocking RAGE could represent a future therapeutic approach for treating Parkinson’s.
The wonder of ageing. Source: Club-cleo
NOTE: Be warned, the reading of this post may get a bit confusing. We are going to be discussing ageing (as in the body getting old) as well as AGEing (the haphazard process processing of glycation). For better clarification, lower caps ‘age’ will refer to getting old, while capitalised ‘AGE’ will deal with that glycation process. I hope this helps.
Ageing means different things to different people.
For some people ageing means more years to add to your life and less activity. For others it means more medication and less hair. More wrinkles and less independence; more arthritis and less dignity; More candles, and less respect from that unruly younger generation; More… what’s that word I’m thinking of? (forgetfulness)… and what were we actually talking about?
Wisdom is supposed to come with age, but as the comedian/entertainer George Carlin once said “Age is a hell of a price to pay for wisdom”. I have to say though, that if I had ever met Mr Carlin, I would have suggested to him that I’m feeling rather ripped off!
George Carlin. Source: Thethornycroftdiatribe
Whether we like it or not, from the moment you are born, ageing is an inevitable part of our life. But this has not stopped some adventurous scientific souls from trying to understand the process, and even try to alter it in an attempt to help humans live longer.
Regardless of whether you agree with the idea of humans living longer than their specified use-by-date, some of this ageing-related research could have tremendous benefits for neurodegenerative conditions, like Parkinson’s.
What do we know about the biology of ageing?
Here’s a good riddle for you:
Many epidemiological studies have suggested that coffee/caffeine consumption reduces one’s risk of developing Parkinson’s. Study after study has suggested that drinking coffee is beneficial.
Recently, however, Japanese researchers have discovered something really curious: people with Parkinson’s have reduced levels of caffeine in their blood compared to healthy controls… even when they have consumed the same amount of coffee. (???)
In today’s post we will look at what coffee is, review the results of this study, and try to understand what is going on.
Kaldi the goat herder. Source: CoffeeCrossroads
Legend has it that in 800AD, a young Ethiopian goat herder named Kaldi noticed that his animals were “dancing”.
They had been eating some berries from a tree that Kaldi did not recognise, but being a plucky young fellow – and being fascinated by the merry behaviour of his four-legged friends – Kaldi naturally decided to eat some of the berries for himself.
The result: He became “the happiest herder in happy Arabia” (Source).
This amusing encounter was apparently how humans discovered coffee. It is most likely a fiction as the earliest credible accounts of coffee-consumption emerge from the 15th century in the Sufi shrines of Yemen, but since then coffee has gone on to become one of the most popular drinks in the world.
Silly question, but what exactly is coffee?
The biotech company Acorda Therapeutics Inc. yesterday announced that it was halting new recruitment for the phase III program of its drug Tozadenant (an oral adenosine A2a receptor antagonist).
In addition, participants currently enrolled in the trial will now have their blood monitoring conducted on a weekly basis.
The initial report looks really bad (tragically five people have died), but does this tragic news mean that the drug should be disregarded?
In todays post, we will look at what adenosine A2a receptor antagonists are, how they may help with Parkinson’s, and discuss what has happened with this particular trial.
Dr Ron Cohen, CEO of Acorda. Source: EndpointNews
Founded in 1995, Acorda Therapeutics Ltd is a biotechnology company that is focused on developing therapies that restore function and improve the lives of people with neurological disorders, particularly Parkinson’s disease.
Earlier this year, they had positive results in their phase III clinical trial of Inbrija (formerly known as CVT-301 – Click here to read a previous post about this). They have subsequently filed a New Drug Application with the US Food and Drug Administration (FDA) to make this inhalable form of L-dopa available in the clinic, but the application has been delayed due to manufacturing concerns from the FDA (Click here to read more about this). These issues should be solvable – the company and the FDA are working together on these matters – and the product will hopefully be available in the new year.
So what was the news yesterday?
Acorda Therapeutics has another experimental product going through the clinical trial process for Parkinson’s disease.
It’s called Tozadenant.
Tozadenant is an oral adenosine A2a receptor antagonist (and yes, we’ll discuss what all that means in a moment).
Yesterday Acorda Therapeutics Inc announced that they have halted new recruitment for their phase III clinical program. In addition the company is increasing the frequency of blood cell count monitoring (from monthly to weekly) for participants already enrolled in the company’s Phase 3 program of Tozadenant for Parkinson’s disease.
The Company took this action due to reports of cases of agranulocytosis.