Tag: MAO-B

Not dead, dormant dopamine neurons?!?

~ Simon ~ 11 Comments

 

Every textbook written about the condition will tell you that the classical pathological characteristic of Parkinson’s is the loss of dopamine neurons in the midbrain region of the brain. It is the distinguishing feature that pathologists look for in order to provide a postmortem diagnosis of the condition.

But what is meant by the words ‘loss of dopamine neurons’? Do the cells actually die? Recently researchers from Korea have published new data exploring this question.

Interestingly, they found evidence of ‘dormant’ dopamine neurons in postmortem sections of brains from people with Parkinson’s – even those with severe forms of the condition.

In today’s post, we will discuss what a dopamine neuron is, what this new research found, and what it could mean for our understanding of Parkinson’s.

 

Source: Bettys

2019 represented the centenary year for an important discovery in Parkinson’s research.

In 1919, the Uzbek neuropathologist Konstantin Tretiakoff (1892-1958) reported his findings regarding an examination of 54 human brains.

Konstantin Tretiakoff. Source: Wikipedia

Six of the postmortem brains had belonged to individuals who had suffered from Parkinson’s and three others had been diagnosed with postencephalitic Parkinsonism. In these brains he noticed something rather striking.

What did he find?

Continue reading “Not dead, dormant dopamine neurons?!?” →

A clever new Trk for Rasagiline

~ Simon ~ 13 Comments

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?

Continue reading “A clever new Trk for Rasagiline” →

An interesting commentary on the interpretation of the Nilotinib trial results

~ Simon ~ 2 Comments

DSK_4634s

“The devil is in the detail”

A frequently used quote and sage words when analysing scientific data, especially clinical trial data.

Nilotinib is a cancer drug from Novartis that has the Parkinson’s community very excited. In October 2015, researchers at Georgetown University announced that a phase 1 open-label clinical study involving 12 people with Parkinson’s had demonstrated some pretty impressive results (click here to read more about this). The results of that first clinical trial have been published (click here to read more on this), but follow up studies have been hampered by study design issues (click here for more on this).

Today a letter to the editor of the Journal of Parkinson’s disease (published in this months issue) was brought to our attention (click here to read the letter). It queries one important aspect of the results from that first Nilotinib clinical trial for Parkinson’s disease.

In the letter, Prof Michael Schwarzschild of Massachusetts General Hospital (Boston) notes that 8 of the 11 subjects in the study had their monoamine oxidase-B (MAO-B) inhibitor treatment withdrawn less than a month after starting the trial. The change of treatment regime was made due to “increased psychosis in the first 2–4 weeks after Nilotinib administration”.


For reasons which we will outline below, a small change like this in a clinical trial could have major implications for the end results.

What are MAO-B inhibitors?

After the chemical dopamine is used by a neuron, it is reabsorbed by the dopamine cell and broken down for disposal. MAO-B is the enzyme that breaks down dopamine.

maoi-inhibitor
Selegiline is an example of a MAO-B inhibitor. Source: KnowMental

As the schematic above illustrates, dopamine is released by dopamine neurons and then binds to a receptor on a neighbouring cell. After this process has occurred, the dopamine detaches and it is reabsorbed by the dopamine neuron via a particular pathway called the dopamine transporter. Back inside the dopamine cell, dopamine is quickly broken down by the enzyme MAO-B into 3,4-Dihydroxyphenylacetic acid (or DOPAC).

Now, by blocking MAO-B, more dopamine is left hanging around inside the cell where it can be recycled and used again. Thus, this blockade increases the level of dopamine in the brain, which helps with alleviating the motor features of Parkinson’s disease. This simple concept has lead to the development of MAO-B inhibitors which are used in the treatment of the condition.

Why is this important to the Nilotinib results?

Dopamine is broken down by MAO-B into DOPAC. DOPAC can be further broken down into Homovanillic acid (HVA), and both DOPAC and HVA are often used in research studies to indicate levels of dopamine activity. Higher levels of both (in theory) should indicate higher levels of dopamine. It is a means of inferring greater dopamine production.

In the published results of the Nilotinib clinical trial, the researchers used increased HVA levels as an indication of greater dopamine production as a result of taking Nilotinib. But Prof Schwarzschild is correct in providing a cautionary warning of over-interpreting this result. You see, by discontinuing the treatment of MAO-B inhibitors shortly after starting the study, one would expect to see a rise in HVA levels regardless of any effect Nilotinib may be having. Without the MAO-B inhibitors, more dopamine will be broken down thus resulting in increased levels of HVA (compared to the baseline measurements at the start of the study).

And this issue is particularly important since HVA measurements taken at the start of the study (before the MAO-B inhibitors were removed) were compared with HVA measurement taken at the end of the study.

Another commentary discussing the Nilotinib results published in July of last year (in the same journal) actually questioned the value of measuring HVA levels, saying that prior studies have suggested that HVA levels can vary greatly between subjects at similar disease stages, and in general do not correlate well with disease progression.

Whether the removal of MAO-B inhibitors alters the overall interpretation of the first clinical study results is a subject for debate. Something interesting did appear to be happening in the participants involved in the first trial (whether this could have been a placebo effect could also be debated). Obviously, as Prof Schwarzschild’s letter indicates, what we really require now is a carefully designed, placebo-controlled, randomised clinical trial to determine if the initial results can be replicated.

And we are still awaiting news regarding a start date for that delayed trial.