Tagged: neuroprotection

The Phase 1/2 CDNF topline results

 

 

 

Neurotrophic factors are naturally occuring proteins that help to keep neurons alive, provide a supportive environment, and encourage growth.

For a long time, researchers have been exploring methods of utilising the power of neurotrophic factors in regenerative strategies for neurodegenerative conditions, like Parkinson’s.

Today, the biotech firm Herantis Pharma announced topline results of their Phase 1/2 clinical trial of the neurotrophic factor Cerebral Dopamine Neurotrophic Factor (or CDNF).

In today’s short post, we discuss what CDNF is, explore what the trial involved, and consider what the

 


Source: Herantis

It is cold this time of year in Helsinki, but there will be some warm smiles there today.

A small biotech firm called Herantis Pharma has announced the topline results of their Phase 1/2 clinical trial exploring the safety and tolerability of a treatment called CDNF.

What is CDNF?

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Deep Mitochondrial stimulation?

 

 

Recently some researchers conducted an analysis of some postmortem brains from people with Parkinson’s and they discovered something rather curious.

Half of the brains that they analysed came from people with Parkinson’s who had been given deep brain stimulation (or DBS) to help manage their symptoms. When the researchers analysed the mitochondria – the powerstations of each cell – in the dopamine neurons of these brain, they found that the DBS treatment had helped to improve the number of mitochondria in these cells.

Specifically, the DBS treatment “seemed to have inhibited or reversed the reduction in mitochondrial volume and numbers” that was observed in the Parkinson’s brains that had not had DBS.

In today’s post, we will look at what DBS is, what the new research report found, and what these new findings could mean for the Parkinson’s community.

 


The worst thing. Source: Greatist

Do you know the worst thing that happens to us in life?

We wake up each day.

Every day of our lives (so far) we have woken up and been given – without any kind of justification – another 16 or so hours to do whatever we want with.

Regardless of one’s physical/mental state, this is a bad thing.

This continuous pattern is what is referred to in psychology as a ‘continuous schedule of reinforcement’. Such regimes instill complacency and – worse – expectation. They quickly lead to people taking things for granted. All of us are guilty of thinking “I’ll do it tomorrow”.

Source: Taskcracker

Such a continuous pattern of reinforcement does not prepare one well for a life in scientific research, where there isn’t a constant schedule of reinforcement (quite the opposite actually). Experiments regularly go wrong (reagents/equipment fail), grants/manuscripts get rejected – it can be rather brutal.

But here is where the addictive component of science comes into effect. Every so often, something works. And even better, every so often something unexpected happens – an ‘intermittent/irregular schedule of reinforcement’. An experiment will occasionally spit out a completely unexpected result, which could change everything.

Source: Granger

These are the moments of insights that researchers are slaving for. The instant that they are the first to “walk on the moon”.

They are moments to savour.

And this must have been the state of mind for some researchers who dicovered something surprising and absolutely remarkable recently while they were looking at some postmortem brains from individuals with Parkinson’s who had been treated with deep brain stimulation.

What is deep brain stimulation?

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The Kiwi Ketogenic study

Being a patriotic ‘kiwi’, I am always very pleased to write about interesting Parkinson’s research originating from the homeland. And recently the results of an interesting clinical study that was designed and conducted in New Zealand have been published.

The clinical study was focused on whether a diet manipulation could influence motor and non-motor symptoms/features of Parkinson’s. 

Specifically, the researchers were looking at the low-fat versus ketogenic diets. 

In today’s post, we will discuss what is meant by a ketogenic diet, we will assess the results of the study, and consider what they might mean for the Parkinson’s community.


The All Blacks. Source: Newshub

Aotearoa (also known as New Zealand) is a remarkable little country (and yes, I know I’m slightly biased).

It flies under the radar for most folks who are not interested in rugby, amazing scenery, great quality of life, or hobbits, but historically this tiny South Pacific nation of 4.6 million people has punched well above its weight on many important matters.

For example, on the 19th September 1893, the governor, Lord Glasgow, signed a new Electoral Act into law. And as a result of that simple act, New Zealand became the first self-governing country in the world in which all women (over the age of 21) had the right to vote in parliamentary election (Australia followed in 1902, the US in 1920, & the Britain in 1928). That achievement, it should be said, was the result of years of dogged effort by suffrage campaigners, led by Kate Sheppard who is today acknowledged with her portrait on the $10 note:

The NZ $10 note. Source: Whaleoil

A New Zealander made the first trans-global radio transmission on the 18th October 1924. Invalided during WWI, Frank Bell revived his childhood interest in wireless communication, and after being the first kiwi to have two-way radio contact with Australia and North America, he achieved something far more impressive. From the family sheep station in ‘Shag Valley’ (East Otago – bottom of the South Island), he sent a Morse code transmission (“Greetings from New Zealand, signed Bell Z4AA”) which was received and replied to by amateur operator Cecil Goyder at Mill Hill School (London).

Frank and his older sister Brenda. Source: NZhistory

New Zealand was also where jet boats was first invented by Sir Bill (William Hamilton). His first jet boat was a 3.6 meter (12 foot) plywood hull with a 100 E Ford engine, and the jet a centrifugal type pump. This craft was tested on the Irishman Creek dam, before it ran successfully upriver in 1953. And from there it kind of went viral. In 1960, three Hamilton jet boats (the Kiwi, Wee Red and Dock), became the first and only boats to travel all the way up through the Grand Canyon.

Sir Hamilton and his first jet boat (1958). Source: ipenz

And the list doesn’t stop there. We could go on with other great firsts:

  • Sir Ed (Hillary) – first to summit Everest (to be fair, it was a team effort)
  • Sir Ernest (Rutherford) – first to split the atom
  • Sir Peter (Blake) – first to sail around the world in less than 75 days (again, a bit of a team effort)
  • Sir John (Walker) – first to run the mile in under 3:50 (now a member of the Parkinson’s community)
  • Georgina Beyer – first openly transsexual mayor, and then the world’s first openly transsexual Member of Parliament
  • AJ Hackett & Henry van Asch –  set up the first commercial bungy jump on the Kawarau Bridge, near Queenstown
  • Helen Clark, Dame Siliva Cartwright & Sian Elias – first country to have women in the top three senior public roles (Prime Minister, the Governor General, & the Chief Justice, respectively)
  • Rocket Lab – first private company in the Southern Hemisphere to reach space (in 2009)

And I guess we better stop there (if only out for fear of making larger nations feel somewhat inadequate), but you get the idea – small nation, doing lots of great stuff.

There is also a very proactive Parkinson’s community – with groups like Parkinson’s New Zealand organising and running support groups across the country, and helping to fund some of the great local Parkinson’s research.

And some of that local Parkinson’s research has been discussed previously on this website (Click here, here and here for examples of previous posts), and it is also the focus of today’s post:

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Ibudilast: A Phosphodiesterase inhibitor

A reader recently asked me about an experimental drug called Ibudilast.

It is a ‘Phosphodiesterase 4 inhibitor’.

Recently there was a very interesting result in a clinical trial looking at Ibudilast in a specific neurodegenerative condition. Sadly for the reader that condition was not Parkinson’s, in fact very little research has been done on Ibudilast in Parkinson’s

In today’s post we will look at what Phosphodiesterase inhibitors are, how they work, and discuss why Ibudilast may not be such a good experimental treatment for Parkinson’s.


On April 21-27th, 2018, the American Academy of Neurology (AAN) will hold their 70th Annual Meeting in Los Angeles (California).

I will not be at the meeting, but I will definitely be keeping an eye out for any news regarding the results of one particular clinical trial. At the meeting, a biopharmaceutical company called MediciNova Inc. will be presenting data regarding one of their clinical trials.

The presentation, entitled Ibudilast – Phosphodiesterase Type 4 Inhibitor – Bi-Modal Therapy with Riluzole in Early Cohort and Advanced Amyotrophic Lateral Sclerosis (ALS) Patients – Final Report and Future Directions (Source) will be presented by principal investigator of the clinical study, Dr. Benjamin Rix Brooks, of the Carolinas HealthCare System’s Neuromuscular/ALS-MDA Center at Carolinas HealthCare System Neurosciences Institute.

Dr Brooks will be presenting the results of a single-center, randomized, double-blind, placebo-controlled clnical trial which was conducted to evaluate the safety, tolerability and clinical endpoint responsiveness of a drug called Ibudilast (or MN-166) in subjects with the neurodegenerative condition, Amyotrophic Lateral Sclerosis (or ALS – also known as motor neuron disease; Click here to read a previous SoPD post about ALS and Click here to learn more about this clinical trial).

What is Ibudilast?

Ibudilast is a phosphodiesterase inhibitor.

What is a phosphodiesterase inhibitor?

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Is there NOP hope for Parkinson’s?

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.


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Source: LUMS

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.

Agonists_and_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.

Source: Bocsci

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?

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The dilemma of success

Late last year, I wrote a post for Parkinson’s UK‘s excellent blog on Medium.

My piece was called the Dilemma of Success, and it explored a hypothetical situation that we may very well face in the not-so-distant future.

Optimistic as I am about the future of Parkinson’s research, I think this is a very serious issue – one which the Parkinson’s community needs to discuss and start planning for. I am re-posting it here today as I am keen for some thoughts/discussion on this matter.

 
BP

Lord Robert Baden-Powell. Source: Utahscouts

My scout master looked around the horse shoe, making eye contact with each of us, before asking a simple question:

“When did Noah build the ark?”

My fellow scouts and I looked at each other. Some of us were wondering if the guy had completely lost the plot and somehow thought that it was Sunday morning and he was doing the sermon. Others seriously looked like they were trying to calculate an exact date.

He waited a moment for one of us to offer up some idiotic attempt at an answer, before he solemnly said:

“Before the rain”

It’s one of those childhood moments that didn’t make sense at the time, but comes back to haunt you whenever you can foresee certain troubles coming over the hill towards you.


The dilemma of success

It will be nice to have this problem, but it will still be a problem.
And we need to plan for it

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The road ahead: Parkinson’s research in 2018

The great ice hockey player Wayne Gretzky once said “A good hockey player plays where the puck is. A great hockey player plays where the puck is going to be” (the original quote actually came from his father, Walter). 

At the start of each year, it is a useful practise to layout what is planned for the next 12 months. This can help us better anticipate where ‘the puck’ will be, and allow us to prepare for things further ahead.

2017 was an incredible year for Parkinson’s research, and there is a lot already in place to suggest that 2018 is going to be just as good (if not better).

In this post, we will lay out what we can expect over the next 12 months with regards to the Parkinson’s-related clinical trials research of new therapies.


Charlie Munger (left) and Warren Buffett. Source: Youtube

Many readers will be familiar with the name Warren Buffett.

The charming, folksy “Oracle of Omaha” is one of the wealthiest men in the world. And he is well known for his witticisms about investing, business and life in general.

Warren Buffett. Source: Quickmeme

He regularly provides great one liners like:

“We look for three things [in good business leaders]: intelligence, energy, and integrity. If they don’t have the latter, then you should hope they don’t have the first two either. If someone doesn’t have integrity, then you want them to be dumb and lazy”

“Work for an organisation of people you admire, because it will turn you on. I always worry about people who say, ‘I’m going to do this for ten years; and if I really don’t like it very much, then I’ll do something else….’ That’s a little like saving up sex for your old age. Not a very good idea”

“Choosing your heroes is very important. Associate well, marry up and hope you find someone who doesn’t mind marrying down. It was a huge help to me”

Mr Buffett is wise and a very likeable chap.

Few people, however, are familiar with his business partner, Charlie Munger. And Charlie is my favourite of the pair.

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Are we getting NURR to the end of Parkinson’s disease?

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.

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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.
PMID: 9092472

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?

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Resveratrol’s neglected siblings

 

We have previously discussed the powerful antioxidant Resveratrol, and reviewed the research suggesting that it could be beneficial in the context of Parkinson’s disease (Click here to read that post).

I have subsequently been asked by several readers to provide a critique of the Parkinson’s-associated research focused on Resveratrol’s twin sister, Pterostilbene (pronounced ‘Terra-still-bean’).

But quite frankly, I can’t.

Why? Because there is NO peer-reviewed scientific research on Pterostilbene in models of Parkinson’s disease.

In today’s post we will look at what Pterostilbene is, what is known about it, and why we should seriously consider doing some research on this compound (and its cousin Piceatannol) in the context of Parkinson’s disease.


Blue berries are the best natural source of Pterostilbene. Source: Pennington

So this is likely to be the shortest post in SoPD history.

Why?

Because there is nothing to talk about.

There is simply no Parkinson’s-related research on the topic of today’s post: Pterostilbene. And that is actually a crying shame, because it is a very interesting compound.

What is Pterostilbene?

Like Resveratrol, Pterostilbene is a stilbenoid.

Stilbenoids are a large class of compounds that share the basic chemical structure of C6-C2-C6:

Resveratrol is a good example of a stilbenoid. Source: Wikipedia

Stilbenoids are phytoalexins (think: plant antibiotics) produced naturally by numerous plants. They are small compounds that become active when the plant is under attack by pathogens, such as bacteria or fungi. Thus, their function is generally considered to part of an anti-microbial/anti-bacterial plant defence system for plants.

The most well-known stilbenoid is resveratrol which grabbed the attention of the research community in a 1997 study when it was found to inhibit tumour growth in particular animal models of cancer:

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Nilotinib: the other phase II trial

DSK_4634s

In October 2015, researchers from Georgetown University announced the results of a small clinical trial that got the Parkinson’s community very excited. The study involved a cancer drug called Nilotinib, and the results were rather spectacular.

What happened next, however, was a bizarre sequence of disagreements over exactly what should happen next and who should be taking the drug forward. This caused delays to subsequent clinical trials and confusion for the entire Parkinson’s community who were so keenly awaiting fresh news about the drug.

Earlier this year, Georgetown University announced their own follow up phase II clinical trial and this week a second phase II clinical trial funded by a group led by the Michael J Fox foundation was initiated.

In todays post we will look at what Nilotinib is, how it apparently works for Parkinson’s disease, what is planned with the new trial, and how it differs from the  ongoing Georgetown Phase II trial.


FDA-deeming-regulations

The FDA. Source: Vaporb2b

This week the U.S. Food and Drug Administration (FDA) has given approval for a multi-centre, double-blind, randomised, placebo-controlled Phase IIa clinical trial to be conducted, testing the safety and tolerability of Nilotinib (Tasigna) in Parkinson’s disease.

This is exciting and welcomed news.

What is Nilotinib?

Nilotinib (pronounced ‘nil-ot-in-ib’ and also known by its brand name Tasigna) is a small-molecule tyrosine kinase inhibitor, that has been approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML).

What does any that mean?

Basically, it is the drug that is used to treat a type of blood cancer (leukemia) when the other drugs have failed. It was approved for treating this cancer by the FDA in 2007.

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