Thank you to Dr. Jonathan Sackner-Bernstein for his excellent, thought-provoking presentation yesterday titled "What if I discovered the Silver Bullet?"
Motivated by a friend’s suffering from Parkinson’s, Dr. Sackner-Bernstein focused on a gap in our understanding of the disease: no one had so far measured the amount of dopamine in the dopaminergic neurons of people with Parkinson’s. This is critically important because dopamine is toxic to these cells, which would then be a driver of neuron dysfunction and death, leading to disease progression.
He published his analysis last summer in the Journal of Parkinson’s disease showing that these critical neurons do not lack dopamine – they have excess dopamine. This led him to design a clinical trial to test a drug that addresses this newly defined mechanism of disease.
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Fascinating. I don't have a medical or scientific background, but it sure seems to me that the next major advance in PD treatment may totally contradict conventional approaches. "Conventional approaches" haven't significantly improved symptoms for more than 50 years and have produced exactly zero proven ways to slow or stop the disease itself. If nothing else comes from this, I appreciate the completely fresh approach...plus, he just might have the silver bullet. The existing PD experts clearly don't.
Hi Nedim. I don’t have that information but I am pretty sure he is in touch with them. Interestingly, Monday’s presentation has led to contacts with potential new financing sources.
Thank you for organising this. Very interesting indeed. Nothing like a new approach to break the mould.
Question for Dr. Sackner-Bernstein, Increasing acetylcholine via supplementation with Citicoline has been shown to improve PD symptoms in many PWP to the point that they can reduce CL. Is this perhaps additional evidence that PD is not just a matter of decreased dopamine? Acetylcholine is a very important pathway that does not rely on dopamine. Additionally, supplementing with Citicoline could help trial participants ease off of CL. I wonder if he is aware of the effect of glutamate Excitotoxicity in PD and how that might affect his hypothesis?
Quote:
In early PD, this increased subthalamic nucleus activity may compensate for cell loss in the SNc by enhancing the activity of surviving dopaminergic neurons.3,41 With disease progression, however, continuous glutamatergic overstimulation of the remaining SNc neurons leads to a large influx of extracellular Ca2+ and creates metabolic changes within the neurons.4 Together, these processes have downstream intracellular consequences, notably increasing oxidative stress, disrupting mitochondrial and bioenergetic homeostasis, and activating apoptosis.4 Ultimately, therefore, glutamatergic overstimulation can result in cell death.24,39
Even in the absence of a major increase in glutamate levels, nigrostriatal dopaminergic neurons are sensitive to indirect excitotoxicity.4 Indirect excitotoxicity can arise from mitochondrial deficits; without a continuous energy supply, a cell membrane becomes depolarised, compromising the Mg2+ blockade of NMDA receptors.8,9,42 As a result, even normal levels of glutamate result in excessive stimulation of glutamatergic receptors.4,39,42 It has been hypothesised that indirect excitotoxicity may be one of multiple mechanisms contributing to PD pathogenesis, by triggering cell death in the SNc.4,39
Please see below the response from Dr Sackner Bernstein. Sorry. “I apologize that I don't feel qualified to answer this question. These issues appear to be separate from the dopamine findings I discussed, though I understand likely to be interrelated.”
Thank you for asking him. I hope he will expand his knowledge to include acetylcholine because as I previously mentioned, it could potentially aid in getting people off of CL and enabling them to use his repurposed drug. And, if it was combined with the repurposed drug it would not be repurposed anymore and could be obviously financially advantageous.
This was REALLY fascinating. Thank you for it. I am actually one of those crazy people considering a trial of tryptophan to see if the lowered dopamine production makes a difference.
But (I think, and only think, 'cause this stuff is really dense and tough to untangle) they are saying the glutamate and zombie cells are contributing to cell death (or living-death re zombi-ism) AFTER some mysterious process has been initiated.
It still could be an excess of intracellular dopamine (what's causing that? I don't think I got that answer.)
BTW, dopamine in the cytoplasm IS toxic, that much is already known. The question is, do pwp really have too much of it?
Here's one thing I want to know: do MAO-B inhibitors help or hinder? They keep the level of dopamine higher in the cell, but do so by inhibiting the breakdown to toxic reactive oxidative products (which I THINK might be what's bad about dopamine in the first place?).
Here's another thing, which I admit could totally be in my head: though I'm not on C/L for about a year I tried Neupro patches, which are true dopamine agonists. I stopped because they gave me a rash but you know what? Over that year I think I got worse.
“AFTER some mysterious process has been initiated.”. TRUE!
“dopamine in the cytoplasm IS toxic, that much is already known. The question is, do pwp really have too much of it?” TRUE and YEP
Regarding MAOB ; hmm, very valid point.
Regarding Neupro, I believe it.
What about a more subtle means? Like anti nausea meds which decrease dopamine?
Interestingly, ADD , OCD and other neurological conditions (I posted on this before) are in part due to too much dopamine and both are associated with a greater risk for PD. This adds credence to his theory. I’m going to dive more in to that and share that with him.
BUT nicotine is protective and it increases dopamine so that contradicts his thirty. Likewise with caffeine and exercise. ???
OK, I'm going to answer this pretending I know what I am talking about but actually I don't. Dr. Google (an intimate buddy of mine) says nicotine, caffeine and exercise promote the RELEASE of dopamine from neurons, which implies that it would lower cytoplasmic dopamine and increase dopamine in the synapse...where one would be able to "use" it.
Anti-nausea drugs work by messing with dopamine RECEPTORS. They shouldn't affect levels inside cells (according to my DH, who is a physician...helpful for some of this stuff, but as befuddled as I am by the basic biochem)
Does that all sound too stupid?
Are we able to actually talk to this guy? Is he answering emails? Let's ask him this stuff!
“nicotine, caffeine and exercise promote the RELEASE of dopamine from neurons, which implies that it would lower cytoplasmic dopamine and increase dopamine in the synapse...where one would be able to "use" it.”YES! Such an important distinction! Thank you!
“Anti-nausea drugs work by messing with dopamine RECEPTORS.” YES! 😀.
Thank you for asking dear old Dr. Google and your Hubby these questions. I obviously hadn’t but I wanted to dump my thoughts on here while you are still online. ☺️
“Research has shown that the drugs most commonly abused by humans (including opiates, alcohol, nicotine, amphetamines, and cocaine) create a neurochemical reaction that significantly increases the amount of dopamine that is released by neurons in the brain's reward center.”
So, RELEASING the dopamine can be neuro protective.
But adding dopamine adds to toxicity. That’s my current understanding.
What else releases our endogenous dopamine and is it neuro protective?
How do addicts who are addicted to substances that increase dopamine recover? I bet whatever is used for that could help shed light on this. If they are dependent on a stimulant to increase dopamine and manage to resolve that addiction they would have to normalize dopamine levels in the process. I have no experience with this at all but I think it could be worth learning about.
Generally, they recover by ceasing use. Most cocaine and meth abusers don't develop PD, at least not before they die of something else. Which suggests again that the key in treating the PD epidemic is going to be around dealing with what distinguishes us, and not the environmental 'causes'.
Tryptophan. There you go. I'm going to try a low dose. Unfortunately it's another one of those things that certainly won't show any symptomatic benefit, so it'll be hard to know anything for a while. I guess if I don't feel worse I'll keep it up.
I need to refind something I happened upon before Dr. Bernstein info was presented. It was some drug used for addiction that showed some benefit in PWP. It started with an I. What the heck was it? I will try and find it again. Tryptophan , I will learn more!
Think of all those folks with obesity and diabetes guzzling down bags of jellybeans for years with doctor approval because they were "low fat" and couldn't possibly do any harm :o(
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Parkinson's and Mitohormesis - presentation by Dr. Matthew CL Phillips
