The Movers & Shakers Podcast: The Science

Last week I described my appearance on The Movers & Shakers Podcast. The episode was titled “The Dopamine Debate” and was a great opportunity to share the possibilities we’ve discovered at Right Brain Bio with this British group comprised of renowned journalists, a judge and an academic focused on innovation.

During the discussion several scientific issues were briefly discussed, and this week I’ll highlight a couple of important ones. My goal is to err on the side of brevity rather than to provide an exhaustive explanation.

You can listen to the podcast here: https://open.spotify.com/episode/3wzy8J0o1aXnd5fFuDiNZw

How can I reconcile the views that Parkinson’s is described as having both low and high dopamine?

When levels of dopamine are measured in brain tissue, the concentration of dopamine is low. That measurement reflects the average concentrations of dopamine in the fluid outside of the brain cells and inside a wide variety of distinct brain cells – including the type most relevant to movement and Parkinson’s disease, the dopaminergic neurons.

The dopamine concentration inside the dopaminergic neurons determines whether they are functional or not — and whether a person is healthy or diseased. More specifically the amount of dopamine that is free inside these cells (referred to as the cytosolic dopamine) is the critical measurement.  Before I reported it in the Journal of Parkinson’s Disease, no one had measured or calculated this level in people with Parkinson’s compared to people without Parkinson’s.

Our calculations revealed that despite low dopamine levels in brain tissue, the dopamine concentration inside the dopaminergic neurons (within the cytosol) from people with Parkinson’s is markedly elevated. This is what we published in the Journal of Parkinson’s Disease in 2021.

So, while Parkinson’s is standardly taught to be a state of dopamine deficiency (based upon low levels of dopamine in brain tissue), the key brain cells that drive Parkinson’s contain excess dopamine. That’s important because excess dopamine creates excess dopamine metabolites which are toxic to these brain cells, causing dysfunction and loss of the dopaminergic neurons, which is the hallmark of Parkinson’s.

In the podcast, I offered the following geographic analogy. If we estimate the concentration of journalists with Parkinson’s disease in London (number of people per square mile), it would be a low number. At the same moment, if we measured the concentration of journalists with Parkinson’s disease in the back room of the Ladbroke Arms Pub in Notting Hill where the Movers & Shakers Podcast was recorded, it would be a very high number. Both measures are accurate, but they answer very different questions.

Since I’m advocating for development of the dopamine reduction therapy RB-190, am I proposing that people stop using levodopa or other dopaminergic therapies?

No.

Based on published data, if I had Parkinson’s and responded to levodopa or any other dopaminergic therapy I would not stop it because levodopa, which forms dopamine in the absence of disease, seems extremely unlikely to cause toxicity to the dopaminergic neurons, and therefore, these drugs appear extremely unlikely to cause the disease to worsen. That does not mean that levodopa and other dopaminergic drugs don’t have risks or produce complications (dyskinesia, impulse control problems etc.), but the data tell me they don’t cause the disease to progress.

I don’t want to dig deeply into the science right now because I want to be sure that my point of view is clear. If drugs cause side effects that are worse than any problems they help, it is worth talking with your doctor about how to adjust your treatment to help you feel better. I see that as separate from the risk of these drugs worsening progression of the disease, which is not supported by the data.

Here’s a way to understand dopamine anatomically. There is a connection between the dopaminergic neurons that send movement signals and the neurons that receive that movement signal. There is a gap between them called the synapse. The neuron located before the synapse (pre-synaptic neuron) is where too much dopamine is being made by the hyperactive enzyme.  It’s this enzyme that RB-190 inhibits. The synapse and the neuron after the synapse (post-synaptic neuron) are where levodopa and other dopaminergic drugs work. It is the excess dopamine in the pre-synaptic neuron that causes toxicity and disease progression, and not a toxic effect in the synapse or in the post-synaptic neuron.

As I emphasized during the Movers & Shakers Podcast, I do not advocate for stopping levodopa when it makes people feel better and/or when a doctor sees an advantage to continuing this treatment.