By the time Parkinson's is diagnosed, 80-90 % of the relevant diamond m dopamine neurons are dead. It's kind of like raising the volume on a call with a bad connection. It kind of helps, but at some point your just amplifying noise and there's not enough good signal no matter how loud you make it.

It actually might. It is currently thought that they could slow or prevent some types of deterioration, but past studies failed due mainly to failure of the study methodology itself.

It seems intuitively right and I'm curious why it doesn't play out in reality.

here's essentially how it did play out in reality:

Researchers expected the drug to have a specific effect on the brain

Experimental studies were conducted. The hypothetical effect did in fact happen, and the brain did respond to the drug in a way that would delay disease progression.

Clinical studies on non-human primates were conducted, with the intent to see whether or not experimental findings translate to clinical study findings. The studies failed. The method in which the studies were conducted, especially in terms of the way researchers attempted to measure results, was not good and did not use very accurate measures that would reflect the potential impacts of the drug. There are many non-motor functions affected by Parkinson's that cannot be accurately measured in monkeys and apes(and were therefore not studied), like apathy, because they can't talk. These would have been the most important functions to study due to how the disease works.

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Current understanding is generally accepted as follows:

"Dopamine reuptake inhibition extends the stay of dopamine in the synaptic left. This pharmacologic principle may improve dopamine substitution in patients with Parkinson’s disease (PD). Experimental researchers described promising positive outcomes on the efficacy of inhibition of dopamine-, respectively monoamine reuptake (MRT). The translation of these findings into corresponding clinical study results for the treatment of patients with PD failed in the past. Further clinical development of MRT inhibition was suspended. One of several reasons was the missing clinical research focus on the effects of MRT inhibition on non-motor symptoms, like fatigue or apathy. Mandatory inhibition of glial inhibition of monoamine metabolism is a hypothetical but essential precondition for the efficacy of MRT inhibitors. Aforementioned reflections shall be considered, if the efficacy of the MRT inhibitor is again investigated in patients with PD. Resurgence of clinical research is warranted on the efficacy of MRT inhibition as a promising therapy approach for patients with PD."

So, it is my understanding that Duadopa is supposed to be less likely to induce tardive dyskinesia than oral ingestion of Levadopa. Is this because it's pumped directly to the GI system? How would it have a positive effect on the lungs & heart that way? And is there a reason that tryptophan isn't used in the treatment of Parkinson's?

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Tryptophan usually is the precursor to serotonin so wouldn't generally affect dopamine production.

Tyrosine is the main AA for dopamine, but its conversion to L-DOPA is the rate-limiting step, so supplementing it doesn't really help. You need to give L-DOPA to bypass that reaction if you want to bump dopamine levels.

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That's a really good analogy. Thanks for explaining it that way!

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It's interesting that the two top comments are "it works" and "it doesn't work," but both are scientifically supported and don't really contradict each other.

I read a few reliable places that methylphenidate may protect neurons in cases of Parkinson's disease, along with some speculation that it might augment levodopa and help lower the dose. You can Google pretty much any hypothesis and find a study to support it.

Previously I'd assumed it was just unpopular because of issues like blood pressure problems and addiction. Then I learned about actual Parkinson's drugs and...holy crap. lol

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As other comment said most substantia nigra dopamine neurons are already dead in Parkinson’s, so there isn’t enough dopamine floating around for DRIs to do much, which is why direct dopamine receptor agonists and dopamine precursors are used instead. However DRIs can help prevent PD because they reduce the concentration of dopamine inside cell bodies, so it causes less oxidative stress

What about before Parkinson's is diagnosed, earlier in the progression? Could it delay the onset of symptoms, or reduce the amount impact?

Basically there is a dysfunction and or loss of vmat2 (vesicular transporter) which is important for dopamine to go through reuptake. I learned about it in some neuroscience classes. Without that transporter the dopamine cant reuptake.

Like most things in science, the devil is in the details, and most people just don't have the expertise to parse those details out. Or, in many cases, the details aren't yet fully known. That's why it seems like there are contradictions, but, in reality, it's just different nuances.

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I would guess that the reason for this is mostly because Parksinson's itself is not that well understood.

It makes sense to say "yes it might work" because we know for sure the drug does xxxx and Parkinson's might have xxxx disease path and therefore cause xxxx which means xxxx symptom of Parkinson's might be due to xxxx which does respond to the drug

On the other hand it makes sense to say "no it might not work" because even though we know the drug does xxxx, Parkinson's might have alternative xxxx disease path and cause xxxx which means xxxx symptom of Parkinson's might be due to alternative xxxx which doesn't respond to the drug

I say it might work because either of these situations might be true

The top comment about it being too late for the actual cells is true, damage brain cells and connections can't be fixed but the damage can be prevented. I'm speaking on the prevention and/or slowing of disease progression

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Wouldn’t that imply that a significant amount of recreational stimulants such as cocaine or many cathinones (‘bath salts’) help prevent parkinson?

What about dopamine release agents such as amphetamine/methamphetamine?

Cocaine probably, I don’t know about cathinones, but dopamine release agents do the opposite because they displace dopamine from synaptic vesicles into the cytoplasm, which is why too much meth actually kills dopamine neurons. A DRI like cocaine or methylphenidate have been shown to prevent this kind of neurotoxicity.

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That's the hope. Similar but different is delaying with l-dopa that makes dopamine production easier. Same idea. Turn up the gain on a fading signal.

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