Submitted by Actual-Pumpkin1567 t3_zxsbm7 in askscience
We know that the PD affects the basal ganglia. However, the adrenal gland and paragangliomas are also capable of secreting dopamine. So why don't they fill the dopamine deficiency in the PD?
Another question, does the pheocromocytoma that secrets exclusively the dopamine hormone "supress" totally the symptoms of the Parkinson disease?
[removed]
[removed]
[removed]
This is very well written.
I'd add that levodopa gets converted to dopamine by decarboxylation, but to ensure this only happens in the brain (where it is actually required) and not in the rest of the body (since a dopamine overdose would not be in our interests) we use carbidopas which are peripheral DOPA decarboxylase inhibitors (DDCI)
[removed]
see, this is why I tell people they're wrong when they call me smart. I understood maybe a quarter of all of this :D You beautiful amazing people are awesome, I love seeing someone talking shop about their craft like this. Keep up the good work and I thank you all for this I now have lots of things to google while I'm stuck here at work.
[removed]
Another way to think of it is that Parkinson's disease isn't a disorder of insufficient dopamine. Its a disorder of insufficient dopamine-releasing neurons. Treatment with dopamine precursors can increase the activity of remaining dopaminergic neurons of the SNpc. As the disease continues to progress, dopamine precursors become less effective.
Everything everyone else said is correct but they haven't addressed the pheochromocytoma question yet. Simply it doesn't secrete dopamine at all, it secretes adrenaline and noradrenaline so wouldn't affect Parkinson's even if the blood brain barrier wasn't an issue.
[removed]
[removed]
[removed]
Lol, I just commented the exact same. Black holes, james web telescope, how stuff behaves at close to lightspeed, no problem. But no idea what these people are talking about
We add an extra medicine to block an enzyme that would convert the medication we want to be converted in the brain too early, out in the peripheries.
Makes more sense, thanks
Some do secrete dopamine. Dopamine is a metabolic precursor to epi and norepi. There are small amounts that get secreted, and certain rare subtypes of pheo will secrete dopamine. However, like everyone else said, dopamine isn’t able to cross the BBB so it’s not useful for treating PD.
It's very rare but possible. The majority of peripheral dopamine comes from peripheral sympathetic nerves which in part use dopamine to communicate. Some of this dopamine is taken up in the blood stream. Interestingly, there's almost as much dopamine in your blood as adrenaline though what it's doing there is not really known.
https://academic.oup.com/endo/article/151/12/5570/2456083?login=true
Mmmm, yes, decarboxylation, I'm definitely familiar with this term for legitimate reasons.
Neuroscience PhD here: Dopamine does different things in different places. Asking why one group of dopamine releasing neurons can't substitute for another is like saying "my toilet valve is broken, but the valve in my shower is fine, so shouldn't my toilet work anyway?"
Dopamine releasing neurons in the substantia nigra and the dopamine releasing neurons in other areas have 1 thing in common, which is the neurotransmitter they use. But what neurotransmitter they use is relatively unimportant to their function. What's far more important is what neurons they get input from, how those inputs are processed, and what neurons they connect to.
Any given group of neurons that releases dopamine can only release dopamine where their axons are, and that dopamine cannot freely diffuse throughout the brain. This is the whole point of synapses: to help confine the spread of neurotransmitters so that neurotransmitters can act as signals from one neuron to another instead of broadcast signals.
If this seems like a significant departure from how you're used to thinking about neurotransmitters, GOOD. Neurotransmitters do not have functions, neurons do. Repeated with emphasis: NEUROTRANSMITTERS DO NOT HAVE FUNCTIONS, NEURONS DO. Two different neurons can use the same neurotransmitter for totally different functions. Dopamine, for example, is also used in the control of lactation, which is totally unrelated to its role in the control of movement.
This made me remember my love for health sciences and pathophysiology. I was so busy with reading self improvement books (thinking I was not good enough) that I forgot to improve my knowledge in the sciences (which is what I'm already good at). You have just made me less depressed ❤️
Also, carbidopa works in this role because carbidopa itself cannot cross the blood-brain barrier. That's why it blocks peripheral absorption of levodopa but won't interfere with levodopa absorption in the brain.
Are the therapies in the works going to prevent PD, stop its advancement, or outright reverse it?
And any insight on how far away from FDA approval they are?
My father has had it for almost 20 years now so I’m trying to keep up with this stuff but it’s pretty far outside my usual field.
People tend to focus way too much on neurotransmitters, rather than neural pathways. It’s like trying to understand a military conflict while only learning about the bullets being used.
As far as I know: no, unfortunately not. There are a few things against the symptoms (medication and deep brain stimulation).
But the mechanism responsible for PD is still more or less unknown , so basic research is still being done. That's why (again: afaik) there is nothing revolutionary in sight at the moment.
(I wrote my MD loosly on the subject, so I have some insight)
The way that you explained it actually makes a lot of sense in my opinion
[removed]
Well, it IS a problem if you have both conditions. The pheo, and the parkinson's, as the dopamine precursors can also cause the tumors to oversecrete their usual levels.
And also some wild mood swings. There are some pituitary paragranulumas that do some pretty evil things. Even if somehow modified, to be a dopamine pump, pheos/paras do not really have an advanced structure inside like and actual organ, and as such you would not be able to get reliable levels out of such a thing. Unless you somehow fused one with a computer/implant, and had the implant juice the thing as needed. An idea that's at least 30-40 years away.
Now, what is a pheo "tumor", about 1 in 12 at autopsy have some kind of nodule that might be called a tumor, non-cancerous, and usually not active. How many people with parkinson's are irritating this natural feature? The technology is kind of a pain here. With an advanced enough one you can sometimes, maybe, pick up the larger ones using the Philips Affinity, Epic, or similar class using a stander C5-1 and tweak the settings a bit. And much of what's picked up is just scar tissue, and random junk, as the living core is usually as translucent as the organs around it.
Other than this, you have to pickle someone with tracers, and the usual song and dance with various types of medical imaging. And it probably doesn't matter, as you still don't know it its just the adrenal cortex being hyperactive, or the poorly differentiated lump, your Pheo producing the excess catecholamines.
So, the neurologist will usually just tweak the mix of drugs, and hope for the best. Because bringing in yet another specialist to decide, even with all the lab tests, and imaging, that yes, that is a pheo.. Is going to be a 2-5 year ordeal, with the patient, insurance company, and everyone else involved getting more and more pissed off.
Because what is a patient with parkinson's going to do, while off meds, for months and months, while in the lead up the surgery, taking alpha and beta blockers, and hoping the surgeon doesn't have a "whoopsie". Only for the remaining adrenal gland to have the same problem 2 years down the road.
Now there is fairly good results with veterinary medicine for treating those in dogs. But for humans, its still a dice roll that the surgery will kill you from the process itself, or stabilization issues with the organ no longer there secreting. And the chemo only route is generally only attempted in proven cancerous tumors.
The last paragraph you wrote is extremely important to note and thank you for stating that, the circuitry is much more interesting haha
Very much so! If you're curious about neural circuits, check out the app Neuronify.. it's a simple spiking neuron simulator, you can play around with using neurons with different properties to create circuits with multiple stable states, circuits that generate periodic output sequences, and circuits that do specific things in response to an input.
[removed]
>increase the activity of remaining dopaminergic neurons of the SNpc
When you say "dopaminergic neurons", do you mean neurons that release dopamine or neurons that are affected by dopamine?
But given that, how come we treat Parkinson's by flooding the brain with dopamine? We wouldn't shovel valves into an apartment to repair a broken toilet valve.
>how come we treat Parkinson's by flooding the brain with dopamine
That's the neat thing! You don't.
You flood the brain with stuff to make dopamine, which lets the surviving SNc neurons release more dopamine, essentially amplifying the signals of the ones that are left. If they all died, L-DOPA treatment wouldn't work. Again, the really important thing is the neurons, what inputs they get, how they process those inputs, and where they send their outputs, not which chemical they are releasing. In fact, most work on realistically simulating the activity of networks of neurons doesn't even bother to simulate neurotransmitters in any way, except to say "when this neuron fires, that one gets excited by +2millivolts after a delay of 2ms" or something to that effect.
So in the valve analogy, it's like we're increasing the water pressure so that the semi-busted toilet valve can still sort of function.
What about this new vibrating glove therapy? I guess that also only affects the symptoms, not the underlying causes, right?
https://news.yahoo.com/scientists-develop-glove-eliminates-parkinson-132644329.html
Excellent question since, of course, the word can mean both. In this case, it is neurons which release dopamine. Note that they aren't just releasing it randomly into a tissue or into circulation, but releasing it directly at a targeted neuron, such as a GABA-releasing neuron of the dorsal striatum in a fine motor control circuit. A more comprehensive explanation of these pathways would probably require a smarter person to explain it.
Thank you for that. Do the dopamine-releasing neurons take up L-dopa, turn it into dopamine, and then release it at the synapse?
Thank you for that. Do the dopamine-releasing neurons take up L-dopa, turn it into dopamine, and then release it at the synapse?
[removed]
That's exactly right! In the synthesis of dopamine, converting tyrosine to L-DOPA is the slowest step, so having extra L-DOPA available significantly increases dopamine production.
And we're not concerned that, with L-dopa treatment, some dopamine-releasing neurons that aren't affected by Parkinson's will now release too much dopamine? I would be afraid of schizophrenia for example.
That's what side effects are. Anytime you take psychoactive medications, they're going to mess with a thousand different brain systems that ALSO happen to use the neurotransmitter(s) affected by the drug, but were functioning normally. Thankfully, the brain is usually pretty good at compensating for stuff like that (which is why drug tolerance is a thing). Otherwise, side effects would probably be a LOT worse in general.
But when you say you're worried about schizophrenia, that's still thinking about it wrong. Schizophrenia is not caused by a simple overabundance of dopamine, it's caused by some kind of complex disturbance in the activity of one or more networks of brain circuits. The fact that some of those circuits have some dopaminergic components, and that some of the drugs that can partially alleviate symptoms affect dopamine among other neurotransmitters does not make dopamine central to schizophrenia.
They state it eliminates the tremor, that is just a side effect of PD so yes, it just deals with the symptoms. Funny enough most people with tremors do not have PD but jus a "Essential tremor". Bad enough but not that severe.
With PD parts of your brain are dying, so if a therapy does not deal with that it is not curing PD.
kruel1 t1_j22mp9b wrote
Unfortunately, dopamine isn’t able to cross the blood brain barrier. The way PD is treated involves use of levodopa (dopamine precursor) in combination with carbidopa (decarboxylase inhibitor;prevents metabolism of levodopa to help it cross the BBB). The nigrostriatal pathway is the dopamine pathway affected in pd, and through this pathway you get your basal ganglia dopamine responsive pathways that modulate motor activity. But in PD these pathways get disrupted so the dopamine system that applies the brakes beats out the pathway applying the gas. I’m very adhd and I suck at explaining things but would be happy to elaborate further! I do have to say there are some very cool therapies in the works for pd, I’m particularly excited about gene therapy