Impaired striatal dopamine in Parkinson associated fatigue 2021

pattismith

Senior Member
Messages
3,469
Likes
6,794
Impaired dopamine metabolism is linked to fatigability in mice and fatigue in Parkinson’s disease patients | Brain Communications | Oxford Academic (oup.com)

june 2021
Abstract

Fatigue is a common symptom of Parkinson’s disease that compromises significantly the patients’ quality of life. Despite that, fatigue has been under-recognized as symptom, its pathophysiology remains poorly understood, and there is no adequate treatment so far. Parkinson’s disease is characterized by the progressive loss of midbrain dopaminergic neurons, eliciting the classical motor symptoms including slowing of movements, muscular rigidity and resting tremor.

The dopamine synthesis is mediated by the rate-limiting enzyme tyrosine hydroxylase, which requires tetrahydrobiopterin as a mandatory cofactor. Here, we showed that reserpine administration (1 mg/kg, two intraperitoneal injections with an interval of 48 h) in adult Swiss male mice (8–10 weeks; 35–45 g) provoked striatal depletion of dopamine and tetrahydrobiopterin, and intolerance to exercise.

The poor exercise performance of reserpinized mice was not influenced by emotional or anhedonic factors, mechanical nociceptive thresholds, electrocardiogram pattern alterations or muscle-impaired bioenergetics.

The administration of levodopa (100 mg/kg; i.p.) plus benserazide (50 mg/kg; i.p.) rescued reserpine-induced fatigability-like symptoms and restored striatal dopamine and tetrahydrobiopterin levels.

Remarkably, it was observed, for the first time, that impaired blood dopamine metabolism inversely and idependently correlated with fatigue scores in eighteen idiopathic Parkinson’s disease patients (male n =13; female n =5; age 61.3 ± 9.59 years).

Altogether, this study provides new experimental and clinical evidence that fatigue symptoms might be caused by the impaired striatal dopaminergic neurotransmission, pointing to a central origin of fatigue in Parkinson’s disease.
 

Learner1

Senior Member
Messages
6,176
Likes
11,315
Location
Pacific Northwest
My mom had Parkinson's. I have found I have common enough gene mutations that both reduce tetrahydrobiopterin (BH4) production and recycling and have a tendency to low BH4.

Taking 20 mg of Kuvan has been very helpful - my chronically low dopamine is now normal, exercise ability has improved, and blood pressure has lowered, I believe because of increased nitric oxide.

When I told both my neurologist and my ME/CFS specialist that Kuvan was working for me, they were both excited about it and said they had tried to figure out how to get it approved for patients. In 2007, BioMarin got approved what used to be a cheap supplement in the US as the expensive orphan drug Kuvan, only available at 7 specialty pharmacies in the US. I believe there is a much greater applicability of this substance, which is involved in several biochemical processes.
 
Messages
2,264
Likes
7,415
My mom had Parkinson's. I have found I have common enough gene mutations that both reduce tetrahydrobiopterin (BH4) production and recycling and have a tendency to low BH4.

Taking 20 mg of Kuvan has been very helpful - my chronically low dopamine is now normal, exercise ability has improved, and blood pressure has lowered, I believe because of increased nitric oxide.

When I told both my neurologist and my ME/CFS specialist that Kuvan was working for me, they were both excited about it and said they had tried to figure out how to get it approved for patients. In 2007, BioMarin got approved what used to be a cheap supplement in the US as the expensive orphan drug Kuvan, only available at 7 specialty pharmacies in the US. I believe there is a much greater applicability of this substance, which is involved in several biochemical processes.
Wish I could get my hands on BH4. In Germany: no way afaik. Josh also thinks that it would help.

What I can tell with some certainly now is that dopaminergic drugs are helpful to some extend. And I've written with many many others who benefit from increased dopamine (from phenylalanine to levodopa, ALCAR and Tyrosine to - of course - Abilify). The problem is: the toxic metabolites it creates. Here comes Bromantane plus ALCAR into play, increasing tyrosine hydroxylase activity but - for some reason - without producing ROS and toxic metabolites and - for some reason - without tolerance issues.

I haven't tried it yet. Two problems: the studies are mostly only in Russian and second Bromantane (Ladasten) isn't produced any longer so that you'd rely on a trusted chemist PLUS getting the customs cleared.

But in the end dopaminergic drugs and their effect on ME/CFS is still worth investigating.
 

nerd

Senior Member
Messages
863
Likes
2,516
I wish I could get Kuvan, but I'm left with dopamine agonists and positive allosteric modulators.

Has anyone tried medium-dose Amantadine? As always with reuptake inhibitors, the real effect on receptor activity might be difficult to predict. This is why a smooth increase and decrease of the dose is important. It's normally used in combination with Levodopa in Parkinson's because it alleviates some of the negative side effects of Levodopa. It also has virustatic, neuroprotective effects and seems to inhibit microglia activation, which is associated with fibromyalgia.

References
  1. Amantadine protects dopamine neurons by a dual action: reducing activation of microglia and inducing expression of GNDF in astroglia (2012) [10.1016/j.neuropharm.2011.04.030]
  2. Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation (2019) [10.1016/j.bbi.2018.09.018]
  3. Fibromyalgia and microglial TNF-α: Translational research using human blood induced microglia-like cells (2017) [10.1038/s41598-017-11506-4]
  4. Amantadine Inhibits SARS-CoV-2 In Vitro (2021) [10.3390/v13040539]
 
Messages
2,264
Likes
7,415
I wish I could get Kuvan, but I'm left with dopamine agonists and positive allosteric modulators.

Has anyone tried medium-dose Amantadine? As always with reuptake inhibitors, the real effect on receptor activity might be difficult to predict. This is why a smooth increase and decrease of the dose is important. It's normally used in combination with Levodopa in Parkinson's because it alleviates some of the negative side effects of Levodopa. It also has virustatic, neuroprotective effects and seems to inhibit microglia activation, which is associated with fibromyalgia.

References
  1. Amantadine protects dopamine neurons by a dual action: reducing activation of microglia and inducing expression of GNDF in astroglia (2012) [10.1016/j.neuropharm.2011.04.030]
  2. Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation (2019) [10.1016/j.bbi.2018.09.018]
  3. Fibromyalgia and microglial TNF-α: Translational research using human blood induced microglia-like cells (2017) [10.1038/s41598-017-11506-4]
  4. Amantadine Inhibits SARS-CoV-2 In Vitro (2021) [10.3390/v13040539]
You think it’s better than Wellbutrin? The downside here is it decreases IFNg, which is itself almost 0 in my blood results and I try to increase it with Tulsi and Equilibrant (playing Don Quixote).
 

pattismith

Senior Member
Messages
3,469
Likes
6,794
Interestingly, the only abnormal finding in fatigued parkinson patients was low DOPAC


Fatigue was independently associated with reduced DOPAC blood levels in Parkinson’s disease patients

In order to translate the experimental findings to a clinical context, the association between demographics, clinical and biochemical data with fatigue scores was determined in 18 patients with idiopathic Parkinson’s disease.

The univariate analysis presented in the Table 1 shows a significant and negative association between blood DOPAC levels (r =0.58; P < 0.03) and PFS-16 scores, a significant and positive association between fatigue symptoms and HADS depression scores (r =0.56; P <0.02), HADS anxiety scores (r =0.44; P <0.08), body mass index (r =0.78; P <0.001) and daytime sleepiness scores (r =0.48; P <0.05).

No statistical association was found between fatigue symptoms and dopamine or BH4 plasma levels, gender, age, disease duration, daily levodopa dose, years of education and Hoehn and Yard or MOCA.

It was also observed a non-significant trend (P 0.20) in the association between the PFS-16 scores and the plasma BH4 levels, age and UPDRS-III.

As shown by the final model of multiple linear regression (bottom of Table 1), only UPDRS-III score (B =0.62; CI 95% 0.09 to 1.12; P <0.02) and blood DOPAC levels (B = −2.27; CI −3.57 to −0.97; P <0.003) remained significant and independently associated with the patients fatigue symptoms.

Taken together, the UPDRS-III score and blood DOPAC levels explains 68%, and DOPAC levels alone 34% of the PFS-16 score variation, suggesting a tight association between altered dopamine metabolism and the presence of fatigue symptoms in idiopathic Parkinson’s disease.
1629041934982.png
 

Attachments

nerd

Senior Member
Messages
863
Likes
2,516
You think it’s better than Wellbutrin? The downside here is it decreases IFNg, which is itself almost 0 in my blood results and I try to increase it with Tulsi and Equilibrant (playing Don Quixote).
It's unclear if Bupropion (aka Wellbutrin) increases dopamine release, but Amantadine certainly does. Most likely, they share most MoAs such as microglia inhibition. So I presume that Bupropion also increases dopamine release or that the definition of dopamine release isn't controlled for reuptake inhibition and that we're talking of one and the same underlying mechanism.

The suppression of TNF-alpha and Interferons is mediated by dopaminergic activity. This means one can not go without the other. This means that all dopaminergic drugs will most likely share this effect. Even Kuvan, although Kuvan only affects dopamine levels indirectly.

The only difference might be antiviral efficacy, though this might be negligible for Amantadine since Influenza is already resistant to it, other resistances are as likely.

Interestingly, the only abnormal finding in fatigued parkinson patients was low DOPAC
This sounds like a MAO <-> COMT dysbalance, COMT overactivation, which has been shown to happen in ME as well. It's possible that this is just an indirect effect though, for Parkinson's as well. I have a genetic MAO predisposition, which makes such a dysregulation more likely.
 
Last edited:
Messages
2,264
Likes
7,415
The suppression of TNF-alpha and Interferons is mediated by dopaminergic activity
You always show me how much I have to learn. What do you think about Memantine? It is also dopaminergic (affinity/agonist to D2, increases dopamine in prefrontal cortex and stratium at 10-20mg/kg i.p. - rats), increases BDNF (which is very low in my serum) and - like Ketamine which seems to help me and others severely affected a lot - acts as an NMDA-antagonist.
 
Last edited:

Learner1

Senior Member
Messages
6,176
Likes
11,315
Location
Pacific Northwest
Interestingly, the only abnormal finding in fatigued parkinson patients was low DOPAC




View attachment 44399
There's a lot more going on in Parkinson's than low DOPAC:

https://www.frontiersin.org/articles/10.3389/fcell.2020.615461/full

Wish I could get my hands on BH4. In Germany: no way afaik. Josh also thinks that it would help.
It is sold in Germany, according to this:

https://www.giiresearch.com/report/dmin916177-global-phenylketonuria-treatment-market.html

If you have had your genes analyzed, you might look for mutations on these genes - PAH, GCH1, PTS, and QDPR.
 

Learner1

Senior Member
Messages
6,176
Likes
11,315
Location
Pacific Northwest
There's a lot more going on in Parkinson's than low DOPAC:

https://www.frontiersin.org/articles/10.3389/fcell.2020.615461/full


It is sold in Germany, according to this:

https://www.giiresearch.com/report/dmin916177-global-phenylketonuria-treatment-market.html

If you have had your genes analyzed, you might look for mutations on these genes - PAH, GCH1, PTS, and QDPR.
Additionally, an amino acid test with high phenylalanine and low tyrosine would be suggestive of a problem.
 

pattismith

Senior Member
Messages
3,469
Likes
6,794
This sounds like a MAO <-> COMT dysbalance, COMT overactivation, which has been shown to happen in ME as well. It's possible that this is just an indirect effect though, for Parkinson's as well. I have a genetic MAO predisposition, which makes such a dysregulation more likely.
The Parkinson picture is actually complicated, and Astrocyte/MOA B is considered upregulated in Parkinson. For this reason MAO B inhibitors are part of the Parkinson treatment. (Selegiline)

1629046218820.png


DOPAL is considered toxic, so a problematic enzyme may be ALDH that converts DOPAL to DOPAC


1629046326562.png


Mechanisms of action of MAO-B in Parkinson's disease. MAO-B is mainly... | Download Scientific Diagram (researchgate.net)

Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson's disease - Goldstein - 2013 - Journal of Neurochemistry - Wiley Online Library
 

Irat

Senior Member
Messages
285
Likes
689

It's a bit much for me today following this post,but as I replied few times before about the danger about up and downregulation I found this post the other day when I was searching something,and also looked at his blog ,outside phönix ,which is interesting....,I remember a study when they gave people with dystonia an opposite drug ,they got worse first then the receptors levelled out,,,,,not sure if this even relate to you,lol,sorry I m really stupid today,but this post might give some more clues to just collect more informations looking at all angles

Hi, it’s been a while since I’ve been here but I saw that I got tagged so I thought I would comment some more on my stimulant misadventure nice I’m a few years wiser than last time I’ve been here and people are reporting things I recognize from my own past.

1. There is an issue of neurotransmitter “turnover” which is more than just amount of released neurotransmitter (NT). Turnover refers to flow of neurotransmitter from one neuron to another and is a net sum of synthesis, release, uptake and degradation. The synthesis and degradation are influenced by metabolic rate. This is why thyroid hormone played such a huge role both in my crash (NDT) and subsequent recovery (T4). The Vyvanse I was taking back then (not Ritalin) has in turn affected the number of receptors My hypothesis is that the range and severity of symptoms progress as more components of this turnover equation get knocked out of balance. It can feel very uncomfortable to address only one because that will disrupt already shattered balance even more. Sometimes you have to get worse to get better but you also need to be very careful with this and patient. It’s not an easy feat.

Of note, thyroid worked for me (despite normal TSH) but you may have other reasons for energy deficit. Any deficiency of vitamin or mineral involved in mitochondrial energy production (i.e. vitamins or mineral) can be involved too.

2. Dopamine is in balance with serotonin. If both are low and you only raise one at a time you once again disrupt balance.

3. The number of receptors will affect binding. Sometimes in order to genetically move the receptors in the right direction (it’s called up regulating or downregulating) you might have to take the drug that actually makes you feel worse and then after you stop it you may find yourself in a new place. But once again - be careful and use sound judgement, I can’t stress that enough. For me that drug was lithium orotate which I also documented on my blog. Again, that was me, your drug might be different. But generally things that make you feel better right away (on day 1) will shift your receptors in the wrong direction if taken long term. They are still fine for occasional symptomatic relief.

4. There might be an issue with calcium flux or with Na/K ATPase that needs to be addressed first before you can restore neurotransmitter levels.

5. Fatty acids, cholesterol and sphingolipids are also important for signaling.

6. Traditional Chinese herbal formulas can be an excellent alternative because they are milder than pharmaceuticals and often tailored to an individual’s chemistry to address many of the issues simultaneously.

There are other things too but those are my main takeaways. If anyone has any questions about all this the best way to reach is me is by commenting on my blog as I don’t log in here much. I can’t provide exact medical advice but I’m always happy to tutor people in neuroscience or TCM or whatever else I’ve written there about. I haven’t updated my blog in a long time because I keep on planning to write an e-book but due to serious family issues and with the pandemic and all couldn’t get motivated. If I see some more interest in folks interested in learning my art and craft of neurohacking then I might finally get motivated to start writing :)
 
Last edited:

Alvin2

The good news is patients don't die the bad news..
Messages
2,396
Likes
5,868
Has anyone tried medium-dose Amantadine? As always with reuptake inhibitors, the real effect on receptor activity might be difficult to predict. This is why a smooth increase and decrease of the dose is important. It's normally used in combination with Levodopa in Parkinson's because it alleviates some of the negative side effects of Levodopa. It also has virustatic, neuroprotective effects and seems to inhibit microglia activation, which is associated with fibromyalgia.
The neurologist i see tries to avoid amantadine, it works ok in some patients but he finds its a messy drug and causes cognitive issues long term. There are many others that often work as well and are less problematic.

Also dopamine agonists are a royal headache, many patients they go loco on them, gambling, sex addiction, the behavioural anomalies can get very nasty. And patients often refuse to come off them because they don't realize they are acting like they were programmed like a machine, they think its great.
What do you think about Memantine?
This is an emerging off label drug for Parkinsons for the majority who end up with cognitive impairment/dementia.
 
Messages
2,264
Likes
7,415
It's a bit much for me today following this post,but as I replied few times before about the danger about up and downregulation I found this post the other day when I was searching something,and also looked at just blog which is interesting....,I remember a study when they gave people with dystonia an opposite drug ,they got worse first then the receptors levelled out,,,,,not sure if this even relate to you,lol,sorry I m really stupid today,but this post might give some more clues to just collect more informations looking at all angles
It is not stupid but I honestly don't get the logic behind it (first get worse than better etc). Not to spam this thread I will come back to this per PM.
 

Alvin2

The good news is patients don't die the bad news..
Messages
2,396
Likes
5,868
If that's true then it's obviously the wrong thing to try. Thx I look into it.
It helps reduce the hallucinations and gives back some higher reasoning. But the dementia still progresses.

The theory is that beyond damaging the dopamine producing neurons the alpha synuclein is damaging acetylcholine producing neurons in some patients.

The neurologist had said that he found patients with Parkinsons that did better physically over time tended to do worse cognitively.
 
Last edited:

nerd

Senior Member
Messages
863
Likes
2,516
You always show me how much I have to learn. What do you think about Memantine? It is also dopaminergic (affinity/agonist to D2, increases dopamine in prefrontal cortex and stratium at 10-20mg/kg i.p. - rats), increases BDNF (which is very low in my serum) and - like Ketamine which seems to help me and others severely affected a lot - acts as an NMDA-antagonist.
Amantadine is an NMDA antagonist as well.

To identify if NMDA antagonism is helpful, an extensive literature research will be necessary. From my understanding, glutamatergic overactivation is part of the ME pathophysiology. This naturally also affects NMDA receptors. But it also involves antibodies against G-protein coupled receptors (GPCRs). mGluRs are GPCRs. My hypothesis is that ME pathophysiology also includes increased histone deacetylation, which regulates GABAergic activity and possibly glutamatergic activity as well. Parkinson's also involves glutamatergic overactivation, but possibly at different receptor types. These things will need to be cross-checked to determine which dopaminergic drugs might be the best candidates for ME.

I think it's worth looking into why cognitive impairment might happen when NMDA antagonism is combined with dopamine regulation. It might translate into theories for why the same happens with ME. If NMDA is inhibited, elevated glutamate will have to be metabolized somehow, and other glutamate receptors will do so if they aren't inhibited as well by the same drug. If we hypothesize that receptor damage at least partially originates from excitotoxicity at these receptors, and that the drug indirectly contributes to the glutamate excitotoxicity at unaffected receptors such as mGluRs or GluRs, this would be one theory for why pure NMDA antagonism can be harmful while glutamate expression is elevated.

If agonists are expressed higher on a permanent basis, normally, the physiology naturally adapts to it by increasing the uptake or increasing receptor expression. Short bursts, however, might be a phenomenon that the physiology can't handle. So the question is if a drug can cause or contribute to bursts of receptor activity.

Another non-exclusionary theory that possibly overlaps is that dopamine activity itself contributes to increased specific binding to NMDA receptors and decreased mGluR binding, meaning that it is the dopaminergic activity that is harmful and not the NMDA antagonism. Within this theory, NMDA antagonism might actually prevent dopaminergic neurotoxicity. But it wouldn't fix the mGluR downregulation, which on a long-term basis, would naturally cause a ME-like cognitive decline. This theory is also consistent with the general understanding that Amantadine alleviates Levodopa-induced dyskinesia (LID).

Changes in glutamate receptors in dyskinetic parkinsonian monkeys after unilateral subthalamotomy (2015) [10.3171/2014.10.JNS141570]

The inverse would also be possible, namely that dopamine pathology from Parkinson's or ME pathophysiology, if untreated, indirectly upregulate mGluRs, thereby enhancing excitotoxicity.

The theory is that beyond damaging the dopamine producing neurons the alpha synuclein is damaging acetylcholine producing neurons in some patients.
This theory seems to make more sense in the context of Parkinson's because the elevated glutamate pathophysiology from ME doesn't translate into the Parkinson's pathophysiology. The effects from the alpha-synuclein could explain cognitive decline that is exacerbated by dopaminergic drugs. But this doesn't necessarily affect ME patients. I'm not sure how well the alpha-synuclein genotypes are understood.

Dynamic Changes in Striatal mGluR1 But Not mGluR5 during Pathological Progression of Parkinson's Disease in Human Alpha-Synuclein A53T Transgenic Rats: A Multi-PET Imaging Study (2016) [10.1523/JNEUROSCI.2289-15.2016]

I think it's important to create a profile for all glutamate receptor types and see how each are affected from the pathophysiology and the drug(s). Maybe you have other ideas as well. Eventually, we can try and wrap all of this up into a clearer picture and do an estimate what drug is most likely to provide the best risk-benefit profile within these theories.
 
Last edited:

Alvin2

The good news is patients don't die the bad news..
Messages
2,396
Likes
5,868
The effects from the alpha-synuclein could explain cognitive decline that is exacerbated by dopaminergic drugs.
Its not believed that dopaminergic drugs exacerbate cognitive decline, the theory is that the disease progresses causing more brain damage.
As the dopamine sensitive neurons that are involved with motor control die off the Levodopa causes more dopamine in dopamine sensitive neurons that are not dead but affect behaviour. Hence in advanced patients Levodopa loses motor control symptom control over time and Levodopa needs to be tapered down.
Two separate issues.