Impaired striatal dopamine in Parkinson associated fatigue 2021

[nerd]

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.

This has nothing to do with what I wrote. Two separate issues indeed. I think we have some kind of misunderstanding here.

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.

Amantadine is a dopaminergic drug. I provided some theories for why this cognitive decline your neurologist describes can happen. There are two working theories why Amantadine works against LID. First, because of its dopamine reuptake inhibition. Second, because of its NMDA antagonism. I've read papers arguing for both of these two theories. I consider the level of receptor activity that causes dyskinesia excitotoxic, which means that neural damage happens. Not necessarily in a clinical fashion, but chronically so that it can gradually contribute to cognitive decline.

Certainly, this isn't the only pathology that happens in Parkinson's and it doesn't have to be. Nothing excludes each other here.

 

[Martin aka paused||M.E.]

To identify if NMDA antagonism is helpful, an extensive literature research will be necessary.

I know that it is helpful for me bc the two ketamine IV I got improved my ME a lot. I think NMDA (glutamate) receptors are overactive in ME. The worse you get, the more this seems to be the case firing at the slightest stimuli like touches or sounds. Some members here report that NAC helps them. NAC is not only a precursor to glutathione but also a glutamate antagonist. The same is true for LDN. There was a study that showed that excessive glutamate leads to imbalances of mitochondrial fusion/fission which then leads to NMDA receptor upregulation (and ox. stress).
Ketamine has a role in treatment-resistant depression: the supposed mechanism is glutamate antagonism.
It is thought - IIRC - that this treatment resistance is due to excessive glutamate leading to inflammation of the brain; proinflammatory cytokines like IL-1b (which are elevated in my serum) inhibit the reuptake of glutamate in astroglial cells and that leads to inflammation.
Interestingly, there is also a link to HHV-6 infections which seem to play a role at least in a subset of ME patients https://pubmed.ncbi.nlm.nih.gov/18247129/

Studies showed that an imbalance of glutamate/GABA leads to kindling of the HPA axis (which could explain findings of hypocortisolism) that spreads to the brain; Jarred Younger is a proponent of the immune priming hypothesis in ME. So very few stimuli are necessary to cause a flare/neuroinflammation, if that theory is right. This could explain many symptoms like of course fatigue, sensitivity to stimuli...

That's all linked to excessive glutamate. Interestingly dopamine plays a role in glutamate regulation as a kind of a gate-keeper. Ketamine is also a dopamine reuptake inhibitor. Maybe it's dopamine that regulates the glutamate expression. Many possible mechanisms here I think.

From my understanding, glutamatergic overactivation is part of the ME pathophysiology

Yep, see above. That also resonates with the very high glutamate levels I found in 2020... In Stanford they found glutamate to be elevated in ME patients too.

My hypothesis is that ME pathophysiology also includes increased histone deacetylation, which regulates GABAergic activity

I only know that HDAC mediate the expression of GABA(A) receptors. But what do you mean with “regulation of activity”? Increased release?
If so, it would as a HDACi (GABA inhibits HDAC1/2/3 and upregulates Histone Deacetylation levels in cells that express GABA receptors) regulate GluR2 expression (ref.:https://pubmed.ncbi.nlm.nih.gov/31090246/)
If this would also influence the glutamate release/reuptake? Because:

Parkinson's also involves glutamatergic overactivation

I wonder if that all (see above) would not lead to irreversibly damaged neurons in ME too, which doesn't seem to be the case.

Glutamate dysregulation is in fact a problem for me... I also often wonder if increased levels are found everywhere in the brain or if there are other areas with low glutamate levels causing brain fog. This combination could also explain the sensitivity to sensory stimuli while being “wired but tired”. But then inhibiting NMDA receptors would worsen the fatigue:

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.

But that is not the case with Ketamine - at least for me.

 

[Boba]

I know that it is helpful for me bc the two ketamine IV I got improved my ME a lot. I think NMDA (glutamate) receptors are overactive in ME. The worse you get, the more this seems to be the case firing at the slightest stimuli like touches or sounds. Some members here report that NAC helps them. NAC is not only a precursor to glutathione but also a glutamate antagonist. The same is true for LDN. There was a study that showed that excessive glutamate leads to imbalances of mitochondrial fusion/fission which then leads to NMDA receptor upregulation (and ox. stress).
Ketamine has a role in treatment-resistant depression: the supposed mechanism is glutamate antagonism.
It is thought - IIRC - that this treatment resistance is due to excessive glutamate leading to inflammation of the brain; proinflammatory cytokines like IL-1b (which are elevated in my serum) inhibit the reuptake of glutamate in astroglial cells and that leads to inflammation.
Interestingly, there is also a link to HHV-6 infections which seem to play a role at least in a subset of ME patients https://pubmed.ncbi.nlm.nih.gov/18247129/

Studies showed that an imbalance of glutamate/GABA leads to kindling of the HPA axis (which could explain findings of hypocortisolism) that spreads to the brain; Jarred Younger is a proponent of the immune priming hypothesis in ME. So very few stimuli are necessary to cause a flare/neuroinflammation, if that theory is right. This could explain many symptoms like of course fatigue, sensitivity to stimuli...

That's all linked to excessive glutamate. Interestingly dopamine plays a role in glutamate regulation as a kind of a gate-keeper. Ketamine is also a dopamine reuptake inhibitor. Maybe it's dopamine that regulates the glutamate expression. Many possible mechanisms here I think.



Yep, see above. That also resonates with the very high glutamate levels I found in 2020... In Stanford they found glutamate to be elevated in ME patients too.


I only know that HDAC mediate the expression of GABA(A) receptors. But what do you mean with “regulation of activity”? Increased release?
If so, it would as a HDACi (GABA inhibits HDAC1/2/3 and upregulates Histone Deacetylation levels in cells that express GABA receptors) regulate GluR2 expression (ref.:https://pubmed.ncbi.nlm.nih.gov/31090246/)
If this would also influence the glutamate release/reuptake? Because:

I wonder if that all (see above) would not lead to irreversibly damaged neurons in ME too, which doesn't seem to be the case.

Glutamate dysregulation is in fact a problem for me... I also often wonder if increased levels are found everywhere in the brain or if there are other areas with low glutamate levels causing brain fog. This combination could also explain the sensitivity to sensory stimuli while being “wired but tired”. But then inhibiting NMDA receptors would worsen the fatigue:

But that is not the case with Ketamine - at least for me.

A neuropsychologist I‘m in contact with stated the same theory about dysregulation of glutamate. The dysregulation could be due to ischemia, like it is when u have a stroke. He said that‘s why Abilify works, it reduces the level of glutamate in the prefrontal cortex or LDN and alcohol, it blocks NMDA receptors.