Everyday´s influence on Acetylcholine

[percyval577]

In a fabulous review on Acelylcholine the following sentence sticked out to me:

"Consistent with a potenetial role of ACh in coordianting caloric need with food-seeking behaviours.
long term maintenance on a high-fat/high-sugar diet significantly downregulated levels of AChE in a number of brain areas that was particularly pronounced in the hyothalamus (Kaizer et al. 2004)."


"Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Functions and Behaviour"; Picciotto, Highley et al. 2012, page 122, the original source:
"Diet-induced changes in AChE activity after long-term exposure"; Kaizer, da Silva et al. 2004

Abstract:
In the present study we investigated a potential mechanism by which high sugar (HS) and high fat (HF) diets could affect acetylcholinesterase (AChE) activity. The treatment with HS and HF diet was done for six months on male and female rats. The results showed decreased hippocampal AChE activity in male and females receiving HS and HF diets (HS 24% and 36%; HF 38% and 32%, males and females, respectively; P < 0.05). The activity in the cerebral cortex was reduced in males (49 and 40%) and females (19 and 17%) (P < 0.05) on HS and HF diets, respectively. In the hypothalamus AChE activity was decreased on HS diet in males (46%) and female (25%) (P < 0.05) and also on HF diet in males (34%) and females (21%) (P < 0.05). However, in the cerebellum no changes in AChE activity were observed. These results indicate that HS and HF diets produced mainly inhibition in acetylcholine degradation. It probably indicates a chronic alteration induced by these diets on the cholinergic system.


A lot of us report effects from choline. A dysregulation of the "choline-carnetine pathway" could be pointed out by the fabulous announcement "Insights into myalgic encephalomyelitis/chronic fatique syndrom phenotypes through comprehensive metabolomics" 2018 (the Lipkin paper) on p.3.
A good effect by choline intake could indicate both, to less ACh (which would be helped) and to much ACh (wich would steadily cause a defiency).
A bad effect might indicate at least high ACh (which would become even higher).
ACh autoantibodies are sometimes found. They might be a counteraction on to much ACh or the cause for to less ACh,
Is there any detailed research already?
Dr Phair and Fred I think have come up with the idea of a trap. I don´t know if it would be possible here that high ACh then would lead to low ACh which would not be wise to elevate. This might be not to be found out without any doctor.
I personally think that ACh would be to high, and that an influence from the immunesystem on ACh exists (iNOS), beside a possible influence from ACh on the immunesystem (eg hypothalamus). It might be a circuit.


Maybe it´s a significiant influence on our disease on the long run?

 

[percyval577]

Since about four weeks I eat vegetables instead of fruits and only one time a day fat.
(But I do eat chocolate).
The success manifests in form of some less weight of the disease in generel,
but induces so far not a structural improvement. I feel quite a bit better and stronger but can not do better.
In some sense there is even a structural worsening, say due to more new possiblities that needed to be structured.

During the last three years my impovement took a similar course, with slow progredient loss of pain and missfeelings,
but a nonprogredient worsening of concentration, which is since about last autumn improving as well (in generel).
See my first thread on the manganese influence on inducible nitric oxide synthase, especially #16-19, #29 and the following. The healing is no joy.

It all seems to be a long journey. Taken together it might be a circuit, and maybe it would not take years (if both would be true or apply to anyone.)

The circuit (predispositioned to drive high when the the illness would set on from what other ever),
or the core would be:

fat, sugar -> AChE -> ACh <-> NO <- iNOS <- manganese
also an influence in this ACh -> iNOS direction possibly via hypothalamus would be part.

The (wide) circuit hasn´t been already shown completly, which would be a task for researchers.

I awake somehow, but I don´t know where I am.

 

[percyval577]

It works.

often fat -> cotton in the brain,
seldom fat -> cement in the brain (with progredient improvement for me)


I am an idiot, but it works.

 

[percyval577]

It seems to be a solution. I feel almost normal now. There is still brainfog enough though.
It might be the main point? Downstream then could occur/stay many things.


I mentioned above the Lipkin, Hornig paper 2018, which reported a dysregulation of the "carnetine-choline" pathway.
Already 2004 Vermeulen and Scholte looked at carnetine: "Exploratory Open Label, Randomized Study of Acetyl- and Propionylcarnetine in Chronic Fatique Syndrom",

S. 276
"Kuratsune et al. () Plioplys and Plioplys () reported a decrease in plasma acylcarnetine In CFS, but this was not confirmed by others (7-9). The first report on carnetine treatment in CFS was by Grau et al. () who found no effect. Plioplys and Plioplys () reported significant improvement of CFS symptoms after 2 months of 3 g daily oarally administered L-carnetine."

S. 280
"The effect of ALC on menatl fatique and attention concentration was significant. The PLC group showed most improvement in general and physical fatique and slightly less in attention concentration. The ALC+PLC group improved very well on general fatique and also, but not significantly, on physical and mental fatique. ...

In the second observation period, 50% of patients deteriorated in th ALC and PLC groups. For most the relapse was hardly acceptable ... The improved patiens in th ALC + PLC group (37%) all deteriorated in the second observation period."


This finding from 2004 shows no cure, but such a strong hint that it must seem strange that eg in the netherlands these findings have been neglected in favour of CBT and GET. -- I can´t belive it.


I say again, I eat almost no sugar now, and fat only and strictly once a day, and it is now a strong good effect.
(There might be synergical effects which would not mean a cure. I´ll see.)

 

[percyval577]

1. (for being complete)
S.278: "Improvement was reported after 24 weeks of treatment by 59% of the ALC group, 63% in the PLC group, and 37% in the ALC+PLC group." (and later most detoriated)

S. 277: "Assessed for eligibility were 114 patients, and 90 were controlled in the study."
"Eight patients stopped because of side effects--3 in the ALC group, 2 in the PLC group, and 3 in the ALC+PLC group. They experienced an overstimulated feeling and sleeplessness. Another 8 patients stopped, because they did not experience any effect from the treatment-- 4 in the ALC group, 1 in the PLC group, and 3 inthe ALC+PLC group. Two patients stopped for reasons unrelated to the treatment."
S. 279: "The nature of the side effects - overstimulatioona and sleeplessness - is different from that reported in most other studies, describing trimethylamine formation or diarrhea in a few patients."

2. Effects (treatment or only blood) by carnetine have been reported about half and half. Now, there is not only the question possible what could go wrong in a trial technically, but also what other circumstances might have hindered a confirmation of these results, eg seasons, culture of food or whatever. I like to come up with this manganese issue, pointing again to a possible indirect circuit
"brain-immunesystem (Mn->iNOS->NO) <--> brain-nerves (possibly ACh<->NO)"


3. ?Downstream effects
----S. 276 "Carnetine is essential for the mitochondrial oxidation of long-chain fatty acids, because it acts as a carrier of acyl groups across the inner mitochondrial membrane to the matrix for beta-oxidation."
----Manganese (sometimes) seems to play a specific role in complex II of the electron transport chain (for some reasons): --Liu, Barber et al. 2013: "Complex II of the mitochondrial respiratory chain is the key mediator of divalent manganese-induced hydrogen peroxide production in microglia" --Bonke, Zwicker, Dröse 2015: "Manganese ions induce H2O2 generation at the ubiqione binding site of mitochondrial complex II." --and MnSOD2/FeSOD2 in generel
----Angajala, Lim et al. 2018: "Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism."


The compounents might seem trivial:
[fat -> carnetine -> beta-oxidation] ?+? [manganese - complex II -> H2O2] ?->? Immune Responses

But the body is a webb, and the outcome might not be trivial.

 

[percyval577]

Scheibenbogen and coworkers write in the paper Sotzny, Blanco 2018 with respect to some (individual) Immune Responses:

• "There is compelling evidence that autoimmune mechanisms play a role in ME/CFS. However clinical heterogeneity in disease onset ... point to the existence of subgroups of ME/CFS patients with possibly different pathomechanisms." (p 606).

But this is not already conclusive in view of a cure, and it might be enough to look at p. 605:

• "A metabolic shift toward aerobic glycolysis resulting in insufficient tricarboxylic acid (TCA) cycle and inadequate ATP production was reported recently, although the underlying basis has yet to be established []."

This might be the main point.

Reducing sugar might reduce too much glycolysis and reestablish the TCA cycle.
Reducing fat might do something similar.

 

[percyval577]

It seems that the body is in a state of "serving wound healing":

• (Almost) all manganese tasks can be associated with wound healing.
• Also Acetylcholine in generel seems to play a role in wound healing (but the picture is thin so far I think)

cf Ren, Tong et al. 2017: "The Protective Effect of Alpha 7 Nicotinic Acetylcholine Receptor Activation on Critical Illness and Its Mechanism." or
cf Kishibe, Griffin 2015: "Keratinocyte nicotinic acetylcholine receptor activation modulates early TLR2-mediated wound healing responses."

The later ones write: "Our findings emphasize the potential benefit of topical nAChR agonists or antagonists to modulate wound healing outcomes." (p.2)


Finally the above mentioned Lipkin paper found free triglycerides in the blood, molekules where fatty acids will bind to, to make membranes. This looks like wound healing.

 

[percyval577]

It works pretty good after about seven weeks (especially) now in august when in addition melatonin begins to grow bigger. Sporadic problems occure further but are less important than the improvement in generel feeling.
-- And it is (obviously) a change in gene expression. If it carries on (itself and/or downstream), what would be the time frame?

-------------------------------------------------
@Learner1 Note that there could be a genuine mitochondria issue, but it could be influenced this way. (the other way round would be logically also possible, of course).

I still have rosacea though, which used to come up parallel with mecfs the last seven years. Could the rosacea get reversed, as well as maybe autoimmune issues? (@crypt0cu1t I wish you the best)

@debored13 I tagg you as well because the paper Vermeulen and Scholte is interesting as ALC vs PLC application induces different effects, mental vs physical ones.

 

[percyval577]

For the first time rather since eight years I dream a bit. This is promising!

But I don´t dare to hope that it would take only a few months. Maybe a year is more realistic.

 

[percyval577]

I am quit often now very tired but in a rather normal manner. Almost like a normal healing.
Often my brain feels like a block of concrete, and when I have eaten something cotton grows.
Eating and then doing is not good.

It seems that the body is in a state of "serving wound healing"....

Could the rosacea get reversed, as well as maybe autoimmune issues?

This speculation/guess/hope gets a bit served by the following finding:

Shanmugam et al. 2012: "Prevalence of Immune Disease in Patients with Wounds Presenting to a Tertiary Wound Healing Center." Abstract:

"... establish the prevalence of immune disease in a cohort of patients with chronic wounds."
"The prevalence of immune disease was higher than expected with 78 of 340 patiens (23%) having associated immune disease."

"The association between immune disease and chronic wounds may provide unique insights into pathways of wound healing and warrants further study."

Well, if there is a state of "wound healing" or "serving wound healing", and this state is chronicle and pathological upregulated, it might be influencable by nutrition.

(@Forçe e Honra and @crypt0cu1t)

 

[StarChild56]

I am really happy that you are gaining improvements in your health

I am not able to understand the information at this time but I hope you get continued good results.

 

[percyval577]

Thank you @Forçe e Honra. Yes the improvement needs to be evaluated more, and how it behaves under different circumstances.
------------
The idea is that fat/sugar and manganese would (obviously they do) serve a state for wound healing, and this state might have become high in us, for some reasons. And now there is this association wound healing - autoimmune disease.
To be importantly more precise:

1. It could be that autoimmuneantibodies are part of a wound healing, for unknown, complicate reasons that would not get figured out within 20 years or so. Different reasosns might be thinkable.

2. More mainstream thinking is that a genuine autoimmune disease would induce neuroligical symptoms. And here any influence via sugar/fat and manganese might be better watched by a doctor - I don´t know how nor do I know if a doctor could figure out anything usefull.
I would think that a danger could be that you get hypersensitive for these nutritions: You would downregulate iNOS and ACh but the genuine autoimmune disease liked to request once more an upregulation (?).
(I am now quite sensivie to fat too and still sensitive enough to manganese, but this would be clearly case1.)

In don´t know if you, Crypr0cu1t, would try it, but the development of your diseases and the fact that you have three autoimmune diseases might point more to the first possibility. But I guess Dr Chedda would be one of the few doctors who might be able to think on it.

 

[percyval577]

So, the sugar/fat diet is not a quick miracle, but feels more comfortable than the manganese diet alone. it might be an acceleration to 15%. The effect seems also to depend on some very very small nickel (probably even ng), as both, nickel and a continued sugar/fat diet without each other do not have this "comfortable" effect.

(@crypt0cu1t, I forgot to tag you one message above).

 

[percyval577]

The medical Mestinon works by PYR which is a known inhibitor of AChE in the motoric endplate.
Here a study on its effects in the brain:

Ropp et al 2008: Pyridostigmine_Crosses_the_Blood_Brain_Barrier_to_Induce_Cholinergic_and_Non-Cholinergic_Changes_in_Mouse_Hypothalamus

from the ABSTRACT (my stretching)

PYR did not affect cortical AChE activity
but inhibited hypothalamic activity after acute exposure.
Subacute treatment with PYR increased hypothalamic AChE activity.

Western blot analysis of the same tissues showed a significant increase in cortical and hypothalamic AChE protein following subacute PHY treatment. Subacute PYR treatment increased hypothalamic AChE protein levels (39%). Real-Time PCR analysis of AChE mRNA revealed significant increases in the cortex following subacute PYR (24%) and PHY (41%) and in the hypothalamus following subacute PYR (16%)

from the CONCLUSION (not my stretching, don´t know why it appeared)

...strongly suggest that PYR does cross the BBB into one of these specific regions,
i.e., the hypothalamus (Figure 5). Subacute treatment with PYR caused changes in AChE
activity, protein levels, mRNA and in non-AChE protein profiles. Although PYR’s primary target
is AChE, other serine hydrolases in the hypothalamus and other accessible tissues are also
potential targets, whether through direct interaction with the active site on an enzyme or via
changes in expression.

I don´t know if this finding in itself is ready to be interpreted for me cfs.
I would test it for sure. @Mel9, congratulations to your success!