An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (2021, Wirth et al)

[Violeta]

Since alpha 1 adrenergic receptors and Beta 2 adrenergic receptors are both stimulated by epi/norepi, if there was a lack of epi/norepi, both would be affected.

I just realized this the other day. Butcher's Broom does help with orthostatic intolerance, and so is helping in some way with a1ar, so I wasn't looking at B2-aR. But now I am thinking it's affecting both.

I suppose insufficient epi/norepi could be the issue, or as nerd said, it could just be compensatory. In which case there would supposedly be autoantibodies (or some other issue) at both sites.

So beta2-adrenergic receptors are found in:
Beta 2 receptors are predominantly present in airway smooth muscles. They also exist on cardiac muscles, uterine muscles, alveolar type II cells, mast cells, mucous glands, epithelial cells, vascular endothelium, eosinophils, lymphocytes, and skeletal muscles.

And yes, I have symptoms related to Beta 2 receptors, too. I am looking for relief from those symptoms by Butcher's Broom, not sure yet. Allergies might also be involved.

 

[Violeta]

An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Klaus J. Wirth, Carmen Scheibenbogen and Friedemann Paul

Link
Full text link

Abstract
There is accumulating evidence of endothelial dysfunction, muscle and cerebral hypoperfusion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). In this paper we deduce the pathomechanisms resulting in central nervous pathology and the myriad of neurocognitive symptoms. We outline tentative mechanisms of impaired cerebral blood flow, increase in intracranial pressure and central adrenergic hyperactivity and how they can well explain the key symptoms of cognitive impairment, brain fog, headache, hypersensitivity, sleep disturbances and dysautonomia.

Do you have links to their previous papers that they mentioned in this article? I searched by authors at BMI but couldn't find them.

Oh, silly me, the links are in this paper.
Here's one. Wow.

"We found elevated ß2 adrenergic receptor (ß2AdR) and M3 acetylcholine receptor antibodies in a subset of CFS/ME patients."

https://www.sciencedirect.com/science/article/pii/S1568997220300823?via=ihub

 

[Violeta]

I am thinking molecular mimicry technology would be helpful with determining possible autoantibodies, and maybe there already is info out there relative to a1-aR and b2/aR.

Along that line I found this paper.

Molecular mimicry theory (MMT) suggests that epitope mimicry between pathogens and human proteins can activate autoimmune disease. Group A streptococci (GAS) mimics human cardiac myosin in rheumatic heart disease (RHD) and coxsackie viruses (CX) mimic actin in autoimmune myocarditis (AM). {Beta2-AdR}
https://www.frontiersin.org/articles/10.3389/fped.2014.00085/full

 

[Violeta]

WIth respect to possibility of epi/norepi insufficiency in this issue,

These results clearly demonstrated that pantothenic acid supplementation stimulates the ability of adrenal cells in male rats to secrete corticosterone and progesterone

https://pubmed.ncbi.nlm.nih.gov/18520055/

Adrenal function in rheumatoid arthritis

https://arthritis-research.biomedcentral.com/articles/10.1186/ar3628l

And weak support for this but nevertheless, some support:
"One study found that people with RA may have lower levels of B5 in their blood than healthy people, and the lowest levels were associated with the most severe symptoms."

 

[Pyrrhus]

Although it doesn't answer the question of whether there is a lack of chemical (epinephrine/norepi) or if the receptors for some reason aren't responding.

There is a third possibility: there is a problem with the nerve cell that is supposed to release the (nor)epinephrine to the cell that has the adrenergic receptor, and therefore (nor)epinephrine is not getting released in the first place.

In this possibility, there is not a lack of (nor)epinephrine and there is not a problem with the receptors, but there is a problem with the nerve cell that is supposed to release the (nor)epinephrine in the first place.

 

[Violeta]

There is a third possibility: there is a problem with the nerve cell that is supposed to release the (nor)epinephrine to the adjacent nerve cell that has the adrenergic receptor, and therefore (nor)epinephrine is not getting released in the first place.

In this possibility, there is not a lack of (nor)epinephrine and there is not a problem with the receptors, but there is a problem with the nerve cell that is supposed to release the (nor)epinephrine in the first place.

That's interesting, so I had to look up release of neurotransmitter from nerve cell and found this.

"A neuron sending a signal (i.e., a presynaptic neuron) releases a chemical called a neurotransmitter, which binds to a receptor on the surface of the receiving (i.e., postsynaptic) neuron. ... The increase in intracellular Ca2+ concentration triggers the release of neurotransmitter molecules into the synaptic cleft." @Crux

Do you know anything else about this, Pyrrhus?

 

[Pyrrhus]

"A neuron sending a signal (i.e., a presynaptic neuron) releases a chemical called a neurotransmitter, which binds to a receptor on the surface of the receiving (i.e., postsynaptic) neuron. ... The increase in intracellular Ca2+ concentration triggers the release of neurotransmitter molecules into the synaptic cleft."

That's right. So, if there is a problem with the neuron that is supposed to send the signal, the neurotransmitters (nor/epinephrine) will not be released, and will not bind to the (adrenergic) receptors on the receiving cell...

 

[nerd]

"A neuron sending a signal (i.e., a presynaptic neuron) releases a chemical called a neurotransmitter, which binds to a receptor on the surface of the receiving (i.e., postsynaptic) neuron. ... The increase in intracellular Ca2+ concentration triggers the release of neurotransmitter molecules into the synaptic cleft."

And we're back at the electrolyte mobilization topic and the question of whether Ca+ influx in ME/CFS enhances or compensates the disease pathogenesis.

 

[Violeta]

Stimulating effect of 6R-tetrahydrobiopterin on Ca2+ channels in neurons of rat dorsal motor nucleus of the vagus

We have recently found that 6R-tetrahydrobiopterin (6R-BH4), a natural cofactor for aromatic L-amino acid hydroxylases and nitric oxide synthase, enhances dopamine release.

"we examined the effect of 6R-BH4 on Ca2+ channels in neurons of rat dorsal motor nucleus of the vagus, where dopaminergic neurons are densely located"


https://pubmed.ncbi.nlm.nih.gov/8660332/

 

[SlamDancin]

@Violeta Ive been wanting to try Kuvan for a while now, it seems promising. I think you’ve inspired me to ask my doctor how I might be able to get a prescription filled for it.

 

[Violeta]

If you try it, keep us posted. I ordered some tyrosine to see if that helps. Trying to figure out the peroxynitrite deal, what to do about it.

 

[Pyrrhus]

This paper has been used to justify the currently popular "ischemia-reperfusion hypothesis", which proposes that PEM is caused by improper blood flow.

Whether or not that is a correct characterization of this paper's intent, the "ischemia-reperfusion hypothesis" falls flat upon further inspection.

Specifically, the symptoms of PEM are nothing like the symptoms of ischemia-reperfusion injuries. Whereas PEM symptoms are generalized and varied, ischemia-reperfusion injuries tend to produce localized, well-defined symptoms.

For example, ischemia-reperfusion injuries in limbs can produce myalgia and paresthesias, which is something like Delayed-Onset Muscle Soreness (DOMS) with Peripheral Neuropathy (PN). PEM, on the other hand, presents with a profound muscle weakness called paresis. Inflammation markers in limb ischemia-reperfusion injuries would likely be elevated, whereas inflammation markers in PEM are not reliably elevated.

An ischemia-reperfusion injury to the brain would produce stroke-like symptoms, as it is essentially a Transient Ischemic Attack (TIA). Although cognitive exertion can trigger PEM, it is not at all clear how cognitive exertion could possibly produce a TIA.

So really, PEM is nothing like ischemia-reperfusion injuries.

 

[Lolinda]

hi guys, I see (and appreciate a lot) that you are discussing in this thread among others: lack of brain epi/norepinephrine, adrenergic antibodies and PEM. just in case anybody is interested in solutions, for me the following things have worked:

• vitamin D has resolved high adenergic antibodies (I know it sounds too simple but it really did the trick. I tested them repeatedly in the same German lab that Prof Scheibenbogen uses and saw that they were gone when supplementing vitamin D).
• huge amounts of transdermal vitamin b3 (open capsule and smear on skin with a little water, refresh regularly with water) resolved PEM (the effect came only after months into this treatment)
• before b3 I needed B2 because without that I didn't tolerate B3.
• having resolved PEM enabled me to do very slight Wim Hof training (you know that crazy/cool Nederlands guy with the tons of Guinness records for running a marathon on the polar circle and climbing the Mount Everest in shorts and more stuff like that . you find dozens of videos on YouTube). no, I didn't take a test to measure my brain epi/norepinephrin (though I have read some research that paleolithic humans were able to drill open living skulls for medical purposes using a drill constructed of animal teeth, and those who received the drilling even survived ). but from the cold water and breathing exercises he teaches, I did get that feeling of "wow I can do everything" (fast thinking, energetic good mood, mild euphoria). I am curious how that relates to brain epi/norepi, or if it does at all...?

here are some lines on the B3 thing: https://forums.phoenixrising.me/threads/france-me-cfs-in-france.79479/page-2#post-2411084
a post further down in the same thread gives some scientific support as to why this may have worked.

you will find a few threads I started on the Scheibenbogen antibody test panel at the German lab Celltrend. somewhere at the end of one of these I posted the vitamin D thing. if I was an anything respectable scientific patient nerd:), I did post before-after values in my cellrend adrenergic antibody test. you will easily find on Google scholar some scientific papers, that vitamin D helps some patients against some types of autoantibodies. of course nobody tested it against the adrenergic antibodies in a study. so you may interested in my humble N = 1 study

the above is the summary of years of self-experimentation, omitting my many failures ... if there are any questions I'm always happy to help. I do know how it feels to have ME for the simple reason that I had it... :-( and I hope you get rid of it! but I am mostly here only to socialize, so it may happen that a week or a month passes by until I come back. and one day I will come more often in order to get rid of my neuropathic POTS which, yes, obviously involves some mysterious blood flow problems which I don't quite yet understand... and some more mysterious issue why my small fiber neurons probably died which should narrow blood vessels in my legs when I stand up... but they can't do that any more. . and I wonder why I have to guess in this regard: why doctors only do the sweat test to find out if my small fiber neurons producing sweat still work (result: they don't work very well, I stayed mostly dry in spite of huge heat and I can't sweat much. this lack of threat occurs in a parchy fashion which gets worse by distance, that is, the lenght of these neurons). why can't they measure the fitness of the small fiber neurons directly which narrow the blood vessels in the legs??

thanks @Pyrrhus and Violeta for your insightful posts.

 

[sb4]

@Lolinda I remember you posting about those antibodies years ago. I even got tested thanks to those threads but unfortunately the results came back normal. I am glad to hear your experimenting has paid off though.

I have tried various vitamin D treatments without much effect. I was using niacin in relatively high doses in order to try and help my carb tolerance early this year but I noticed that after a few days, around evening time my symptoms would kick up a notch and I would feel very depressed and sickly. I tried stopping and restarting sometime later and the same thing happened.

Perhaps this was something to do with immune activation. Particularly as it started around 4pm, this is when cortisol should be lowering and thus immune system increasing. I recently caught covid (which I'm still getting over) and I noticed in the day time I would feel better but around 3:30pm I would start feeling significantly worse like clockwork.

I am hesitant to retry the B3 as I felt awful but not in a sense of coming down with something, more just increased POTS and depression.

 

[Consul]

Wirth & Scheibenbogen with a follow up experiment on the sodium hypothesis outlined in this paper

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03616-z

 

[Violeta]

Wirth & Scheibenbogen with a follow up experiment on the sodium hypothesis outlined in this paper

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03616-z

Oh my, oh no. Salt.

 

[Consul]

Could reduced sodium dietary intake do anything positive here?

 

[Wishful]

Could reduced sodium dietary intake do anything positive here?

This is ME, so the correct answer is: "Try it yourself and see if it helps you." Whether there is or is not a theoretical basis for it makes no difference, since we don't know what mechanisms affect ME. For that matter, if there is a theory that says that "factor x will affect ME in this way", an individual's response might be opposite, since ME is so poorly understood (not understood at all). When it's an easy, safe, convenient, inexpensive experiment, there's no reason not to try it. Sodium intake doesn't affect my ME, but that doesn't mean that it couldn't affect someone else's.