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New video: Is acetylcholine toxicity the cause of CFS?

Discussion in 'Autonomic, Cardiovascular, and Respiratory' started by Emootje, Apr 18, 2011.

  1. Emootje

    Emootje Senior Member

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  2. Sing

    Sing Senior Member

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    The low blood pressure I have on standing, NMH, which is a very consequential problem in my life--I wonder if this is related to lack of acetylcholine?
     
  3. Emootje

    Emootje Senior Member

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    I think the biggest problem with NMH is the low blood volume and the excess vasodilation.
    Increasing acetylcholine will result in greater sympathetic tone and this sympathetic activation can contribute to hypovolemia and beta receptor mediated vasodilation.
    Beside, acetylcholine stimulates nitric oxide mediated vasodilation.
    If my hypothesis is correct, higher acetylcholine levels will make you worse unless you suffer from a autonomic neuropathy or a sympathetic neurocirculatory failure.
     
  4. Sing

    Sing Senior Member

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    Emootje,

    I don't understand all the terms you used. I do have small fiber neuropathy. I expect I have low blood volume even though I eat lots of salt and I do use compression stockings. When I took Midodrine, which constricts small vessels, the NMH was better, but I suffered too much from coldness and shivering so I stopped that in the fall. I live where it is cold! Then I found out I have the small fiber neuropathy and that this is what is contributing to the numbness, aching, shooting pains and intolerance for most fabrics, etc. Now that it is getting warmer, I think perhaps it would not be wise to take Midodrine again, even though it helped last year--because of the small fiber neuropathy. Maybe those little nerves need whatever blood supply they can get? What I wish is that there were a better treatment for NMH which worked on the brain end of the problem, the lack of signaling to increase BP upon standing!
     
  5. lansbergen

    lansbergen Senior Member

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    Inhibitory role of cholinergic system mediated via ?7 nicotinic acetylcholine recepto

    http://ini.sagepub.com/content/16/1/3.abstract

    Inhibitory role of cholinergic system mediated via ?7 nicotinic acetylcholine receptor in LPS-induced neuro-inflammation

    1. Ethika Tyagi 1. Rahul Agrawal 1. Chandishwar Nath 1. Rakesh Shukla

    1. Division of Pharmacology, Central Drug Research Institute, Lucknow, India

    Abstract

    This study investigated the influence of the cholinergic system on neuro-inflammation using nicotinic and muscarinic receptor agonists and antagonists. Intracerebroventricular (ICV) injection of lipopolysaccharide (LPS, 50 g) was used to induce neuro-inflammation in rats and estimations of pro-inflammatory cytokines, ?7 nicotinic acetylcholine receptor (nAChR) mRNA expression were done in striatum, cerebral cortex, hippocampus and hypothalamus at 24 h after LPS injection. Nicotine (0.2, 0.4 and 0.8 mg/kg, i.p.) or oxotremorine (0.2, 0.4 and 0.8 mg/kg, i.p.) were administered 2 h prior to sacrifice. We found that only nicotine was able to block the proinflammatory cytokines induced by LPS whereas, oxotremorine was found ineffective. Methyllycaconitine (MLA; 1.25, 2.5 and 5 mg/kg, i.p.), an ?7 nAChR antagonist or dihydro-?-erythroidine (DH?E; 1.25, 2.5 and 5 mg/kg, i.p.), an ?4?2 nAChR antagonist, was given 20 min prior to nicotine in LPS-treated rats. Methyllycaconitine antagonized the anti-inflammatory effect of nicotine whereas DH?E showed no effect demonstrating that ?7 nAChR is responsible for attenuation of LPS-induced pro-inflammatory cytokines. This study suggests that the inhibitory role of the central cholinergic system on neuro-inflammation is mediated via ?7 nicotinic acetylcholine receptor and muscarinic receptors are not involved.
     
  6. adreno

    adreno 3% neanderthal

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    Here is the full abstract of the original study that showed prolonged acetylcholine-induced vasodilatation in CFS:

    The authors of the study speculate that the prolonged acetylcholine-induced is due to a viral infection. From the full text:

    Studies have also found autoantibodies against acetylcholine receptors:

    And here it was found to contribute to orthostatic hypotension/intolerance:

    So it looks to me like acetylcholine "toxicity" is involved in CFS, either due to a viral infection or autoimmune antibodies (both?).

    I would like to know if the theory of methylation block in CFS still is valid in this scenario? Doesn't methylation increase acetylcholine levels even further? Not trying to bash anyone; simply looking for a solution.

    My POTS/OI symptoms seem to be exacerbated by cholinergics (or vasodilators), whereas anything increasing pressor response (dopamine, norepinephrine) seems to improve them.
     
  7. richvank

    richvank Senior Member

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    Hi, adreno.

    The situation is complicated because several of the neurotransmitters are depleted in ME/CFS. This results, in my opinion, from the partial block in the methylation cycle, which impacts neurotransmitter production and metabolism at several places. I continue to suspect that acetylcholine is low in ME/CFS, for the reasons I have discussed earlier in this thread. I look forward to better measurements of choline in the brain to settle this issue. I think this is going to happen, based on the progress and funding of Dr. Shungu's group.

    Best regards,

    Rich
     
  8. lansbergen

    lansbergen Senior Member

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    I am with you on this one. An acetylcholine agonist helped me a lot.
     
  9. adreno

    adreno 3% neanderthal

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    Ok, thanks. If there is still a theoretical chance of the methylation protocol working, I'm going to try it. I've already tried lower doses of the protocol (in the order of 0.4mg MTHF and 1-2mg B12) for more than 6 months without seeing much change in symptoms, so now I'm trying Freddd's hyperdosing protocol. So far (after increasing to 0.8mg MTHF and 4mg B12) I'm seeing a worsening of symptoms, that seem to be ameliorated by taking extra potassium. I also dumped the NAC I was taking before. We'll see how it goes; thanks for your great work.
     
  10. Jenny

    Jenny Senior Member

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    That's interesting as there is someone on one of the Lyme message boards who is being helped by fly agaric tincture, which is apparently an acetylcholine agonist and others are starting to try it.

    Jenny
     
  11. Hip

    Hip Senior Member

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    Two types of cholinergic receptor: nicotinic and muscarinic

    Remember that there are two basic types of acetylcholine receptor: the nicotinic acetylcholine receptor, and the muscarinic acetylcholine receptor, so depending on the receptor a cholinergic supplement targets, the effects will be very different.

    These two receptor types are distributed in a particular way in the autonomic nervous system (ANS). The distribution is as follows (you can skip this bit and go straight to the "in summary" below):

    The ANS has two branches, the sympathetic nervous system, and the parasympathetic nervous system.

    Each of these two branches has a preganglionic part (the nerve before it reaches the ganglion "junction box"), and the postganglionic part (the nerve that continues on from the ganglion and runs to the organ that is controlled by that nerve).

    The parasympathetic nervous system uses the neurotransmitter of acetylcholine throughout, but the receptors in the preganglionic part are nicotinic acetylcholine receptors, whereas the receptors in the postganglionic part are muscarinic acetylcholine receptors.

    The sympathetic nervous system uses the neurotransmitter of acetylcholine in its preganglionic part (and like the parasympathetic, has nicotinic acetylcholine receptors in the preganglionic part). However the postganglionic part of the sympathetic (mostly) uses a completely different neurotransmitter: noradrenaline, and it therefore uses a completely different receptor there: the adrenergic receptor.


    In summary: in the ANS, both sympathetic and parasympathetic use nicotinic acetylcholine receptors;

    however, for the most part[SUP][/SUP], it is only the parasympathetic uses muscarinic acetylcholine receptors (so you would target these receptors if you just want to modulate the parasympathetic only);

    and only the sympathetic uses the neurotransmitter noradrenaline and the corresponding adrenergic receptors (so you would target these adrenergic receptors if you just want to modulate the sympathetic).

    (In fact, some small parts of sympathetic also use muscarinic acetylcholine receptors: the postganglionic sympathetic nerves that run to the sweat glands uses muscarinic acetylcholine receptors.)

    Adrenergic, nicotinic acetylcholine, and muscarinic acetylcholine receptors are all found in the brain too.


    The fly agaric mushroom contains muscarine, which activates the muscarinic acetylcholine receptors of the parasympathetic. Though I just read in Wikipedia that muscarine is not the main active component of fly agaric, rather muscimol is and muscimol is potent GABA-A agonist.
     
    Sing and Snow Leopard like this.
  12. Jenny

    Jenny Senior Member

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    He seems to be helped by it.

    http://flyagarictincture.blogspot.com/
     
  13. Sushi

    Sushi Moderator and Senior Member Albuquerque

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    This may explain why norepinephrine reuptake inhibitors helped me so much with OI. The autonomic specialist I was seeing believed that many of us with OI have damage to the postganglionic receptors in the sympathetic system.

    Best,
    Sushi
     
  14. Hip

    Hip Senior Member

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    It may be that autoimmune attack on the adrenergic and/or muscarinic receptors is a major cause of orthostatic intolerance. There was some research that showed lots of CFS patients have autoantibodies to muscarinic receptors. And this new study finds that people with orthostatic hypotension have autoantibodies to both adrenergic and muscarinic receptors.
     
    Sing likes this.
  15. Emootje

    Emootje Senior Member

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    After re-reading this tread, I came to the conclusion that we are not all the same...
    It is necessary to distinguish between the different kinds of dysautonomia groups in ME/CFS.
    I think that there are two main groups in ME/CFS: Sympathetic dominance (with a decreased parasympathetic tone) group and a underactive autonomic nervous system group.
    I guess that most ME/CFS patients have an increased sympathetic tone and a decreased parasympathetic tone.

    Symptoms of sympathetic dominance:
    *Paleness (sympathetic dominance decreases skin blood flow)
    *Gut problems (sympathetic dominance decreases gut blood flow which results in gastroparesis, malabsorption, dysbiosis and leaky gut)
    *Immunosuppression
    *Excessive sweating
    *Anxiety
    *Increased (nor)epinephrine
    *Irritability
    *Exacerbation of symptoms by stress, cold and exercise.

    Therapy:
    *Deep breathing, Meditation, Yoga (decrease sympathetic tone and increases parasympathetic tone)
    *Muscarinic acetylcholine receptor agonist.
    *Beta blockers
    *Alpha 2 agonists
    Therapies that increases acetylcholine will promote the parasympathetic tone (good thing) but also sympathetic tone (bad thing).
    The therapeutic effect will depend on how much each systems is stimulated.

    The second ME/CFS dysautonomia group, the underactive autonomic nervous system group:

    Symptoms underactive parasympathetic nervous system:
    *Urine retention
    *Constipation
    *Decreased salivation

    Therapy:
    *Urecholine
    *Huperzine A
    *Choline, Citicholine, L-Alpha Glycerylphosphorylcholine
    *Cholinesterase inhibitor
    *Alpha Lipoic Acid
    *Acetylcarnitine

    Symptoms underactive sympathetic nervous system:
    *Orthostatic hypotension
    *Decreased sweating

    Therapy:
    *Midodrine
    *Amphetamines
    *Yohimbine

    I guess, it's best to be guided by your symptoms...

    For more information:
    http://www.ndrf.org/NDRFHandbook.htm
     
  16. Hip

    Hip Senior Member

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    Nice theory, Emootje.
     
  17. Sing

    Sing Senior Member

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    Hip or Jenny, any suggestions for where one might get some of this fly agaric mushroom tincture? I think it might be vauable in my system, given the
    symptoms I show. Have either of you, or anyone else here, tried it?

    Thanks,

    Sing
     
  18. Jenny

    Jenny Senior Member

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    Hi Sing

    Here is a blog from the person who has been preparing it and taking it. You can email her via the blog. She sent me some - not sure if she has any more though. I tried 2 drops a day so far - not sure if it's doing anything - one day I didn't feel anything, the next I had a very bad spell of tachycardia, sweating and nausea, but that may have been because I had two glasses of wine as well!

    I'm a bit scared of taking it actually.....

    http://flyagarictincture.blogspot.com/

    Jenny
     
  19. Hip

    Hip Senior Member

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    One thing worth investigating in the cholinergic activities of ME/CFS patients in the fact that 50% of patients have have auto-antibodies to the acetylcholine muscarinic receptors. Reference: here, and also in this following study:


    See also this study of anti-muscarinic autoantibodies in ME/CFS:

    Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome


    Autoantibodies to muscarinic receptors and beta-adrenergic receptors are also found in orthostatic hypotension:

    Autoantibody activation of beta-adrenergic and muscarinic receptors contributes to an "autoimmune" orthostatic hypotension


    And in Sjgren's syndrome (dry mouth), which a lot of ME/CFS patients suffer from, signal transmission in the parasympathetic nerves is inhibited by these muscarinic receptor autoantibodies, and this is the likely reason the saliva glands do not get fully activated:

    Inhibitory effects of muscarinic receptor autoantibodies on parasympathetic neurotransmission in Sjgren's syndrome

    Antimuscarinic antibodies in primary Sjgren's syndrome reversibly inhibit the mechanism of fluid secretion by human submandibular salivary acinar cells

    Inhibitory effects of autoantibodies on the muscarinic receptors in Sjgren's syndrome

    I believe an underactive parasympathetic can also cause circulation problems: cold hand and feet common symptoms in ME/CFS



    So if in Sjgren's syndrome, these anti-muscarinic antibodies inhibit signal transmission in the parasympathetic nerves such that the saliva glands remain under activated, then these anti-muscarinic antibodies in ME/CFS patients will presumably be causing body wide inhibition of the parasympathetic nervous system.

    I believe that the sympathetic/parasympathetic balance has an impact on the Th1/Th2 immune system balance, so a parasympathetic nervous system inhibited by these anti-muscarinic antibodies may shift the immune response away from Th1 and towards Th2, thus impeding viral clearance.

    I would not be surprised if these anti-muscarinic antibodies were deliberately triggered by invading viruses as a means to stop the immune system from attacking them (ie, as an immune evasion tactic).

    So it would seem that for ME/CFS with anti-muscarinic auto-antibodies, it might be a good idea to take supplements that boost the parasympathetic nervous system; or better still, find some medications that can treat this ME/CFS autoimmune condition that targets the muscarinic receptors. Rituximab can treat of autoimmune diseases; perhaps this is the reason rituximab benefits ME/CFS patients: because it helps reduce auto-antibodies to muscarinic receptors.

    Actually, this is probably along the right lines, as it seems rituximab can treat Sjgren's, and its anti-muscarinic auto-antibodies:

    Rituximab treatment in patients with primary Sjgren's syndrome
     
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  20. Emootje

    Emootje Senior Member

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    According to the article below, increased sympathetic tone will suppress Th1 cells, NK cells, macrophages and cytotoxic T cells. So I think you might be right...

    sympathetic immune.JPG

    http://pharmrev.aspetjournals.org/content/52/4/595.full.pdf html

    In my experience, the best way to boost the parasympathetic nervous system is to breath slow and deep.

    The science:
    http://thevirafoundation.org/images/Trauma_Treatment_Breathwork_Part_I.pdf
     

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