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Glutathione depletion and disruption of the sleep-wake cycle in ME/CFS

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by richvank, Aug 9, 2011.

  1. richvank

    richvank Senior Member

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    Hi, all.

    As many of you know, I am the proponent of the Glutathione Depletion--Methylation Cycle Block hypothesis for the pathogenesis and pathophysiology of ME/CFS.

    If glutathione depletion coupled with a partial block in the methylation cycle is indeed the core mechanism in the pathophysiology of ME/CFS, then the various abnormalities in ME/CFS must stem from it. In the past, I have been able to find biochemical connections between this basic mechanism and many of the abnormalities in ME/CFS.

    One feature of ME/CFS that I have not yet connected to this mechanism is the disruption in the sleep-wake cycle that many PWMEs experience.

    Recently I came upon a paper that I think will enable me to make this connection. The abstract is below, and the full paper is available from PubMed.

    This paper discusses the presence of a disulfide bridge in the serotonin N-acetyltransferase enzyme molecule. This enzyme catalyzes one of the steps in the conversion of serotonin to melatonin, and this conversion is important in controlling the sleep-wake cycle. Under reducing conditions, the disulfide bridge does not form, and the enzyme can catalyze its reaction. Under oxidizing conditions, when the disulfide bridge forms, the reaction is not catalyzed.

    I suggest that if glutathione becomes depleted in the pineal gland, the resulting oxidizing conditions will cause formation of this disulfide bond, shutting off the conversion of serotonin to melatonin, and disrupting the sleep-wake cycle.

    If this is true, I think we can expect that if glutathione is brought back up by lifting the partial methylation cycle block using one of the methylation treatment protocols, the sleep-wake cycle abnormalities in ME/CFS should be corrected. I note that some people who have tried this type of treatment have indeed reported improvements in sleep.

    Best regards,

    Rich


    J Biol Chem. 2002 Nov 15;277(46):44229-35. Epub 2002 Sep 4.

    An intramolecular disulfide bridge as a catalytic switch for serotonin N-acetyltransferase.

    Tsuboi S, Kotani Y, Ogawa K, Hatanaka T, Yatsushiro S, Otsuka M, Moriyama Y.
    Source

    Department of Biochemistry, Faculty of Pharmaceutical Sciences, Okayama University, Japan.
    Abstract

    Serotonin N-acetyltransferase (EC. 2.3.1.87) (AA-NAT) is a melatonin rhythm-generating enzyme in pineal glands. To establish a melatonin rhythm, AA-NAT activity is precisely regulated through several signaling pathways. Here we show novel regulation of AA-NAT activity, in which an intramolecular disulfide bond may function as a switch for the catalysis. Recombinant AA-NAT activity was irreversibly inhibited by N-ethylmaleimide (NEM) in an acetyl-CoA-protected manner. Oxidized glutathione or dissolved oxygen reversibly inhibited AA-NAT in an acetyl-CoA-protected manner. To identify the cysteine residues responsible for the inhibition, AA-NAT was first oxidized with dissolved oxygen, treated with NEM, reduced with dithiothreitol, and then labeled with [(14)C]NEM. Cys(61) and Cys(177) were specifically labeled in an acetyl-CoA-protected manner. The AA-NAT with the Cys(61) to Ala and Cys(177) to Ala double substitutions (C61A/C177A-AA-NAT) was fully active but did not exhibit sensitivity to either oxidation or NEM, whereas the AA-NATs with only the single substitutions retained about 40% of these sensitivities. An intramolecular disulfide bond between Cys(61) and Cys(177) formed upon oxidation and cleaved upon reduction was identified. Furthermore, C61A/C177A-AA-NAT expressed in COS7 cells was relatively insensitive to H(2)O(2)-evoked oxidative stress, whereas wild-type AA-NAT was strongly inhibited under the same conditions. These results indicate that the formation and cleavage of the disulfide bond between Cys(61) and Cys(177) produce the active and inactive states of AA-NAT. It is possible that intracellular redox conditions regulate AA-NAT activity through switching via an intramolecular disulfide bridge.

    PMID:
    12215431
     
  2. suzanne

    suzanne Senior Member

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    Rich,
    Thanks for the information that the sleep wake cycle may should be corrected by correcting the methylation cycle- and thereforre glutathione levels. It is 3.30 am here in Australia and despite taking melatonin each night this week, i still find it difficult to get to sleep within a 'normal' time frame. I have only been on the methyl b2 protocol for 3 weeks, and a seeing some improvements to my energy but at the sae time some exacerbation to other symptoms like headaches and body itching...I am just hopeful that in titrating up slowly on the methyl b12 as i can tolerate ( all other co factos are in place) that the sleep cycle will some day return. I relise i am probably in what others seem to call start up and that my symptoms of exacerbation are typical- they are just tolerable so i am not going to increase again on methyl B12 until i can tolerate.

    Any thoughts on how long it might take to see the return of a more norml wake sleep cycle? Oh, what bliss that would be.

    regards

    Suzanne
     
  3. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    1-3 grams of l-tryptophan a couple of hours after eating at night can also help although i dont think it has much to do with methylation, it does help with serotonin and melatonin which help sleep. There are some of us with such bad insomnia that we have to rely on medication but if u can sleep with a more natural approach then go for it.

    cheers!!
     
  4. suzanne

    suzanne Senior Member

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    Thanks heapsreal for the suggestion. i am trying to wean off the valium and sleeping tablets, now that my migraines seem to be less than daily. I am trying melatonin but not with much success- my dr has said to try a sublingual melatonin and spray and see if i get a better result. So, I will do that first and if that doesnt work, I'll research the tryptophan and give it a shot. Anything to try and improve sleep- in fact, i has got wose these past few weeks since I started the B12 and methyl folate?
     
  5. richvank

    richvank Senior Member

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    In our clinical study, our first check point was at 3 months. At that time, most of the patients reported significantly better sleep.

    I think the worsening of sleep at the beginning of methylation treatment is due to increased excitotoxicity. Other symptoms of this are anxiety and nervousness or a "wired" feeling. I think this is caused by an initial further drop in glutathione, as more of the homocysteine is converted to methionine, and less is available to supply cysteine for the synthesis of glutathione. As the methylation cycle function improves, this should be corrected automatically. Lately I have been suggesting that taking some liposomal glutathione or perhaps the new acetyl glutathione during the initial part of the treatment may help to correct the excitotoxicity.

    Freddd has pointed out that potassium can become depleted during the early part of methylation treatment, also, as the folate will enable new cells to form rapidly, and they will need potassium, because it is the main ionic substance in cells. So you might consider supplementing some potassium, also.

    Best regards,

    Rich
     
  6. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    sleep could also be worse because your trying to wean off valium, so it could take awhile for natural things to help, also taper off benzos very slowly, i have heard people taking months to slowly wean off.

    good luck,
    cheers!!!
     

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