1. Patients launch $1.27 million crowdfunding campaign for ME/CFS gut microbiome study.
    Check out the website, Facebook and Twitter. Join in donate and spread the word!
Knitting Equals Pleasure, Despite ME/CFS
Jody Smith loves knitting. Again. She thought her days of knitting and purling were long over but ... she's back ...
Discuss the article on the Forums.

Nitric Oxide, Peroxynitrite, and the Impairment of Mitochondrial Replication in CFS

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Hip, Apr 5, 2011.

  1. Hip

    Hip Senior Member

    Messages:
    3,003
    Likes:
    2,852
    Nice suggestion. I found this page which says: "both taurine and magnesium act as regulatory molecules which can lessen calcium influx into the cells". This is confirmed here.

    I have collected a list of supplements that can help protect against excitotoxicity (excitotoxicity is typically NMDA receptor overstimulation by glutamate, which then leads to too much calcium influx into the cell):

    malate
    pyruvate
    DHA (from fish oil)
    ascorbate
    magnesium
    methylcobalamin
    S-Allylcysteine (from garlic)
    carnitine
    lithium

    So I guess these would also generally help lower calcium influx, directly or indirectly. If anyone knows any others, please post.
  2. Hip

    Hip Senior Member

    Messages:
    3,003
    Likes:
    2,852
    Inducers of Mitochondrial Biogenesis

    Inducers of Mitochondrial Biogenesis

    I have also been collecting information on supplements and drugs that can boost mitochondrial biogenesis:

    Nitric oxide -- potent
    Triiodothyronine (T3) -- potent
    Erythropoietin
    Resveratrol -- Ref: [1]
    Quercetin -- increases brain and muscle mitochondrial biogenesis and exercise tolerance. Ref: [1].
    Pyrroloquinoline quinone (possibly a new vitamin)

    DHEA
    Pyruvate
    Lactate
    Lithium
    Isoflavones (such as genistein and daidzein)
    Calcium

    Pioglitazone (Actos)
    SRT1720 (new drug from Sirtris Pharmaceuticals)
    Estradiol
    Glucocorticoids -- increased occupancy of glucocorticoid receptors is a necessary, but not sufficient, condition to increase mitochondrial biogenesis
    Caffeine
    Hydroxytyrosol (from olive oil, and olive leaf extract). Commercial name: Hidrox
    VEGF (Baicalin increases VEGF expression)

    Caloric restriction (fasting) promotes mitochondrial biogenesis
    Cold exposure
    Hypoxia Ref: [1]
  3. Hip

    Hip Senior Member

    Messages:
    3,003
    Likes:
    2,852
    I did try your full protocol, with all the recommended supplements but not with a superior B12 brand. I have just now ordered some Jarrow Formulas B-12 Methylcobalamin 5000 mcg x 60, and will compare to the B12 methylcobalamin I am currently experimenting with.
  4. Joopiter76

    Joopiter76 Senior Member

    Messages:
    137
    Likes:
    10
    Hi Hip,

    another new inducer of mitochondrial biogenesis is PQQ available from LEF.org I tried it and think it is good, I think I experienced some improvement from PQQ. But most improvement came from the Yasko methylation cycle treatment I think the nucleotides and RNA made a big difference.
    Thyroid problems occur because of peroxynitrite inhibition of T3 and T4 synthesis as well as thyroid synthesis is BH4 dependant which seems to be low in CFS. What I posted on the first page here, is quite from Prof. Palls research. I cant say its a therory because it is all proven the only thing that is the theory is that palls says this is the cause of CFS the pathology is not theory. The dicussion about low nitric oxide is not so useful because high nitric oxide is already proven in CFS as well as brain abnomalities from blood-perfusion abnormalities or abnormalities in glucose use of the brain. Im doing FIR sauna and it is good but if someone wants to try only do 5 minutes at 100F every 2-3 days at the beginning. this raises BH4 so much. And my brain functioning improved a can remember things again and it works faster. Low BH4 is known to lead to brain dysfunction, neurotransmitter dysfunction and so on. A well running methylation cycle will support the BH4 genesis, maybe this is one of the main effects, I dont know, but could be. Pall suggest using low dose BH4 or biopterin. The natural source of biopterin is royal jelly. Dont take if allergic to bees.


    any form of cystein is a NMDA stimulator. I can feel this. I tried a NMDA blocker (dextromethorphan) but felt worse which may be a result of decreased metabolism rather than non blocking of NMDA but I think in my case it comes from the stimulation of Vanilloid receptor which itself stimulates NMDA. Vanilloid receptors are the receptors for hot things in food like chilli or pepper which I cant tolerate at all. Capsaicin (from chilli) is known to cause cough and I have cough all the time although I avoid and hot things. I once saw a list that showed that 58% if PWCs have cough. so.....
    the only things discussed to block vanilloid receptor is guaifenisin (one positive one negative study in FM I think) and red or white ginseng. I will try the last one shortly.....
  5. aprilk1869

    aprilk1869 Senior Member

    Messages:
    294
    Likes:
    57
    Scotland, UK
    I have also been researching NMDA receptors along with glutamate, aspartate and GABA. Here is a list of supplements which appear to be beneficial.

    glycine
    alanine
    zinc
    vitamin E (alpha tocotrienol appears to be the best)
    progesterone
    L-Theanine (Suntheanine is supposed to be best) - converts to GABA in the brain
    Niacinamide - appears to stimulate GABA receptors
    Valerian and gotu kola herbs both stimuate the GAD enzyme which converts glutamate into GABA
    Inositol- enhances serotonin and GABA
    Genistein

    I have also read this, however in order to find out the exact details you need to buy the eBook:-

  6. Hip

    Hip Senior Member

    Messages:
    3,003
    Likes:
    2,852
    In terms of relaxing the neurons, there are two main routes: blocking NMDA receptor activation (since NMDA acts to excite the neuron), and/or stimulating GABA receptors (since GABA acts to relax the neuron).

    (Plus there is a third route, which is lowering levels of the chemicals that activate NMDA, such as glutamate, quinolinic acid, and ammonia. Supplements that reduce brain inflammation can lower glutamate.)

    A lot of anti-anxiety drugs/herbs work by stimulating GABA. The trouble with these, though, is that the GABA receptors build up tolerance, so the effect of the drug gets less with time, and also, for the same reason, you get terrible withdrawal symptoms on discontinuation. Lower doses of GABA stimulating drugs are I understand are OK, but higher doses run into this tolerance/habituation problem.

    This tolerance does not really occur on the NMDA receptor when you block it, so in the long term it may be better to use an NMDA blocker like magnesium, rather than GABA activators like benzodiazepines, even though both act to relax the neuron.

    Though a bit of GABA stimulation is fine. I have got fairly good anti-anxiety and anti-depressant results with inositol power (10 - 15 grams a day), and I often take L-Theanine powder.

    But in trying to avoid excitotoxicity, and reduce anxiety levels due to overestimation of neurons, the main focus should probably be on NMDA blocking (and reducing brain inflammation). The problem is that there are not many supplements that block NMDA, and few drugs that effectively block NMDA, as far as I am aware.

    I have also collected a list of all the NMDA-blockers (antagonists), as follows:

    NMDA blockers (antagonists):

    Magnesium -- potent
    Zinc -- quite potent
    Taurine
    Progesterone
    Agmatine
    L-Huperzine A

    And some more obscure NMDA blockers:

    Amantadine (antiviral drug)
    Riluzole
    Dextromethorphan
    Memantine (Namenda)
    Guaifenesin (possibly?)
    Xenon gas

    Some NMDA blockers with strong side effects and/or neurotoxicities:
    Use of these would be considered very experimental and possibly very dangerous. They are not recommend, just included here for information purposes and completeness.

    Ketamine (anesthetic)
    Nitrous oxide N2O (anesthetic, laughing gas)
    Ibogaine (potent hallucinogen)
  7. Hip

    Hip Senior Member

    Messages:
    3,003
    Likes:
    2,852
    I also tried PQQ (pyrroloquinoline quinone) from LEF. It seems quite expensive at the moment, but no doubt the price will come down as other vitamin manufactures start to sell it. I got the impression PQQ at 40 mg a day eliminates my anhedonia symptoms (though I am not entirely sure), but at this dose level it is expensive.

    I did not realize that far infrared saunas can boost BH4. I have a FIR ceramic heater, which I often use as a type of sauna. I wonder if long, hot baths also raise BH4? A long, hot bath is one of my favorite brain fog alleviating treatments.
  8. Joopiter76

    Joopiter76 Senior Member

    Messages:
    137
    Likes:
    10
    Heres the publication from Pall:
    http://www.ncbi.nlm.nih.gov/pubmed/19581054

    its the FIR that stimulates an enzyme that itself stimulates BH4 synthesis. If you do too much FIR you will get very bad detox reactions possibly including fever and a very increase in flu-like feeling together with cold symptoms. So only do some minutes at 100F. The bad symtoms will occur after some sessions if it was too much but not after the first one.

    Zinc is a NMDA stimulant.
    Glycine can stimulate or inhibit but too much glycine in CFS is not good.

    I think you should delete those agents that make no sense like nitrous oxide which inhibits methionine synthase and steals the B12 through oxidation.

    L-Carnitine is neuroprotective but I dont know its effects on NMDA receptor.
  9. Hip

    Hip Senior Member

    Messages:
    3,003
    Likes:
    2,852
    I have included all the NMDA-receptor inhibitors I found, just for completeness. Well, not all: lead is also a potent NMDA inhibitor, but obviously extremely poisonous.

    I have read a story of people with auto-immune diseases have amazing temporary remission from their symptoms after having nitrous oxide anesthesia at a dentist (see the comments on this page): "Many [with autoimmune diseases] say that the nitrous oxide gives them more relief of pain than almost anything else. It has (only temporarily) improved eyesight, hearing, relieved pain of headaches, joint pain, carpal tunnel pain, other pinched nerve pain, peripheral neuropathy in feet and hands, and the list goes on in these patients".

    So I think N2O is a point of interest, though clearly habitual use of nitrous oxide is probably not going to be a good thing, and is something I would probably steer clear of.


    Ibogaine, the hallucinogenic active principle from the African plant iboga, is interesting in that it has a potential for treating Parkinson's.

    Zinc: from what I have seen, this is an NMDA-receptor inhibitor, but seems to increase AMPA receptor-mediated toxicity (ref: here). Since AMPA activation can contribute to excitotoxicity, I guess this puts a bit of a question mark by zinc.
  10. Hip

    Hip Senior Member

    Messages:
    3,003
    Likes:
    2,852
    I have just been doing some reading on the effects of reverse T3, and it seems that RT3 definitely does directly oppose the functioning and effects of the T3 hormone, and presumably this includes opposing T3's effects on mitochondrial biogenesis. So high RT3 may well inhibit the creation of mitochondria, which is not good.

    High RT3 seems to arise from high cortisol. Cortisol inhibits the conversion of T4 to T3, and instead favors the conversion of T4 to RT3.

    Reverse T3 Syndrome (also called Wilsons Syndrome) does not seem to be fully medically recognized; however, it would appear that high RT3 could conceivably be a factor behind the presumed low mitochondrial biogenesis in CFS.

    You can imagine that if there were already some problems with incorrect nitric oxide levels that cause reduced mitochondrial biogenesis, plus additional problems with high RT3 that also reduces mitochondrial biogenesis, together these may lead to a significant deficit in new mitochondria.

    I wonder just how many people with CFS do have high RT3?

    Some treatment for high reverse T3: http://surviving-cfs.blogspot.com/2010/07/gamma-globulin-injections-t3-for-cfs.html. Here is the relevant text copied from this link:

    "My reverse T3 thyroid levels were sky high (550, where the upper bound of normal is 310), which Doc explained it as my body chronically suppressing itself (reverse T3 increases with normal illness to keep you from over-exerting yourself by making you feel tired etc....we just seem to ignore that sign!). So he started me on T3 (3mg and just now increased to 15 mg because of my cardiac issues). It's supposed to keep the T3 levels slightly elevated so that the body reabsorbs the reverse T3. And so far it's been working! My reverse T3 is now dropped to 310 (upper bound, within range!) but he wants it even lower at 200."

    I also read that treating high RT3 would work well with timed-release T3 medications (which are not yet available), rather than the immediate-release T3 drugs (like Cytomel). If you divide your current T3 dose into six smaller parts, and take them at spaced intervals during the course of the day, this would be equivalent to using a time release T3 formulation.
  11. Freddd

    Freddd Senior Member

    Messages:
    4,543
    Likes:
    905
    Salt Lake City
    Hi Hip

    Ibogaine, the hallucinogenic active principle from the African plant iboga, is interesting in that it has a potential for treating Parkinson's.

    Recent research has shown that those with parkinson's have low CSF cobalamin. Another study shows that it has high CSF MMA, that the mitochondria are malfunctioning and they speculate that the malfuntioning mitochondria over a 20 year period cause the damage that becomes Parkinson's. Malfunctioning mitochondria producing MMA in an environment low in cobalamin appears to indicate low adb12. So the trick appears to be to get into the CNS/CSF enough adb12 and cofactors to allow the proper functioning of mithochondria so they no long produce MMA instead of ATP starting at least 20 years before overt Parkinson's symptoms. Of course it helps if one recognizes all those "nonspecific" "meaningless" symptoms and treats them instead of saying they don't matter.
  12. Joopiter76

    Joopiter76 Senior Member

    Messages:
    137
    Likes:
    10
    N2O is very toxic, this is the reason why there must be a break between operations of about 6 weeks. There are 246 studies showing neurological illness signs after N2O exposure/narcosis there is also at least one report about death after two N2O narcosis within a short time! So please stop to favorite N2O as a possible "treatment".
  13. lizw118

    lizw118 Senior Member

    Messages:
    277
    Likes:
    29
    I have a tendency to get high RT3 so I can only take T3 (cytomel) and not T4 only or T4/T3 combination. I think RT3 is very complicated. Wilson's syndrome is not quite hitting the nail on the head with the treatment, either. I believe he says to go way up on T3, then back down, and that the syndrome is temporary. In my case, as well as others it is not temporary. It seems to be a permanent tendency. I also believe there are many reasons people get RT3 other than high cortisol. Low B12 is actually one of the reasons, according to my own research. I wish there was more literature on RT3, because so much is not known.
  14. Hip

    Hip Senior Member

    Messages:
    3,003
    Likes:
    2,852
    I think N2O neurotoxicity is not so different to ketamine's, yet ketamine has been used in CFS/?bromyalgia (see here). Remember, we are talking about very low doses, not the high doses used to anesthetize a person for an operation.

    However, to address your concerns, I have placed ketamine, N2O and ibogaine under a new heading of "NMDA blockers with strong side effects and/or neurotoxicities".

    It seems that N2O and ketamine are more toxic to older people: The anesthetics nitrous oxide and ketamine are more neurotoxic to old than to young rat brain

    See also:

    A single dose of the drug Ketamine acts like "magic" lifting people out of depression in hours and lasting more than a week, scientists claim.
    Mechanism behind ketamine's rapid antidepressant effect revealed
  15. Freddd

    Freddd Senior Member

    Messages:
    4,543
    Likes:
    905
    Salt Lake City

    Hi HIP,

    Nitrious oxide, N2O is especially dangerous for everybody with CFS/FMS. People with FMS/CFS have been found to have low CSF cobalamin which may mean that we have difficulty getting cobalamin in to out brain. Everybody with CSF/FMS has dozens if not hundreds of b12 deficiency symptoms. Nitrous Oxide (N2O) permanently oxidizes the active forms of b12 in the brain and can cause a b12 deficiency crisis with the brain and CNS shutting down. It may take a large sublingual dose of mb12/adb12 exceeding 50mg sublingually or an injection of mb12 of 10mg to force some into the CSF/CNS by diffusion. When I have N2O for dental work I take a couple of sizable sc injections so that I have a steady input of mb12 during the exposure and for hours after as well as additional injections as soon as I get home and sublinguals for the ride home. Nitrous Oxide caused at least one of my severe deficiency crises. Be very careful. Ketamine doesn't quickly destroy mb12/adb12.
  16. Hip

    Hip Senior Member

    Messages:
    3,003
    Likes:
    2,852
    I take your point.

    This reminds me: Freddd, do you have a view on the hydrogen sulfide CFS hypothesis?

    Since hydrogen sulfide will deplete hydroxocobalamin B12 (and possibly other forms of B12?), and since the high levels of nitric oxide (NO) generated by iNOS activity in CFS will also deplete B12, it looks like that there are at least two drains on the body's B12 levels. So constant supplementation of B12 seems to be needed.

    I was concerned that B12 scavenging NO generated by iNOS would impede the the antiviral effect of NO. NO deactivates a range of viruses and bacteria (ref here). However, this paper indicates that the antiviral effect of NO is not that great (at least as far as coxsackievirus B is concerned), so it is probably not a tragedy if your are scavenging for NO using B12.

    In fact, if you could reduce the output surges of iNOS produced NO by taking B12, by Dave Whitlock's theory, one might speculate that this may help increase mitochondrial biogenesis. Whitlock's theory says that any large outputs of NO (such as via iNOS), performed under the initial conditions of low basal NO, will serve to further lower basal NO levels, in a vicious cycle. This is what he calls the low NO ratchet, which he posits is the basis for regressive autism (he says each further regression in autism is due to a further progression into the low NO ratchet) as well as chronic fatigue syndrome.

    Whitlock believes that the way to escape this low NO ratchet vicious cycle in both CFS and autism, is to increase the basal level of NO. Since the plasma half life of NO is in the order of seconds, the basal level is not determined by any free NO, but by the amount of NO that has bound to blood albumin. It is these plasma levels that he says you need to raise.


    Here Is How Dave Whitlock Describes The "Low NO Ratchet" Vicious Cycle:




    This is one of the most interesting mechanisms I have heard regarding the biochemistry CFS.
  17. Freddd

    Freddd Senior Member

    Messages:
    4,543
    Likes:
    905
    Salt Lake City
    hi Hip,

    Hmmmm. It's going to take some reading. What I will say is that there is some sort of ratcheting effect going into b12/folate deficiency that makes it a difficult trap to escape from. Merely trying to reach the former equilibrium doesn't work at healing the damage and doesn't reestablish the former.
  18. Hip

    Hip Senior Member

    Messages:
    3,003
    Likes:
    2,852
    Whitlock's blog entry Mechanism for mitochondria failure during immune system activation is the best place to start reading about his low NO ratchet theory of CFS and autism.

    What I find interesting about this low NO ratchet theory, as that it provides a complete biochemical system of understanding of CFS and autism. That is not to say the theory is right; that remains to be seen; but it is an all-ecompassing theory whose starting premise is that CFS and autism are caused by mitochondrial failure.

    The theory then goes on to say that this mitochondrial failure is actually caused by poor replacement and renewal of old mitochondria in our cells (ie, insufficient mitochondrial biogenesis), rather than it being a mitochondrial problem per se.

    Whitlock's theory then focuses on the mechanism behind this insufficient mitochondrial biogenesis: namely, (in Whitlock's view) the low basal levels of nitric oxide existing at the same time as high nitric oxide output from the immune system (from iNOS), and how this combination of circumstances forces basal NO levels to get lower and lower, by the "ratchet" system he describes.

    Since NO levels control the rate of mitochondrial biogenesis, as the basal NO level get lower and lower, mitochondrial replacement and renewal gets correspondingly less and less, so that you end up with a load of old, leaking, inefficient mitochondria in your cells, that are not replaced as they should be by new mitochondria.

    These old mitochondria not only don't produce enough energy, they also create a lot of superoxide and hydrogen peroxide, which then cause even more damage and problems in our cells.

    Whitlock then goes further and proposes three ways to raise your basal NO levels, which he thinks will then return your mitochondrial biogenesis back to normal, or at least improve it, and thereby improve your CFS and autism symptoms:

    The first way to raise your basal NO levels is by including more nitrates into your diet (nitrates are found in green leafy vegetables, and in high amounts in beetroot juice).

    The second way is via meditation, which is known to increase nitric oxide levels.

    The third and probably most powerful way is,... well, I shall let you discover that yourself - it is unusual to say the least.
  19. Freddd

    Freddd Senior Member

    Messages:
    4,543
    Likes:
    905
    Salt Lake City
    Hi Hip,

    The second way is via mediation, which is known to increase nitric oxide levels.

    Mediation doesn't seem like the right word. Are you sure you don't mean meditation?


    The third and probably most powerful way is,... well, I shall let you discover that yourself - it is unusual to at the least.

    And I can't help but think that you have left a word out.

    My only half facetious suggestion was Viagra assisted exercise. My more serious suggestion would be extended tantric feast, meditative massage and ecstatic practice. That can be very healing and changes the biochemistry for some days following.


    Since writing the above I have read the one article. So there is "meditation", consumption of nitrate (makes the Viagra and Ciallis alternative sound interesting) and bacteria films through not bathing. Hmmm. I like the tantric practices alternative, complete with ritual bathing, better. That includes consumption of b12, carnitine, omega3 oils, other nutrients, possibly some nitrates, meditation and ecstacy.

    Now an interesting thing mentioned is the immune system stress of vaccines which I have also mentioned as being a trigger for the plunge into deficiency. He also mentions the upregulation of ATP production in fewer mitochondria, which I have suggested needs to be reset and down regulated after the b12 is taken thus making the participation and formation of new mitochondria possible. It is very interesting to read all these things that I have talked about from the NO viewpoint affecting the mitochondria as opposed to adb12 lack. In other reading concerning fast twitch and slow twitch muscles it was mentioned that mitochondria can be casued to form in the slow twitch muscles via aerobic exercise, assuming that adb12 is present to occupy it. I demonstrated that to myself in my own rehabilitation efforts. The overlap in description and effects is amazing. The one thing in his description that is unspoken is the assumption of adequate b12, that is never questioned in what I read. Without the adb12 things could not unfold in the way he suggests. I think that yet again a result of low adb12 is being described as causal.
  20. Hip

    Hip Senior Member

    Messages:
    3,003
    Likes:
    2,852
    Yes, I meant to type meditation, not mediation.

    Whitlock mentions Viagra, but he also makes the point that if Viagra was a cure or an amelioration for CFS, we would no doubt know it by know, as someone would have reported it.

    There is an interesting nitric oxide page on Jan Dixon's website "Biology of Kundalini", that looks at the spiritual connections of nitric oxide.

    It may well be that there are quite a few esoteric practices that raise nitric oxide levels. I know that acupuncture has an effect on NO.

    I just found this stuff:

    A study done by Jon Lundberg and Eddie Weitzberg of the Karolinska Institute in Sweden has shown that the daily humming or "Om" chanting may actually prevent infections from taking hold. They found that humming increased nitric oxide levels fifteenfold, compared to quiet exhalations without sound. The exhalations of people with healthy sinuses tend to have high nitric oxide levels, indicating that more air is able to flow between the sinuses and the nose. Ref: Scientific Basis For Some Yoga Practices In Sinusitis

See more popular forum discussions.

Share This Page