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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. tealady

    tealady

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    Its been many years since I looked at HC.. but I just googled and found a bit I looked it and I'll copy it here
    "Ved HS, et al.
    > > http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=2473427&dopt=Abstract
    > > Effect of hydrocortisone on myelin basic protein in developing primary brain cultures.
    > > Neurosci Lett. 1989 Apr 24;99(1-2):203-7.
    > > [PubMed - indexed for MEDLINE]
    > > PMID: 2473427; UI: 89314566.
    > > Effect of hydrocortisone on myelin basic protein in developing primary brain cultures.
    > > Ved HS, Gustow E, Pieringer RA
    > > Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140.
    > > The hormones hydrocortisone (HC) and triiodothyronine (T3) are known to regulate myelinogenic parameters in cultures of brain cells. However, the effect of glucocorticoids on the myelin-specific metabolite, myelin basic protein, has not been previously studied. In the present studies we show that the concentrations of myelin basic protein (MBP) in developing primary cultures from mouse cerebra are significantly higher in HC (0.3 microM)-treated as compared to untreated cultures after 15 days in vitro. Further, this effect of HC on MBP appears to be T3-dependent. Since HC stimulates oligodendroglia to produce MBP, the effect of HC on the activities of the enzymes, glutamine synthetase which is primarily associated with astrocytes, and acetylcholinesterase, which is primarily associated with neurons was was determined. HC stimulated both enzymes, suggesting that all 3 cell types may be regulated by HC."

    I THINK from memory you'll find (but check it with google) that acetylcholinesterase breaks down T3 (thyroid hormones)..or does something to it!
    This study is just one that shows how HC works WITh T3 and regulates T3 (or helps in its use ..that's actually what it does feel like speaking from self experience), In utilising the T3 the T3 gets used up...as expected? This is entirely different in feeling to not having the cortisol and not having the T3. The T3, I assume is converted to T2 etc..
    At least back many years ago when I looked there was not much RT3 studied...couldnt even get ranges in Oz of it and I found it diffuclt to get tested!

    I've always thought a simplified view of T3 and RT3 in the body like a car with an accelerator (T3)and a brake (RT3)- really you DO need both in a car, and you do need both in our body. Nothing wrong with a brake in a car and nothing wrong with RT3 in our body either! Yes RT3 is like an inhibitor of T3 (it seems folk here understand inhibitors and binding) as they "bind"probably in similar places and the Rt3 would prevent the T3 from working...but hey that's precisely what our bodies need MOST of the time this happens. I'm not saying that the brake can't get jammed sometimes or in a bind and need unsticking or a bit of help due to toxicities in the body or something going wrong... just usually we do nned both and usually its just fine and what you need!
    Rt3 will increase when the body needs to slow down..as in illness so the body can rest and repair, its what it was designed to do..or at least that's my understanding. I'd expect(but have no idea other than a tealady-hypothesis) RT3 to increase therefore when there is some danger if the body metabolism runs at too fast a speed for the substrates it has...like say if cobalamin was in short supply, or folate or both, or iron(ferritin). The RT3 may increase as a self defense mechanism until the substrates can be found..rather than depleting them even more to dangerous levels. (please read free RT3 and free T3 where I typed T3 and RT3. )
    So if your low on B12, you'd kinda expect RT3 is to highish..at least that's my hypothesis :)
    I think its a known that RT3 is high in starvation(to slow doen and conserve fuel I'd expect) , but check it as my memory is not great! (that would fit with trying to slow the body down until it gets enough food).

    edited to add: That view is simpified to the point of being incorrect, but better than what is around the web usually I think. However IF you want to understand more and have an interest and time, try reading this paper
    http://ro.uow.edu.au/cgi/viewconten...oidhormone, is sometimes more potent than T3"
    There's references to papers where RT3 is more potent in some sitiuations that T3, and some of the known (at that time, year 2000) breakdowns of T4..including T4.

    Then there's a great paper of the differing deiodinases,
    http://findarticles.com/p/articles/mi_m0FDN/is_4_5/ai_65068470/?tag=content;col1
    over 30 pages if you want to read it! Its written in 2000, so much has been discovered since (google on thryoid hormone deiodinases)... theres all the is it conjugates of thryoid hormones also..like sulfonation, nitration, hydroxylation, the thryoid amine etc ..which speed or slow down , change function etc Its a huge , mostly unknown ..and not able to be fully understood by me in my lifetime stuff, so just looking at RT3 and T3 is really over-simplistic to be meaningful , but I guess a start?
    Here's some other abstracts ..just to get an idea
    http://www.ncbi.nlm.nih.gov/pubmed/20051527

    Maybe its best looked at like temperature. We get a fever in RESPONSE toi something. Its a life saving mechanism to aid our bodies, but sometimes we need to step in and reduce it. I look at RT3 the same way maybe and cortisol (both I thiink) could be viewed as coping responses to something going on. Yes we all have some Rt3 , we are supposed to have, and we all have a temperature as well. Its the level, and its a response.
    end of edit.

    Also growth hormone increases T3...and exercise (especially when fasting,say in the morning before you eat breakfast increases growth hormone), so one fairly easy way I'd hazard a guess of increasing T3 to RT3 ratio is to start exercising for a couple of hours each morning?..safe way too. (i think there are studies on that..or some people starting to think that way)
    It's what humans used to do before the modern time..get up hunt/gather/milk the cows, farm etc ..then cook breakfast (after separating the milk/cream, baking the bread, fetching the egges etc). Not get up and eat straight away. People who get up and say go for a run or row etc in the morning usually stay lean and have high growth hormone, and probably don't have a high Rt3 unless there is something wrong with them like an illness...
    just a thought, and something I think may be starting to catch on.
    eating many times a day I suspect increases RT3, I think we are not really designed to do this if ou look at the native communities. Feasting occasionally was more the norm.
    The growth hormone /T3 is in a study somewhere- the rest is just observation I've made over the years and guesswork, I could be wrong but its my personal belief.
    http://thyroid-insulin.blog.co.uk/2006/08/30/growth_hormone_stimulates_conversion_of_~1081430/
    link chosen as is on folate, homocysteine, growth hormone etc...

    Hope this helps- my thoughts higher levels of cortisol , and higher RT3 is are coping reactions, usually just what we need , but they may imply something is stressing us in some way

    Adding a SR T3 would be expected help the T3: RT3 ratio and may sometimes be of benefit (but its something like a last resort really), although I have myself personaly done it- out of desperation I guess:) (scrip from a german trained GP...they study metabolism more over there than in Oz I think). As above shows there are other things to trial first that will change the ratio. Hopefully stepping down now...:)
     
  2. tealady

    tealady

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    http://forums.phoenixrising.me/show...ent-of-Mitochondrial-Replication-in-CFS/page7 my post no 61 may give you a start on the literature
     
  3. tealady

    tealady

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    Time release (slow release) with Methocel e4M
    http://www.dr-bob.org/cgi-bin/pb/mget.pl?post=/babble/20030828/msgs/255832.html 3rd post down re time released at a compounding pharmacy
    (sugars like lactose increase speed of release, carbs like rice flour release speed slower, all mthocel usually too slow ie not all released by time passed thru for many).

    also in that thread note thehomocysteine - thyroid connection suspected. The sulfur -methione- homocysteine b12/folate etc
    when you get the homocysteine lowered and working better, from this , then you should convert the T4 to T3 better. perhaps?
    I do know that people who have tended towards hypothyroid side for many years(decades usually seem to do better on a higher T3 ratio in meds when they start and as their body recovers they usually need less T3 in their meds. that's the case with me. Maybe the homocysteine connection, or maybe something else. Too complicated to say for sure! I do know my selenium had no problems and made no difference. So perhaps getting the homocysteine/B12/folate corrected the thryoid may cope with less T3 directly. T4 is definitely needed, but for some people may be supplied by their own thyroid. Uor thyroids supply T4 AND T3 , but its released mostly bound to proteins, very little as "free"hormones- I have no idea what happens to the meds and how much they get bound as we digest them! I suspect a lot more "free"hits the bloodstream, but I've no idea. We definitely need BOTH T4 and T3 and use both and all our organs cant be "normalised"without having both, as has been "proved"'in research on animals where they have actuallu ciut them up and examined the organs! There maybe other ways that T3 can be iodinated and become T4?? if there is anyone wihout a thyroid who takes T3 only meds? although I don't know of anyone who has done this without any thryoid, but its not all known- try reading some of the links I provided if interested, its complicated.
    Thyroid hormones are stored in cell membranes of every cell in our body for starters!! They act like cholesterol to "stiffen"the cell membranes.

    This si getting a bit offtopic of B12 though, so I'll stop now.
     
  4. Freddd

    Freddd Senior Member

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    I think maybe brewers yeast is OK?

    I had the same paradoxical folate deficiency from food extract folate as folic and folinic acids. I have no idea how it might affect you. There are an awful lot of unknowns currently.

    I'm waiting for the Metafolin to be available (hopefully) on herb again

    I would expect it to be as it appears, a simple "out of stock" situation. Solgar is a licensed brand from Merck and costs half the price of Folapro yet both sell identical Metafolin.
     
  5. tealady

    tealady

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    I threw out my 5-MTHFR folate AND the folinic acid tablets. Here's why.
    http://tealady-health.blog.co.uk/20...-mthfr-and-folinic-may-be-dangerous-11203372/

    My blood test results after about 6 of the 5-MTHFR tablets over 2 mths showed RBC folate had risen from the above range 1250 to 1280 ish (molar units) to over 1900 (molar units).
    My B12 with the methylcobalmin sublinguals and hydroxocobalamin injections (every 2 mths or so) was 590 (molar units)(fimne I was aiming for 500-600(before supps was 345.(molar units)

    My liver function tests showed elevated liver enzymes for Gamma Gt and ALP, and my previous blood tests shows low e-GFR, so kiver and kidneys may be possibily be affected, although that could be anything . The RBC folate has never been over 1300 before., so I'm avoiding even multBs with folic acid in it.
    Hope any of that wrong type of M5-MTHFR leaves my liver soon, if that is contributing at all I have no idea why my liver function test reults showed eslightly elevated ALP and Gamma GT. I was feeling very anxious at the time and unable to sleep, and my breath really stank and taste in mouth bad I have no idea if related to folate or not..proably not, but I wanted to check ?

    Has anyone else got raised ALP and Gamma GT after taking 5-MTHFR or folinic acid (the racemic kind, not the Metafolin which ONLy has the 6S kind?) or a lowered e-GFR (foltration rate for kidneys?)
    Jan
     
  6. tealady

    tealady

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    An order from iherb with Metafolin(l-5-mthf) arrived yesterday. my blood RBC- folate level is always high(1900molar units last test, usually with no supps over 1250), but when Iwoke up as usual about 4am and thought I'd trial a little of the Metafolin. I took just 1/8th tablet (100mcg of l-5-mthf) and slept soundly (no dreams that I know of) and awake witha slpitting headache which lifted on taking an aspirin, but wiped..been wiped all day? Any ideas? is this normal on starting?

    background, as previous posts, I'd taken hydroxocobalamin and methycobalamin and andenosylcobalamin and some limitedf olfic acid in multis(which I'd stopped a couple of weeks ago), some folic acid (limited hopefulloy added to bread-about one slice a day),but I'm still concerned about the precious taking of thorne research 5mg 5-MTHF (racemic). That's all I've taken. I never tried the folinic I had at home (my husband did though).
    I did add in some lecithin granules and some DHEA(15 only) with a compounded multi with no folic acid and the tingling and some anxiety seemed to almost resolve(much improved, although I can't say for sure what it was..
    If anyone if interested my concern on racemic 5-MTHF is on here in previous posts and also (for ease of finding)
    concerns on racemic here, my concerns re folic acid in foods here

    Mostly wanting to know about the headache, my head is still not right. Is this normal on starting Metafolin?

    edited to add:
    I recall being fed phenergan-(if my memory is correct-I do recall these little light blue pills I used to be given presumably not at a few days old!t!) as a baby (from almost birth) as I was snuffly and couldnt feed easily...and my Mum is the kind to give a pill from the doc without question (still is). I was given these presumably until I was old enough not to rrequire bottle feeding. Mum went to a Karitane home to try to breast feed me when I was born, but for some reason I couldnt feed, and she told me I had to be given phenergan I think, so I wouldnt be so snuffly and could breathe to feed??.. so histamine high then? I also had hives as a child about 11 or so. Other than that I dont take antihistamines, but I always have a stream of phelgm like stuff down the back of my nose/throat(so does my Dad and his dad before him)-unsure if that has top do with histamine...actually unsure about anything to do with histamine.
    Also-similar to my Mum, I always have high red blood cell folate on blood tests without any supps(above normal range), and low normal B12 (around 350nmol/L) without supps (same as my Mum. My Mum now has brain shrinkage and dementia, and also has difficulty taking B12 injections - same hands/feet reaction(red/bluish and tingling)., headache and wiped. I have read in several studies that there is a subgroup of women who have high folate levels and B12 in bottom third or so of range,who are in danger of dementia and the highiosh folate seems to increase the risk. Some studies find this group and conveniently ignore it as an anominaly, others have commented- I and my Mum fit this group, its hereditary, (her grandnmother died of dementia...and she seems to be going the same way).
     
  7. Freddd

    Freddd Senior Member

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    Hi Tealady,

    Taking Metafolin could have kick-started cell formation and caused a sudden drop of potassium. That is a good indicator that DNA transactions (a major methylation activity) have started up.

    Sounds like your mother needs to get methylb12 and adenosylb12 into her CNS. Dementia is a common b12 deficiency symptom. All sorts of things can go wrong with specifically low adb12 and/or specifically low methylb12 in the CNS/CSF. Low CNS/CSF is a probably hereditary marker in CFS, FMS, Parkinson's, MS, Alzheimer's and other neurological diseases. It is estimated by some researchers that nearly 50% of dementia diagnosed as Alzheimer's dementia is actually b12 deficiency dementia. This of course is one of the "functional" b12 deficiency symptoms that Rich likes to mention. These hundreds of "functional" symptoms can cause damage and death. It takes generally larger doses of mb12/adb12 to penetrate thje CNS in situations where CNS/CSF levels are low despite "normal" or "high" blood serum levels. It takes even more to correct neurological damge to some degree. Methylb12 is said to have neurological healing characteristics massively superior to all other forms of cobalamin by those researching it.
     
  8. Wayne

    Wayne Senior Member

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    Hi Hip, I was just perusing your profile, and noticed you take 15 ml of flaxseed oil daily. Since I just found out I'm extremely hypothyroid, I've been doing a fair amount of research on it. One thing I ran across was a fairly dramatic reference to flax seed being able to create hypothyroidism. A woman wrote about having a normal TSH reading, had it go up to 25, and after discovering flax can cause this, eliminated it from her diet. She did nothing else, and soon her hypothryoidism symptoms went away, and a followup TSH test was normal. -- Just thought I'd pass that along.
     
  9. Hip

    Hip Senior Member

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    Thanks very much for pointing that out, Wayne, I did not know flaxseed oil could affect the thyroid gland. It seems that flaxseed oil contains cyanogen and goitrogens, which can reduce iodine take up. I had a thyroid hormone test not so long ago, so I know I am fine, but I will look into this potential danger of flaxseed oil further.
     
  10. Wayne

    Wayne Senior Member

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    Hi Hip,

    Perhaps one thing to consider is that some people don't have the ability to convert omega-3 fatty acids of plant origin into DHA and EPA, which are essential for brain function, immunological function, and more. This is why fish based oils are often recommended over plant-based ones. I wonder if people who can't do this kind of conversion are the ones whose thyroid glands are affected. In which case, it might not be the flax that is directly inhibitory of thyroid function, but an individual's unique makeup that is more responsible.

    I recall an incident a few years ago where a miner in West Virginia was trapped in a mine, and eventually went into a coma from carbon monoxide poisoning. His case looked very bad, but they apparently infused extremely high doses of DHA/EPA into his system, and were almost shocked that he came out of his coma, and demonstrated remarkable brain function besides. It was viewed as a miracle at the time.

    My own doctor has recommended I take 4 tsp (20 ml) of cod liver oil daily, and so far I've noticed a bit of calming in my body. I have to say however that I've been doing other things as well, so the correllation is not necessarily definitive. But after remembering the above incident, I've decided to increase my DHA/EPA intake even more in the coming weeks. Heaven knows I need lots of support for my brain, neurological system, immune system, etc.
     
  11. Lotus97

    Lotus97 Senior Member

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    Cruciferous vegetables also have goitrogens, but couldn't you just take extra iodine or take it at separate times of the day?
     
  12. Jarod

    Jarod Senior Member

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    Wayne

    I find I need fish oil. Lecithin granules work really good too. If I don't take any for a day, my hair gets really dry.

    I read somewhere that one can get too much vitamin "A" from cod liver oil. Might be something to check out.
     
    Wayne likes this.
  13. Lotus97

    Lotus97 Senior Member

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    Retinol, the type of vitamin A in cod liver oil and certain supplements can block vitamin D, but natural occurring vitamin A in the form of beta carotene seems to be ok. I think some supplements have synthetic beta carotene which might not be the same, but I'm not sure.
    http://articles.mercola.com/sites/a...pplement-vitamin-d-will-not-work-as-well.aspx
     
    Jarod likes this.
  14. Freddd

    Freddd Senior Member

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    I am going to comment on the original posting for this thread

    Dave Whitlock has an interesting theory that autism and CFS are underpinned by low nitric oxide in the brain. He thinks that low brain nitric oxide causes the behavioral changes found in autism, and to an extent, in CFS too.

    In addition, apparently, ambient nitric oxide levels control the rate of mitochondrial biogenesis - the producing of new mitochondria and replacement and removal of the older mitochondria in cells. Whitlock says that mitochondria in cells have a normal lifespan of a few months, and they get regularly replaced because they wear out pretty quickly.

    When mitochondria wear out, they become leaky (leaking out protons, which then lead to more reactive oxygen species being produced in the cell) and much less efficient. So there needs to be a constant process of creating new mitochondrial, and replacement and removal of the older ones in the cell (otherwise cellular production is impaired, and the amount of damaging reactive oxygen species being created in the cell goes up).

    Whitlock thinks that the supposed mitochondrial problems in CFS / autism come from a lowered rate of turnover of mitochondria, simply due (according to Whitlock) to levels of nitric oxide being low (since the nitric oxide level sets the mitochondrial turnover rate). This lowered turnover means that we are not replacing the old and leaky mitochondria.

    In others words, people with CFS / autism may be going around with damaged mitochondria, because their mitochondria are not getting renewed, due to low nitric oxide.
    Just recently I finally wrote it out so it stuck in my mind when I re-investigatged this. I was estimating the tissue halflife of AdoCbl. What had puzzled me was that approximately 1% daily loss, about 71 days or so tissue halflife makes terrible sense as loss of muscle cells. It makes great sense as mitochondrial halflife. "Whitlock says that mitochondria in cells have a normal lifespan of a few months, and they get regularly replaced because they wear out pretty quickly. ... Whitlock thinks that the supposed mitochondrial problems in CFS / autism come from a lowered rate of turnover of mitochondria,"
    I would agree quite thoroughly. What it took for me to me able to replace mitochondria at more suitable rate and allow my muscles to grow again was MeCbl, AdoCbl, L-methylfolate and L-carnitine fumarate, in the right balance and all other necessary factors. It was very noticable when the mitochondria started forming much more quickly. Then it was equally noticable when my muscles started growing. It also required exercise for each of these to occur. However, when these mito get going at full blast arobic capacity increases quickly.

    http://forums.phoenixrising.me/index.php?threads/the-stages-of-methylation-and-healing.21725/

    See the stages of healing.
     
  15. dbkita

    dbkita Senior Member

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    I find this interesting. http://circ.ahajournals.org/content/91/1/248.full

    Note that BH4 is needed to make NO otherwise H2O2 is made.

    However, we also know adb12 works with BH4 to reduce peroxynitrites from the "Gorilla in the Room" article.

    So maybe we see a connection here with low tetrahydrobiopterin which is also a critical cofactor for dopamine and serotonin production, not to mention removal of ammonia in the periphery.

    So my question is do we know how the methylation cycle affects BH4? I think some studies show recycling from BH2 to BH4 by folic acid, but I suspect actual natural folate forms are more relevant since folic acid has not existed for that long in human history. But I am intrigued also if methylfolate also affects actual production. There could be a important connection between methylation -> BH4 -> NO synthesis & peroxynitrite removal.
     
  16. Freddd

    Freddd Senior Member

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    Hi Dbkita,

    In the people with the anxiety marker we maight call it, when LCF is started a tiny tiny bit sure does affect dopamin, at least after the cobalamin and folate os there. One person had no effect at all from a capsule of LCF. A week later the person added the Adocbl, MeCbl and l-methylfolate. Later was then when everything went overboard when ATP startupt in the limbic sytsems started affecting the dopamine related symptoms started up at <1mg.

    NO synthases belong to large family of closely related enzymes that utilize a number of cofactors, including BH4, for production of NO from l-arginine. In the absence of BH4, NO synthases no longer produce NO but can catalyze reactions leading to the production of hydrogen peroxide (H2O2). In certain blood vessels, H2O2 mediates relaxation, and this may compensate for the loss of NO production due to the absence of BH4

    A study I read maybe a year ago had increased H2O2 production linked to hair turning gray or white. Premature gray or white hair is a symptom of b12 deficiency according to at least some reading I have done and some countries' lists.
     
  17. dbkita

    dbkita Senior Member

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    Understood. I still don't see the biochemical pathway for how methylation increases BH4. It seems for sure that it does but it is not clear if it is merely improving recycling or also increasing production or even neutralizing things which steal from BH4. The dopamine increase is a likely "biomarker" of this net effect. But then again VDR binding at the Taq domain increases dopamine as well.

    Still it is probably reasonable to assume that provided a person has iron, is not COMT -/-, and has some ATP, that the main reason dopamine increases with the deadlock quartet is in fact effective boost of BH4. But again if this is true we should also see a boost with serotonin. Again though ... how?

    I am also tying this in to the NO and peroxynitrite theories discussed in this and other threads. Martin Pall suggests the peroxynitrite link to CFS. Fine. We know now that adb12 with BH4 are the primary pathway to reducing that by virtue of the Gorilla article and hb12 is a poor secondary. But as has been discussed, CNS low levels of NO may be a problem too. Well now BH4 is a necessary catalyst by the article I linked and the paragraph you pasted. I think we can agree also that excessive H202 is damaging.

    So the real question is how does methylation (not simply methylfolate for instance) stimulate or help bolster BH4. For some of us with A1298C mutations that could be a big thing to try to understand.
     
  18. Freddd

    Freddd Senior Member

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    Hi Dbkita,

    Questions Questions Questions! Whatever it takes to get our "wee grey cells working"


    But again if this is true we should also see a boost with serotonin. Again though ... how?

    I had been depressed most all my life. I have been in folate insufficiency most all my life. It wasn't a psychological depression. On the grading scales for depression I didn't come out depressed. It was a feeling, not a thinking. So my remark to the psycholgist doing an assessment with a particular scale was that it didn't have the range to fit me in because the least depressed answers were all more psychologically depressed than I had ever been. When I took the MMPI (II?) normed on chronic pain patients I was thoroughly normal

    Tri-cyclics didn't work, terrible side effect. SSRIs didn't work, no effect of note. St John's wort gave me a boost similar to a mug of coffee. It was the best of the bunch and I took it for 15 years or more until MeCbl. After that it had no effect.


    has some ATP,

    How much is enough? Where it is made may be very important. That is one thing that has surprised me in all this, how local these insufficiencies can be. The body's triage system has always been talked about in b12/folate iterature wondering how/why different rtissues would be blocked an others not. Finding out that neurons made ATP via AdoCbl etc was a complete surprise for Rich. He, as I had up until I felt the difference of CNS penetrating dose of AdoCbl, thought about the brain in terms of glucose metabolism , as decades of reference material had said. I had an 8 year headstart so I have been thinking about this differently for 8 years. So finding that the osteoblasts also made their own ATP it become obvious that lack of LCF/AdoCbl would hinder mitochondria formation and hence prevent cell formation and bone strenghtening. Different foundational understandings lead to different hypotheses.

    If one doesn't think there are mitochondria in neurons, a hypothesis that says 20 years of malfunctioning neuronal mitochondria can cause damage leading to Parkinson's isn't believable if one can't accept neuronal mitochondria.
     
  19. LaurieL

    LaurieL Senior Member

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    This is exactly why I believe I need so much adB12.

    Since you don't specifically name "the anxiety marker", I am going to assume you are referring to MAO-A. But I think where the effects of LCF come in are in those not only with the MAO-A marker, but those also with ACAT mutations. Having both of these would compound the magnitude of the problems there of.

    This theory is illuminating, but let us keep in mind, that although CFS/ME has many pathways and biochemical/physiological similarities to Autism/ASD, they are not the same identity. It is an avenue to pursue further....but

    Whitlock in his own personal investigations has found decreased levels of NO, but in the CFS/ME arena, are they not finding the opposite? He also stated he is using rather strange and unusual techniques to raise his NO levels, but fails to expound on other current practices in which could affect the downstream effects of raising NO, such as ROS, H202, increases in calcium ion flux, NMDA receptor activation, high glutamate levels, and lipid peroxidation.

    I find Pall's work more provactive.

    What I find interesting about this whole exchange, is the lack of the one unifying pathway to everything that has been discussed thus far, as well as lack of one very potent neurotoxin produced from that pathway resulting in microglia activation.

    Its the Janus Face of the Kynurenine Pathway and its production of QUIN.

    The kynurenine pathway is the major route for tryptophan breakdown and one of these products is quinolinic acid. QUIN is not just for Lyme disease and is involved in a number of inflammatory neurological diseases.

    The predominant pathway of ONOO is the rxn of ONOO- with CO2. The product, nitroperoxycarbonate or ONOOCO2 then forms one of two free radicals. Either a caged free radical of carbonate and nitrogen dioxide, or these caged radicals can escape the caged pairing and can become free radicals onto their own. It is these free radicals associated with peroxynitrate and cell damage. It is also connected to the caspase activation of the mitochondria initiating apoptosis. There by damaging/destroying the mitochondria.

    NO induces IDO or Indoleamine oxidase which induces the Kynurenine pathway. From there, it can go one of three ways, with one being production of QUIN. With the production of QUIN and the addition of NO and/or peroxynitrite which contributes to QUIN directly, neurotoxicity occurs. Add the free radicals of ONOO and QUIN, which are synergistic, and you have one hell of a neurotoxic situation on hand.

    NO and ONOO= QUIN toxicity

    Lets look at some of the sources for known ROS/RNS production. Those being the mitochondrial electron transport cahin, NAD(P)H oxidase, Xanthine oxidase, Cytochrome P450's, Lipooxygenase, Cyclooxygenase, eNOS, and iNOS. Combine those with induction of the Kyn pathway, and I think you will find some startling revelations concerning CFS/ME.

    QUIN is an NMDA receptor agonist causing the inhibition of glutamate uptake in the synapse, which then leads to neurotoxicity through excessive glutamate in the micro-environment(glutamate toxicity) in the acute phase. QUIN can potentiate its own toxicity and that of other neuro-excito-toxins in the context of energy depletion. Mitochondrial or microglial. It is also induced by macrophages.

    AB (amyloid protein): Its production correlates not with cholesterol levels but with intracellular cholesterol ester levels or ACAT. ACAT (Acyl-coenzyme A:cholesterol acyltransferase) catalyzes the formation of cholesterol esters and modulates the generation of AB. ACAT controls the equilibrium between free cholesterol and cholesterol esters in the cell membrane.
    ........Rudzite, et al., reportss a correlation between KP metabolites and cholesterol content in the cell membrane. In Alzhiemer's, the level of Kyn induction equals the level of cognitive impairment. QUIN=promotion of the formation of amyloid.

    Going back into the past of CFS/ME history, they were finding bright spots on the MRI's of Cheney's patients. And then onto others. I posit that those bright spots were the result of toxin upregulation of amyloid. Some alzheimers treatments reduce the existing plaques or decrease the formation of. This occurenece also mirrors the improvements and in some the resolution of those early year patients in CFS/ME.

    I believe ACAT determines the degree to which KP is activated. I wonder how many with more pronounced neurological affects have mutations in the ACAT?

    And while we are on genetics...they absolutely play a role in NO and Interferon, as well as playing a part in the ability of the CYP P450's to detoxify. So mutations here may also predispose one to neurological disease as well. Guillemin & Brew, 2002...activation may vary according to unexplained differences between individuals, perhaps rendering some more susceptible to neurological disease.

    LaurieL
     
    Lotus97 likes this.
  20. Freddd

    Freddd Senior Member

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    Hi LaurieL,

    This is exactly why I believe I need so much adB12.

    My daughter and a fair percentage of people need more AdoCbl, and need more into their brain perhaps.

    In the people with the anxiety marker we maight call it, when LCF is started a tiny tiny bit sure does affect dopamin, at least after the cobalamin and folate os there.

    Since you don't specifically name "the anxiety marker", I am going to assume you are referring to MAO-A. But I think where the effects of LCF come in are in those not only with the MAO-A marker, but those also with ACAT mutations. Having both of these would compound the magnitude of the problems there of.

    Having CFS/ME/FMS symptoms with chronic anxiety and maybe panic attacks, an often fearful outlook,. The anxiety itself is a marker for this extreme reaction to LCF or occasionally ADoCbl or less often MeCbl. So far it appears quite reliable. The questions comes in as to what intesity etc. So far that hasn't been the question.
     

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