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Tetrahydrobiopterin (BH4) Therapy for Gastroparesis

Discussion in 'The Gut: De Meirleir & Maes; H2S; Leaky Gut' started by Emootje, Dec 29, 2012.

  1. Emootje

    Emootje Senior Member

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    The Netherlands
    Gender Bias in Gastroparesis: Is Nitric Oxide the Answer?
    Accumulating evidence suggests that gender-related differences are prominent in gastric motility
    functions in both health and disease. Women are more susceptible to gastroparesis than men.
    Though the mechanism(s) involved are not fully understood, impairment of the nitrergic system is
    one of the main factors responsible for the disease. Uncoupling of neuronal nitric oxide synthase
    (nNOS) causes a decreased synthesis of NO leading to a reduction in smooth muscle relaxation.
    Tetrahydrobiopterin (BH4) (an essential cofactor for nNOS) is a key regulator of nNOS activity
    for stomach dysfunction and gastroparesis. In addition, BH4 has been shown to be a potent
    antioxidant and anti-inflammatory agent. Well established by results from our laboratory, a
    diminished intracellular (BH4:total biopterin) ratio in diabetic female rats significantly impairs
    nNOS activity and function. Recent research has been focused on BH4 biosynthesis and
    gastroparesis because reduced BH4 cofactor levels can alter the production of NO by nNOS.
    Researchers are now paying more attention to the possibility of using BH4 as a therapeutic
    strategy in gastroparesis. The purpose of this review is to provide an overview of the regulation
    and function of nNOS by sex hormones and BH4 and its potential role in the treatment of
    gastroparesis.
     
  2. alex3619

    alex3619 Senior Member

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    Logan, Queensland, Australia
    BH4 is an interesting substance in ME research. Some data suggests that both BH4 and adenosyl cobalamin are necessary for NOS function. We do appear to have NO issues. Is this causing our reduced gut motility? Its an intriguing thought as BH4 can be corrected with a drug formulation (Kuvan) used in PKU.
     
  3. LaurieL

    LaurieL Senior Member

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    Midwest
    I have been seeing a lot about tetrahydrobiopterin on this forum lately. Its is something I started looking at a couple of years ago, as I developed vitiligo-like scarring from minor injuries, and there are correlations between the two. I have been all around the methylation cycle, the trans-sulfuration pathway, the tetrahydrobiopterin cycle, and the urea cycle. What I have failed to see is the consideration of low level tryptophan as the main contributor to the tetrahydrobiopterin cycle.

    It took me two years of whittling away at this and treating, to finally pinpoint, that my BH4 cycle wasn't running because I am low on tryptophan. I even supplemented tryptophan with horrendous results. We found out why later......but my response to high dose niacinamide therapy has been....well the other gorilla in the room besides the adenosylcobolamin. I no longer suffer from vitiligo. It stopped its progression in its tracks.

    The gastroparesis can be tied to the downstream affects of these cycles not functioning as they should. I only tell all of you this, as direct supplementation, although beneficial, may not solve the original problem. I supplemented with the closest form of BH4 I could find in a supplement, and yes, it was beneficial, but it didn't solve my problems.

    Whats missing upstream will affect the downstream. The niacinamide also allowed me to gain control of my trans-sulfuration pathway. I do not have the 699 mutation, the 40 fold increase, but I do have the 62H. And it explains why I needed so many supplements, high doses, to function. And it didn't wack out my neurotransmitters like tryptophan did. (Please have a doc supervise this, don't go off and try it on your own as there are risks). I just post this for your consideration.

    Without enough BH4, the cycle will preferentially produce peroxynitrate and SOD, leading to neural damage and oxidative damage. And NO will not, cannot be produced. For others, tyrosine may also be a contributor as well.

    Tryptophan helps to explain why I have a problem with my DNA and RNA base nucleotides, as the BH4 cycle contributes to that as well. So they have now started me on 5- formylmethyltetrafolate in addition to the solgar methyl folate I have taken faithfully since I started all this on top of the niacinamide. And of course, the adenosylcobolamin.

    Laurie
     
  4. invisiblejungle

    invisiblejungle Senior Member

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    Chicago suburbs
    There's one thing I'm confused about. Some research points to nitric oxide deficiency as playing a role in gastroparesis, as it leads to reduced blood flow to the ICC cells.

    However, Martin Pall's hypothesis claims that CFS is caused by excess nitric oxide/peroxynitrite.

    Does anybody know how to reconcile these opposing views?
     
  5. alex3619

    alex3619 Senior Member

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    Logan, Queensland, Australia
    These are not opposing views, not now, depending on whether or not you think some of the recent science is valid. Excess nitric oxide might drive excess peroxynitrite under certain conditions. However under a recent (and still not validated I think) model peroxynitrite is produced via NOS under conditions of either low BH4 or low adenosyl cobalamin. Marty's model is really about excess peroxynitrite. The actual NO state is not as relevant as oxidative stress and ONOO. The body is driven to make more NO, and so stimulates NOS, but this tends to produce ONOO instead.

    There are also conditions I am examing under which there might be deficient NO, only to have excess NO be produced as the biochemistry changes. Its too early for me to say much about that as it could be wrong. Sometime mid or late next year I hope to blog about this if I can sort the issues out. There are many layers of interacting biochemical feedback loops. Its crazymaking stuff in its complexity.

    Marty also discusses low BH4 though I forget the details offhand. Look at figure two and text: http://www.thetenthparadigm.org/
     
    invisiblejungle likes this.
  6. triffid113

    triffid113 Day of the Square Peg

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    Michigan
    I posted one time before a list of stuff I had found on the web that would raise BH4 since I have 3 genes that lower BH4 myself:

    Things that raise BH4
    ·Methylfolate
    ·Vitamin C
    ·Niacin, niacinamide
    ·Saunas
    ·Estrogen
    ·Insulin (normal/low blood sugar) [5]
    ·Possibly helpful: purine GTP (BH4 can be made from it)

    Things that lower BH4
    ·Genetic polymorphism MTHFR A1298C
    ·High protein (Ammonia -- 2 BH4 required to eliminate 1 NH3)
    ·ROS (radical oxygen species)
    ·Salt
    ·High blood sugar (due to oxidative stress)
    ·Aspirin (interferes with folate absorption)
    ·Excessive exercise? (Protein breakdown into ammonia)
    ·Hypothyroid (oxidative stress)
    ·Lithium, if it causes hypothyroid (it can)
    ·Hypopituitary (causes oxidative stress)


    I also read that melatonin can help raise BH4.
    The above is not the only gene affecting BH4 as I have 2 others that lower it also which include the CBS mutations.

    I have also 3 genes that cause high blood pressure (which is how you know you are making ONOO instead of NO). I completely control my stage 3 hypertension to normal taking calcium citrate:magnesium citrate 1:1 ratio and DHEA (high dose). The cal-mag brings my b.p. down 30 points, but w/o the DHEA it goes right back up in 2 hours. The DHEA keeps it safely down.

    I take high dose antioxidants (have my whole life) and always felt they were key. It says here for BH4 genetic defects (of which I have 3), antioxidants are very important to preserve BH4. I believe I read something similar for CBS genetic defects. I knew there was some connection between BH4 and diabetes, not sure if the above is the only one, but DHEA is how I keep my blood sugar stable now, and so protect my BH4. WHen I turned 50 not only did I go in 1 day from normal b.p. to stage 3 hypertension, but I also could suddenly no longer maintain my blood sugar (which DHEA took care of in 15 minutes). (Diabetes runs in my family and I am positive I would be diabetic today if not for DHEA).

    Too bad I have so many genetic defects that that is not the end of the story for me. It seems like any stress, illness, medication, or life event can throw me off track and I need to start rebalancing my stupid genes to wrest my health back.
     
    Emootje and Bdeep86 like this.
  7. triffid113

    triffid113 Day of the Square Peg

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    Michigan
    Diabetes causes BH4 deficiency (Gee I thought it was the other way around)

    http://circ.ahajournals.org/content/116/8/944.short

    Proteasome-Dependent Degradation of Guanosine 5′-Triphosphate Cyclohydrolase I Causes Tetrahydrobiopterin Deficiency in Diabetes Mellitus

    Background— Tetrahydrobiopterin (BH4) deficiency is reported to uncouple the enzymatic activity of endothelial nitric oxide synthase in diabetes mellitus. The mechanism by which diabetes actually leads to BH4 deficiency remains elusive. Here, we demonstrate that diabetes reduced BH4 by increasing 26S proteasome-dependent degradation of guanosine 5′-triphosphate cyclohydrolase I (GTPCH), a rate-limiting enzyme in the synthesis of BH4, in parallel with increased formation of both superoxide and peroxynitrite (ONOO).
    Methods and Results— Exposure of human umbilical vein endothelial cells to high glucose concentrations (30 mmol/L D-glucose) but not to high osmotic conditions (25 mmol/L L-glucose plus 5 mmol/L D-glucose) significantly lowered the levels of both GTPCH protein and BH4. In addition, high glucose increased both the 26S proteasome activity and the ubiquitination of GTPCH. Inhibition of the 26S proteasome with either MG132 or PR-11 prevented the high glucose–triggered reduction of GTPCH and BH4. Exposure of human umbilical vein endothelial cells to exogenous ONOO increased proteasome activity and 3-nitrotyrosine in 26S proteasome. Furthermore, adenoviral overexpression of superoxide dismutase and inhibition of endothelial nitric oxide synthase with NG-nitro-l-arginine methyl ester significantly attenuated the high glucose–induced activation of 26S proteasome and the reduction of GTPCH. Finally, administration of MG132 or a superoxide dismutase mimetic, tempol, reversed the diabetes mellitus–induced reduction of GTPCH and BH4 and endothelial dysfunction in streptozotocin-induced diabetes mellitus. ...
    blah-blah-blah...
    Conclusions— We conclude that diabetes mellitus triggers BH4 deficiency by increasing proteasome-dependent degradation of GTPCH.
     

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