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Is cAMP suppressing our innate immune system?

Discussion in 'Antivirals, Antibiotics and Immune Modulators' started by Emootje, Feb 3, 2011.

  1. Emootje

    Emootje Senior Member

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    Cyclic adenosine monophosphate (cAMP) is a second messenger important in many biological processes. Increases in intracellular cAMP generally suppress innate immune functions, including inflammatory mediator generation and the phagocytosis and killing of microbes.

    cAMP.JPG
    http://ajrcmb.atsjournals.org/cgi/reprint/39/2/127

    Intracellular Cyclic AMP is stimulated by:

    -Norepinephrine (beta 2-adrenergic receptor)
    -Epinephrine (beta 2-adrenergic receptor)
    -Prostaglandin E2
    -Prostaglandin D2
    -Prostacyclin
    -Histamine
    -Glucagon
    -Parathyroid hormone
    -Vasoactive intestinal peptide
    -Vasopressin

    In ME/CFS the increased sympathetic activation (probably due to low plasma volume/cardiac output) is cranking up cAMP and suppressing our innate immune system.

    symp nk cells.JPG
    http://pharmrev.aspetjournals.org/content/52/4/595.full.pdf html

    Prostaglandins (inflammation) and Histamine (inflammation, food intolerances) are probably also major players in ME/CVS.

    Possible treatments:

    Lowering epinephrine/norepinephrine (treat low blood volume, slow-deep breathing, beta blocker)
    Lowering Prostaglandins (Non-Steroidal Anti-Inflammatory Drugs)

    HIV protocol and cAMP
    http://www.lifeextensionvitamins.com/hivnahivpr.html
  2. Emootje

    Emootje Senior Member

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    Is there anyone with good or bad experiences with cAMP enhancing/reducing drugs?

    Enhancing drugs:
    -Caffeine
    -Beta agonists
    -Forskolin
    -Papaverine

    Reducing drugs:
    -NSAIDS
    -Beta blockers
  3. sacha

    sacha

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    I stopped taking NSAIDS because they are considered to be a contributing factor to leaky gut.
  4. alex3619

    alex3619 Senior Member

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    Hi Emootje, disturbed cAMP has been part of my own model for ME/CFS since 2001 or 2002. I think its more complicated than elevated cAMP, but I could be wrong, and I can't prove it. I think we have both Ca++ and cAMP surges. I looked at forskolin all those years ago but decided not to try it as the risks were too high. I drink caffeine all the time. I also modified my diet in the late 90s to decrease series two prostaglandins. Avoid excess polyunsaturated fat, take omega-3s, and consume monounsaturated fats such as extra virgin olive oil, but if you want to cook at temperature I recommend macadamia oil.

    Many of the chemicals you mentioned in post one are under investigation for their involvement in ME/CFS. We will have more answers over time. I respond very badly to beta blockers. My guess is that the Ca++/cAMP surges have a circadian bias, more Ca++ in sleep, more cAMP when awake. This is only a model however, and could easily be wrong.

    I stopped working on my model because of lack of resources (eg cash) and brain fog - my memory is too fubar to do good research.

    Bye,
    Alex
  5. Emootje

    Emootje Senior Member

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    Thanks Sacha and Alex3619,

    sacha
    Yep...NSAIDS are contraindicated if you have a leaky gut. Maybe Alex's dietary changes could help lower PGE2, PGD2 and PGI2.

    alex3619
    If you are low on blood volume/cardiac output, you are very dependent on your sympathetic nervous system.
    Beta blockers could increase your NK cell activity, TH1/TH2 ratio, Tc and Macrophages function but it can also reduce your cardiac output.
    I think the effect of caffeine is reversed: increases your cardiac output and lowers your innate immune system.
    I guess we must choose the lesser evil
    Thanks for the macadamia oil recommendation.

    Emootje
  6. undcvr

    undcvr Senior Member

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    I take Foskolin at quite high levels, about 100mg after standardisation. I remembered that about a year ago it used to help especially with depression. It gave me some energy too. I figured that anything that helps with depression cannot be a bad thing. Then I stopped it for a while, just part of cycling whatever I take. Now when I take it again, it does not seem to have any effect on me. Its antidepression effect is pretty much gone. I take it now for weight (fat) loss and energy. I take it in the mornings if I do take it. I am not so sure if it is doing anything for me now.
    I have never been able to take much caffeine. If I take about 100mg for a few days, it over stimulates my CNS and I end up crashing and falling sick in about 3 days. In the same way, ephedrine and amphetamines never worked for me too. The only way I found to get around that was to take Trypt at night before bed and calm my CNS down by taking sedating supplements spaced out throughout the day.

    I personally average 1gm of asprin on a daily basis, it has helped alot in terms of inflammation.
  7. FunkOdyssey

    FunkOdyssey Senior Member

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    Pentoxifylline appears to improve outcomes in HIV infection and its mechanism of action is TNF-a suppression via increasing cAMP levels. CD4 counts up, muscle wasting stops and patients gain weight (lean mass), etc.

    Buspirone appears to improve outcomes in HIV infection and its mechanism of action is restoration of the proliferative and cytotoxic capacity of T-cells via decreasing cAMP levels.

    If you make any sense of it let me know.
  8. Emootje

    Emootje Senior Member

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    I guess it does make sense:
    "cAMP suppresses the expression of pro-inflammatory cytokines such as tumor necrosis factor-alpha"
    Tumor necrosis factor alpha is thought to play an important role in wasting
    Tumor necrosis factor alpha increases NF kappa beta witch's promotes HIV replication.

    "While the effects of cAMP on mf inflammatory mediator generation were originally reported to be mediated by PKA rather than Epac-1 (16), Epac-1 has been implicated in the suppression of endotoxin-induced interferon-b production in a mf cell line"
    Interferon b increases proliferative and cytotoxic capacity of T-cells

    http://ajrcmb.atsjournals.org/cgi/reprint/39/2/127
  9. Emootje

    Emootje Senior Member

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    I hoped that reduction of cAMP would enhance patients health.
    Unfortunately it is not so simple.
    I'm confused....
  10. alex3619

    alex3619 Senior Member

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    Hi Emootje, just to make it more confusing, the chemistry I was looking at that might boost Ca++ at night and cAMP during the day might work differently. The chemistry is disturbed at night with a probable reduction in Ca++, but I have presumed that this will result in a massive release of Ca++ when stimulated. However, while this is a known mechanism, it is by no means certain that it is happening in CFS.

    Almost anything that disturbs cell function will alter the Ca++/cAMP axis. These two work against each other, and it is the balance that is important. The elevated response to acetylcholine that is observed in the peripheral vascular system indicates that calcium is dominant at some point in the circadian cycle. What I am saying is that cAMP is dominant at other times. Many hormones are linked to circadian production - if an imbalance in Ca++/cAMP occurs at a particular time, any hormones produced or released at that time might not be correctly regulated. This is very complicated, and I do not claim to fully understand this.

    It is highly probable that any attempt to modify Ca++ or cAMP will have to take circadian factors into account. This needs a lot more research. Drugs that appear to work, or fail, might give different results taken at another time of the day.

    Bye
    Alex
  11. Emootje

    Emootje Senior Member

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    Thanks Alex,

    My knowledge concerning cAMP and Ca++ is very limited.
    I know cAMP causes vasodilation in the vascular system by lowering intracellular calcium.
    Sometimes beta blockers are helpful in POTS because they block cAMP meditated vasodlatation despite it's cardiac output lowering effect.
    I also know norepinephrine and epinephrine have a circadian rhythm.
    They are high during the day and low in the evening/night.
    This may explain why cAMP is high during the day and low in the evening/night.
    But I'm not sure we are talking about the same thing.
    I guess I just have to study more on this topic

    Emootje
  12. ggingues

    ggingues $10 gift code at iHerb GAS343 of $40

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    Not familiar with this, but just want to caution that NSAIDs (if used for pain), you need to do something to keep your pain in check, otherwise you could go into an exacerbation of your symptoms! At least that is what happened to me! I suffered the most pain than I have in my life for months!

    GG

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