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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. *GG*

    *GG* Senior Member

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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
     
  13. Lolinda

    Lolinda Senior Member

    I just came across this old thread.
    Is there still anyone interested in this topic?
    Great insight about cAMP!!
    I just made an experience with this: started supplementing with AGP-choline. This increases acetylcholine, the neurotransmitter of the parasympathicus, see here:
    http://forums.phoenixrising.me/inde...se-acetylcholine-at-low-cost-naturally.46037/

    I started taking agp-choline. A bit too much, 600mg/day in two doses, 300mg each.
    For two days, I was not speedy/wired as usual, but deeply relaxed in a way I did not experience since I have been sick. Very very nice feeling! That was such a happiness for me... I take it as an indication that all the noradrenaline etc cited above went down. -> according to the things written above, this means less cAMP.
    Now, apparently, it is true that cAMP inhibits the immune system. Because to my surprise, it suddenly started working:
    I got die-offs. Chills such that I needed 3 pullovers in hot summer weather, plus sleeping at night with 2 x 60°C water filled warm water bottles. now, neither dietary choline, now the acetylcholine produced from that does not kill microbes. A more active immune system does. So the best explanation seems to me:

    agp choline -> more acetylcholine, that is, more parasympathicus -> less catecholamines -> less cAMP -> less immune system suppression -> more pathogens killed -> die-off -> big stress for my body -> sympathicus -> more cAMP

    Unfortunately, this got me back to square 1: I lost all that beautiful deep relaxation. The die-offs then stopped, and now I am recovering slowly, the chills getting less and less.
     
    Last edited: Aug 19, 2016
    wastwater likes this.
  14. wastwater

    wastwater Senior Member

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    Good thread resurrection,not seen this before,I'm interested in cAMP as a keyword,not sure what it is or does.
     
    GreyOwl likes this.
  15. anciendaze

    anciendaze Senior Member

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    I don't have a lot to contribute to this thread, but this looks like a good group to ask a question about purinergic signalling. (ATP, ADP, AMP are purines.)

    For a long time people trying to deal with ME/CFS have been getting fixated on particular organ systems, tissues, cells or even organelles inside cells. Arguments about which are responsible have produced "more heat than light".

    Some time back I realized I did not know how the muscles holding me upright got increased flow of oxygenated blood when they were active. It turned out researchers are still not sure how this works in healthy athletes. The changes are localized and episodic, two words that don't go well with convenient medical research.

    Activity generally causes a shift toward sympathetic activation, which causes vasoconstriction. This is handy when we stand upright because it prevents blood from pooling down low. The problem is that this restricts flow to active muscles. The mechanism which locally reverses vasoconstriction where more blood is needed is called "functional sympatholysis", and I wrote a preliminary blog post about my understanding. (It wasn't my best effort, but then I explained the circumstances.)

    Eventually, I gave up on trying to pin the action on nerves or muscle fibers, and cast a wider net. It turned out the normal connection between hypoxia and vasodilation is mediated by red blood cells (erythrocytes). Naturally RBCs release any oxygen molecules they are holding. If that is not enough, and the local environment remains hypoxic, they proceed to release ATP, which starts a signalling cascade leading to local vasodilation and increased blood flow.

    At least for those patients in the group investigated at Brigham and Women's hospital exhibiting low fill pressures at the heart it appears their venous systems are stuck in the vasodilation phase, which means alternating vasoconstriction/vasodilation between check valves in veins is not doing a proper job of returning blood to the heart.

    This leads me to a question about ATP, etc. not inside cells, but leaking into the bloodstream. If this is going on constantly when patients are active it would mess up functional sympatholysis in precisely the way that group above reports. Does anyone here have clues about ATP, ADP, AMP or adenosine escaping from cells or muscle fibers?

    Another line of research has to do with hypoxia inducible factors, but I haven't gone far in that direction.

    I remain convinced that episodic localized hypoxia is central to a number of unexplained pathologies.
     
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  16. lansbergen

    lansbergen Senior Member

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    I do not know it is central but I have no doubt it is an impotant part.
     
  17. Lolinda

    Lolinda Senior Member

    Testing for cAMP / vasodilatation

    A high/low cAMP essentially corresponds to excessive/diminished vasodilatation (see posts above). This is a much better test than blood pressure, because BP is the sum of all vasodilation and vasoconstriction. So a test for cAMP could help to detect the following pathologies:
    • hidden vasodilatation suppressing the immune system. This seems to be what I have: BP is largely normal or somewhat low but the body gets sick from all the vasodilation which produces cAMP (which is immunosuppressive, see posts above). The BP is compensated by any vasoconstrictor ranging from aldosterone to noradrenaline. Actually, I guess this is the normal reaction of the body in case of high cAMP: there are regulatory mechanisms to maintain BP. After labs showed me elevated vasoconstriction but my BP was slightly lowish, I searched where the vasoconstrictor is...
    • Inability of working muscles to mount vasodilation as described by @anciendaze above, that is insufficient production of cAMP when needed.
    What I know about cAMP testing:
    • In Europe, Synlab and Unilabs offer a cAMP test, but only at some of their sites. If you look up their test directories, it is not easy to find cAMP: it comes under variousest names such as "cyclic AMP", "cyclic A.M.P", etc.
    What I do not know is how to meaningfully use the test for diagnosis:
    • For example, I have excessive vasodilatation. In order to find out if too much cAMP is the cause, would the 24h urinary test be the right one or the plasma test? I guess that would then also answer the question for @anciendaze , if there is too little cAMP in muscles. Or, does all this need to be tested in some standing-laying sequence?
    • So far I was unable to find a paper that could hhealthy ü sick comparison values AND it addresses issues we discuss here
    • The cAMP that causes the immune suppression is intracellular in phagocytes.
      http://www.atsjournals.org/doi/full/10.1165/rcmb.2008-0091TR#.V7Nl48-lH3Y
      Some of it spills over into the blood. Is plasma cAMP a valid measure of what we are interested in? What other processes produce cAMP and can falsify measurements?
    • can one test the immune suppression resulting from cAMP?

    Reacting to the post above by @anciendaze :
    The challenge with theories such as
    is that no doctor can help you any further.... Well, this won't be news to you, I guess :( I have been chasing similarly research-grade stuff a lot and my finding is that it all boils down to the question if I can come up with something that is testable. Break down the complex stuff into sthg trivial that doctors understand and can test. So, if you like this line of thought, here are testing methods I am (somewhat) familiar with, in case you want to find out if you have hypoxia/bloodflow issues or not:
    • if you have hypoxia anywhere in the body, then hypoxia-related cytokines are produced. These are: vegf, il-8 and pge2. in Europe, Redlabs, Belgium, can test for vegf and pge2. il-8 any bigger lab can do, such as unilabs. actually, unilabs does vegf too. the difficult guy is pge2, which only Redlabs does. in USA, labcorps should do all (?). So what I did with myhypoxia issues: do a 2-stage test: A) when I am in thesituation where I believe I dont have hypoxia and B) test the same panel when I believe I do. The trick is essentially, that local hypoxia is difficult to test, but cytokines get into the bloodstream thus are easy to test.
    • infrared spectroscopy: while this is again a fancy research topic, you can simply head to pubmed, restrict search to your country and find out who has the expensive device. With that device you can look some 5 cm or so into tissues and find out about oxygen & blood in that tissue. If you know how SpO2 measurements work by infrared rays, then you will see how infrared spectroscopy works. infrared spectroscopy is used by sports experts to lok at muscle perfusion of top athletes, so there we are close to your suspected muscle perfusion issues.
    • and before all this: why not make a plain simple doppler flow measurement? It only works in bigger blood vessels. but if the bigger vessels have too low flow, then the small ones cant have too much, either.
    My experience with all such fancy things is that testing is everything, because the result almost always turned out to be different than I thought or any doctor thought... :)
     
    Last edited: Aug 16, 2016
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