Cyclic AMP, Adenosine and Inflammation

[nanonug]

Cyclic AMP Represents a Crucial Component of Treg Cell-Mediated Immune Regulation

Extracellular Adenosine is Required to Limit a Potentially Self-Destructive Inflammatory Immune Response

Inflammatory immune reactions are accompanied by the release of high amounts of ATP in the extracellular space where it is converted into AMP by CD39 and dephosphorylated to adenosine by CD73 (33). Adenosine has strong anti-inflammatory influence on immune cells preferentially by triggering A2A and A2B receptors leading to the generation of intracellular cAMP. Interestingly, the anti-inflammatory action of adenosine is exploited by tumors where adenosine was shown to accumulate, thereby preventing immunological tumor regression (34, 35).
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COMMENT: Lately, I've been thinking a lot about cyclic AMP and I'm curious about what one may accomplish by artificially increasing its amount. One can so do easily with forskolin so I have embarked on a trial to see what happens. There are some unwanted side effects associated with indiscriminate increases of cyclic AMP so it's not risk-free. In particular, increases in heart rate are not to my liking. On the other hand, I'm looking forward to reduction of mast cell activation as a nice side effect.

 

[NotThisGuy]

Inosine can increase intercellular cAMP as well and decrease inflammatory cytokines.

http://www.jimmunol.org/content/164/2/1013

But few members here mentioned it activated mast cells.....
maybe other purines or RNA itself can have the same effect without activating mast cells?

 

[nanonug]

Inosine can increase intercellular cAMP [...] But few members here mentioned it activated mast cells.....

Yes, it is my understanding that inosine promotes mast cell degranulation. I am comfortable taking forskolin, though.

 

[nanonug]

UPDATE

I am currently taking ~50mg BID of forskolin. Because of a certain effect of forskolin, I know it's doing its thing (the water increase in the colon is very noticeable.)

Forskolin works by upregulating the activity of adenylate cyclase. This enzymes converts ATP into cyclic AMP. Because of my "hypometabolism protocol", I expect that more ATP be available for conversion. I had used forskolin in the past but the effects are definitely much more pronounced this time.

One of the consequences of increasing cytosolic levels of cAMP is that more AMP, and consequently more adenosine, is produced. Adenosine is known to be an anti-inflammatory "healing" molecule and this is definitely good. If I'm not mistaken, Naviaux et al found that adenosine levels are low in people with SEID so this is potentially good news. On the other hand, adenosine is an inhibitory neurotransmitter in the CNS and I am definitely feeling that as well: I feel sleepier, and also more relaxed, than before. Considering that coffee competitively antagonizes adenosine, I've been drinking more of it during the day and it works. At night, I stopped melatonin for now and I've been sleeping quite well.

 

[wigglethemouse]

@nanonug What were your final conclusions on your self-experiment?

I've just been reading that cAMP has an effect on carbohydrate metabolism (even including lipid metabolism).

The Role of Cyclic AMP in the Control of Carbohydrate Metabolism
http://diabetes.diabetesjournals.org/content/18/12/797

Cyclic AMP plays an important role in the regulation of metabolism generally. Emphasis in the present review has been placed on carbohydrate metabolism, but lipid metabolism has also been discussed to some extent. The chief role of cyclic AMP in several tissues seems to be to facilitate or promote the mobilization of glucose and fatty acid reserves. In the liver, glucagon and the catecholamines cause an increase in the intracellular level of cyclic AMPby stimulating adenyl cyclase. This increase in the level of .cyclic AMP leads to a net increase in hepatic glucose production by at least three mechanisms: stimulation of phosphorylase activation, suppression of glycogen synthetase activity, and stimulation of gluconeogenesis. The catecholamines also stimulate adenyl cyclase in muscle and adipose tissue. Among the principal effects of cyclic AMP in these tissues are glycogenolysis in muscle and lipolysis in adipose tissue.

 

[Jackb23]

UPDATE

I am currently taking ~50mg BID of forskolin. Because of a certain effect of forskolin, I know it's doing its thing (the water increase in the colon is very noticeable.)

Forskolin works by upregulating the activity of adenylate cyclase. This enzymes converts ATP into cyclic AMP. Because of my "hypometabolism protocol", I expect that more ATP be available for conversion. I had used forskolin in the past but the effects are definitely much more pronounced this time.

One of the consequences of increasing cytosolic levels of cAMP is that more AMP, and consequently more adenosine, is produced. Adenosine is known to be an anti-inflammatory "healing" molecule and this is definitely good. If I'm not mistaken, Naviaux et al found that adenosine levels are low in people with SEID so this is potentially good news. On the other hand, adenosine is an inhibitory neurotransmitter in the CNS and I am definitely feeling that as well: I feel sleepier, and also more relaxed, than before. Considering that coffee competitively antagonizes adenosine, I've been drinking more of it during the day and it works. At night, I stopped melatonin for now and I've been sleeping quite well.

This is quite interesting to me as I noticed whenever I would drink coffee, within 30 minutes my brain mud much more foggy even though I had an increase in motivation.

 

[alex3619]

I considered forskolin in the 90s as my investigations suggested it even then. I rejected it on safety grounds. In recent years I have tried using resveratrol, a PDE4 inhibitor. It helped, but as my symptoms changed and not for the better after some years on it I am only using it when I really need it. It greatly assists with some of my breathing issues.

In the short term I think resveratrol is likely to be helpful. In the long term we just don't know, particularly in ME.

 

[pattismith]

@nanonug @NotThisGuy

My experimentations with thyroid meds made me investigate TSH activity.
I was initially interested in its action over intracellular calcium levels, but found it elevates intracellular cAMP (in some cells)

Differential effect of thyroid-stimulating hormone (TSH) on intracellular free calcium and cAMP in cells transfected with the human TSH receptor.
(1998)
Abstract
The thyroid-stimulating hormone (TSH) binds to a receptor which activates adenylate cyclase and elevates cAMP concentration.

However, TSH receptors are not present in all kind of cells...only thyroid cells and a few others

Extrathyroidal expression of TSH receptor
...
In recent years it has become evident that the TSH receptor is also expressed widely in a variety of extrathyroidal tissues including: anterior pituitary; hypothalamus; ovary; testis; skin; kidney; immune system; bone marrow and peripheral blood cells; white and brown adipose tissue; orbital preadipocyte fibroblasts and bone....


4.2 Thyroid stimulating hormone (TSH)
TSH receptors (TSHR) are present in B and T cells, NK cells, monocytes and at high levels in dendritic cells (DC). TSHR are not detectable on foetal and neonatal immune cells.
TSH significantly stimulated IL-2 and IL-12, IL-1β responses and enhanced the phagocytic activity of DCs from adult animals, enhanced the proliferative response of murine spleen cells to IL-2, significantly increased IL-2 induced NK cell cytotoxicity and enhanced the expression of MHC-II by human thyroid epithelial cells [149,152-156].
In bone marrow cells IL-6, IFNβ, TNFα, TNFβ, TGFβ2, and lymphotoxin-β responses were reproducibly induced by TSH [158]. Lymphocytes and monocytes synthesize TSH [149,158].

This is quite interesting to me as I noticed whenever I would drink coffee, within 30 minutes my brain mud much more foggy even though I had an increase in motivation.

Hello Jack, would you explain the link between cAMP and Coffee please?

 

[pattismith]

Yes, it is my understanding that inosine promotes mast cell degranulation.

"Adenosine and inosine accumulate in tissue during periods of ischemia and both molecules have been shown to degranulate mast cells in the hamster cheek pouch via activation of an A3 receptor. An A2-mediated inhibitory action of adenosine on mast cell degranulation has also been reported (16),...

We conclude that mast cell degranulation can be inhibited via activation of an adenosine A2α receptor; which activation occurs at a lower concentration of adenosine than stimulatory A3 receptor activation."

https://www.tandfonline.com/doi/abs/10.1080/sj.mn.7300101

 

[pattismith]

@nanonug

no news from you for a long time, hope you are fine.

This is quite interesting to me as I noticed whenever I would drink coffee, within 30 minutes my brain mud much more foggy even though I had an increase in motivation.

considering that adverse effect (worsening of ME/CFS) to caffeine may be the consequence of the inhibition of adenosine receptors, you may be a good responder to Inosine (adenosine metabolite that activates adenosine receptors as well).

 

[pattismith]

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COMMENT: Lately, I've been thinking a lot about cyclic AMP and I'm curious about what one may accomplish by artificially increasing its amount. One can so do easily with forskolin so I have embarked on a trial to see what happens. There are some unwanted side effects associated with indiscriminate increases of cyclic AMP so it's not risk-free. In particular, increases in heart rate are not to my liking. On the other hand, I'm looking forward to reduction of mast cell activation as a nice side effect.

cAMP increase in heart (and in neurons as well) activates HCN channels, which can produce:

-tachycardia
-pain
-epilepsy, anxiety etc

so not sure if increasing cAMP would be beneficial.

On the other hand, if you can simutaneously increase your cAMP and take Ivabradine (a HCN channel blocker), you may reach your goal to increase cAMP in some cells, without experimenting detrimental side effects.

(The only problem would be that Ivabradine has difficulties passing the blood brain barrier, if at all...)