BRAIN ADENOSINE MODULATION

[pattismith]

Adenosine levels and activity are key actors for many of us, I quote @Hip post from another thread to keep discussing this issue in this devoted place...

Below are my notes on substances that act on adenosine receptors.


Adenosine Reuptake Inhibitors:

Inosine (also an adenosine A3 receptor agonist)

Acetic acid

Progesterone

Ethanol

Hydroxyzine

Tricyclic antidepressants

Propentofylline — may be helpful for schizophrenia. 1

Dipyridamole — may help schizophrenia. 1 2

Allopurinol (gout drug) it inhibits purine degradation and subsequently increases adenosine levels. Helpful in schizophrenia. 1

More: Adenosine reuptake inhibitor - Wikipedia



Adenosine Receptor Agonists:

Inosine (adenosine A3 receptor agonist)

D-Limonene (adenosine A2A receptor agonist) — also a potent anti-anxiety, antioxidant and anti-inflammatory (dose 1,000 mg to 3,000 mg per day) 1

More: Adenosine receptor agonist - Wikipedia



Adenosine A2A Receptor Agonists

D-limonene (half-life 12 to 24 hours, oral bioavailability of D-limonene 43%)

Cannabidiol

Zeatin riboside

Sake yeast (a type of Saccharomyces cerevisiae) activates A2A receptor. 1

More: Adenosine A2A receptor - Wikipedia



Allosteric Modulators of Adenosine Receptors

Amiloride is an allosteric inhibitor of antagonist binding at A1, A2 and A3 adenosine receptor. 1 So amiloride in effect acts like an agonist.



Adenosine Receptor Antagonists

Quercetin antagonist at A1 adenosine receptor. 1

Quercetin is an adenosine receptor antagonist (similar to caffeine), with a Ki value of approximately 2.5μM. Although this is approximately 10-fold more potent than caffeine (25μM) quercetin has failed to confer caffeine like effects when orally dosed at 200mg (despite caffeine being active). This is thought to be related to the poor neural bioavailability of quercetin. 1

Caffeine antagonises all adenosine receptors: A1, A2A, A2B and A3. 1

I wish to add

Theophylline Non selective adenosine receptors antagonist
Istradefylline AR2a selective antagonist drug for parkinson that was suggested for ADHD and Restless Legs

Methotrexate enhancing Adenosine level by it's metabolic effect (drug for auto-immune diseases)

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.22643

https://www.mdpi.com/1422-0067/22/14/7685

https://www.mdpi.com/1422-0067/21/10/3483

 

[pattismith]

Adenosine is an important actor for us because of it's immunomodulation and because of it's direct neurological effect

promoting sleep via AR1 and AR2a

The effect of prostaglandine PGD2 on adenosine release and sleep promotion

In the striatum, AR2a has a motor excitatory effect involved in parkinson (and possibly in restless legs and ADHD)


https://pdfs.semanticscholar.org/f4d6/af226e9a0f97a8a180d2c66d992a9021d1c7.pdf
https://www.frontiersin.org/articles/10.3389/fnins.2019.00740/full
https://pubs.acs.org/doi/10.1021/acschemneuro.2c00660#

 

[pattismith]

Adenosine and the cardiovascular system

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290927/

 

[datadragon]

Zinc deficiency potently decreases the activities of extracellular adenine-nucleotide-hydrolyzing ectoenzymes, delaying both extracellular ATP clearance and adenosine generation. Our findings indicate that the activity of ENPP1, ENPP3, NT5E/CD73, and TNAP, which are involved in the regulation of purinergic signaling, decreased under zinc-deficient conditions.. Thus, the zinc status can alter extracellular adenine-nucleotide metabolism. Zinc can promote non-REM sleep, whereas defective non-REM sleep responses to sleep deprivation are found in Nt5e/Cd73-KO mice. Zinc can prevent diarrhea, whereas allergen-induced diarrhea (inflammatory diarrhea) is found in Enpp3-KO mice. Both ATP/ADP and adenosine are widely recognized to mediate opposite physiological effects, such as pain signaling by ATP and ADP vs. pain relief by adenosine, and pro-inflammatory effects of ATP vs. anti-inflammatory effects of adenosine; zinc alleviates pain, whereas zinc deficiency is associated with pain. Zinc is also a potent anti-inflammatory nutrient, and its deficiency leads to a pro-inflammatory state. Moreover, zinc supplementation has been shown to ameliorate some defects associated with the loss of zinc-requiring ectoenzymes involved in extracellular adenine-nucleotide metabolism.
https://www.nature.com/articles/s42003-018-0118-3 Zinc is involved with sleep in other ways covered here https://forums.phoenixrising.me/thr...-sleep-insomnia-post-links.78501/post-2442576

The P2X7 receptor is a cation channel activated by high concentrations of adenosine triphosphate (ATP) and activates the NLRP3 inflammasome which can be suppressed by active B6 that requires zinc and also magnesium sulfate which does not. The P2X7 receptor also regulates β-cell proliferation/survival but seems noone read that.
https://forums.phoenixrising.me/thr...zu-anti-purinergic-therapy.52427/post-2438658

Adenosine and INF(a) synergistically increase ifn-gamma (y) production of human NK cells. Here we show that the adenosine A(3) receptor agonist iodobenzyl methylcarboxamidoadenosine potently inhibited proliferation, IFN-gamma production, and cytotoxicity of activated human lymphoid cells. Stimulation of the A(3) receptor also caused apoptosis of activated PBMC. However, when PBMC were stimulated with IFN-alpha, adenosine did not decrease, but synergistically increased, the IFN-gamma production of NK cells. https://pubmed.ncbi.nlm.nih.gov/19095736/ IFN-y increases GRP78 and therefore WASF3 levels.

Adenosine A3AR stimulation inhibits the respiratory burst, interleukin (IL) 1β, TNF-α, chemokine macrophage inflammatory protein (MIP) 1α, interferon regulatory factor 1, iNOS (inducible nitric oxide synthase), and CD36 gene expression. However, adenosine reduced the expression of adhesion molecules on monocytes and decreased cytokine production, effects that were potentiated by an A3AR antagonist. In addition, A3AR stimulation increased TNF-α production in activated macrophages https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756520/

The adenosine A3 receptor, also known as ADORA3, is an adenosine receptor, but also denotes the human gene encoding it. Adenosine A3 receptors regulate serotonin transport via nitric oxide and cGMP. Activation of an A3 adenosine receptor results in an increase of 5-hydroxytryptamine (5HT) uptake in RBL cells, due to an increase in maximum velocity (Vmax). The A3 adenosine receptor-stimulated increase in transport is blocked by inhibitors of nitric oxide synthase and by a cGMP-dependent kinase inhibitor. In fact, compounds that generate nitric oxide (NO) and the cGMP analog 8-bromo-cGMP mimicked the effect of A3 receptor stimulation, suggesting that the elevation in transport occurs through the generation of the gaseous second messenger NO and a subsequent elevation in cGMP. https://pubmed.ncbi.nlm.nih.gov/7525554/

Adenosine inhibits activity of hypocretin/orexin neurons by the A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect. https://pubmed.ncbi.nlm.nih.gov/17093123/ Orexin A strongly ameliorated ongoing EAE, limiting the infiltration of pathogenic CD4+ T lymphocytes, and diminishing chemokine (MCP-1/CCL2 and IP-10/CXCL10) and cytokine (IFN-γ (Th1), IL-17 (Th17), TNF-α, IL-10, and TGF-β) expressions in the CNS. https://pubmed.ncbi.nlm.nih.gov/30894198/

Adenosine Receptors: Expression, Function and Regulation​

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3958836/

 

[pattismith]

Zinc deficiency potently decreases the activities of extracellular adenine-nucleotide-hydrolyzing ectoenzymes, delaying both extracellular ATP clearance and adenosine generation.

Yes I have already noted this study.
I also found that Extracellular free Zn may block P2X7R
Zn deficiency also has negative impact on deiodinase1 affecting T4 to T3 conversion

https://forums.phoenixrising.me/threads/zinc-deficiency-alters-purinergic-signaling.62679/

 

[datadragon]

Extracellular ATP can cause P2X receptors to activate the NOD-like receptor 3 (NLRP3) inflammasome and cause IL-1β and IL-18 maturation and release. https://pubmed.ncbi.nlm.nih.gov/23434541/

Yes I have already noted this study.
I also found that Extracellular free Zn may block P2X7R
Zn deficiency also has negative impact on deiodinase1 affecting T4 to T3 conversion

Yes, and its the zinc deficiency/unavailability that is causing much of those secondary downstream effects including the adenosine issues.

During inflammation or infection, zinc uptake levels are lowered by also lowering levels of Shank3. we have reported expression of SHANK3 in human enterocytes, where SHANK3 was functionally linked to zinc (Zn) transporter levels mediating Zinc absorption. We detected decreased expression of Zn uptake transporters ZIP2 and ZIP4 on mRNA and protein level correlating with SHANK3 expression levels, and found reduced levels of ZIP4 protein co-localizing with SHANK3 at the plasma membrane. We demonstrated that especially ZIP4 exists in a complex with SHANK3. Zip2 and Zip4 proteins act as key players of zinc absorption in enterocytes. Low enterocytic SHANK3 levels result in diminished Zn transporter levels that could eventually explain reduced Zn concentrations in tissues and organs https://www.ncbi.nlm.nih.gov/pubmed/28345660/

Interleukin-6 (IL-6) up-regulates the ZIP14 gene expression ZIP14 (Slc39a14)., which in turn, is responsible for an excess of intracellular zinc and, at the same time, for hypozincemia that accompanies the acute phase response to inflammation and infection. Infection and inflammation produce systemic responses that include hypozincemia and hypoferremia. Interleukin-6 regulates the zinc transporter Zip14 in the liver and contributes to the hypozincemia of the acute-phase response. https://www.pnas.org/doi/10.1073/pnas.0502257102

The cytokine interleukin 6 (IL6) induces the expression of Metallothionein and α2-macroglobulin (A2M) and consequently reduces zinc availability. IL-6 is released during the acute phase of an inflammatory response. This mechanism is beneficial to the acute immune response, however, a long-term decrease in zinc availability may contribute to pathological processes in conditions of chronic inflammation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490603/

We demonstrated that prenatal LPS exacerbates proinflammatory cytokine production in the offspring. These proinflammatory cytokines produced after LPS exposure induce metallothionein, which sequesters zinc and induces maternal and fetal hypozincemia. (Metallothionein (MT) is a zinc-binding protein that when induced in the mother's liver during the acute phase response such as infection or inflammation has been found to cause a fetal Zinc deficiency.) https://pubmed.ncbi.nlm.nih.gov/18793679/

Interferon-a (IFN-a) and inflammatory cytokines IL-1, IL-6 and TNF-a, have all been shown to induce metallothioneins (Numerous links) Type 1 interferon responses reduce plasma Zinc concentrations by inducing hepatic metallothionein expression in various model organisms (Sato et al., 1996, Guevara-Ortiz et al., 2005, Van Miert et al., 1990, Morris and Huang, 1987), as well as in human cells.

Increased propionic acid production and a corresponding reduction in butyric acid were also associated with zinc deficiency in young lambs https://www.sciencedirect.com/science/article/abs/pii/S002231662314346X?via=ihub

and briefly, NLRP3 activation lowers Shank3 levels from other studies. NLRP3 is upregulated by ER Stress among numerous reasons so it can both cause ER Stress and be a downstream effect of ER Stress.
Further, the shank3 gene itself regulates intestinal barrier function. The protein encoded by the SHANK3 gene also turns out is regulated by zinc as well in the studies so when NLRP3 is upregulated and SHANK3 is lowered you will have zinc deficiency/unavailability. Zinc deficiency increases ER Stress that leads to increase of WASF3 and the exercise intolerance as well, that was mentioned here https://forums.phoenixrising.me/thr...s-chronic-fatigue-syndrome.90582/post-2443553

Dysregulation of TRP melastatin subfamily members (TRPM) and calcium signalling processes are implicated as being involved. In this earlier review here for example, they presented TRPM7 as a potential candidate in the pathomechanism of ME/CFS (one part), as TRPM7 is increasingly recognized as a key mediator of physiological and pathophysiological mechanisms affecting neurological, immunological, cardiovascular, and metabolic processes inherent in ME/CFS, That also has a zinc link https://forums.phoenixrising.me/thr...fatigue-syndrome-patients.90588/#post-2441274

 

[SlamDancin]

@datadragon Somehow or another my regimen of supps includes Zinc, TMG (methylates homocysteine), Tributyrin and Melatonin (protects from ER stress). Next month I plan to add TUDCA and P5P. I also take a sublingual B12 which I’ve found helpful too. I believe you mentioned B12 availability in an earlier post. Edit: found a study. B12 deficiency activates all the relevant ER stress targets.

https://www.nature.com/articles/cddis201369

“The impaired cellular availability in vitamin B12 induces irreversible ER stress by greater acetylation of HSF1 through decreased SIRT1 expression, whereas adding vitamin B12 produces protective effects in cells subjected to ER stress stimulation.”


I have had consistently high levels of blood B12 and Folate which seem to indicate intercellular deficiencies. I also had low SAM, low glutathione and high SAH/homocysteine/adenosine

I’ve always wanted to know exactly what caused the high adenosine because that’s a good candidate for the subjective feelings of tiredness.

 

[pattismith]

adenosine receptors can build heteromer with other receptors like Dopamine D2 or endocannabinoid CB1, or between different adenosine receptors.
This phenomenon change the affinity of the adenosine receptors and the effects of the binding.

searcher Ferré's team is working on this topic and it's fascinating.

here an example:

https://journals.lww.com/nrronline/...missense_mutation_of_the_adenosine_a1.24.aspx

 

[pattismith]

Istradefylline AR2a selective antagonist drug for parkinson that was suggested for ADHD and Restless Legs

Interestingly, proper dosage of Inosine + caffeine might produce an effect almost similar to that of Istradefylline at a very low cost...

https://forums.phoenixrising.me/thr...th-inosine-caffeine.62649/page-2#post-2458577

..