Role of Adenosine and ADA in MECFS?

Remy

Administrator
I'm just going to leave this here for the time being...this was a theory I was working on for a while a couple of years ago but I hit some walls and put it aside. I still think there's something to this adenosine-inosine-uric acid pathways though and it's been a fairly common topic of research through the years in MECFS too. Most notably Cheney...

Here's the letter I wrote to my doctor trying to get her help to try a drug called Adagen that breaks down excess adenosine...I was unfortunately unsuccessful and Adagen is way out of my budget.

My adenosine deaminase level was 8.3 (0-15) through LabCorp. I decided to investigate this range further because a level of "0" would almost certainly mean SCID and that is decidedly NOT normal.

My investigations led me to a number of articles that did specify a normal range for ADA. While there is some variation, It turns out that a better range for healthy, control individuals is 15-23 U/L (supposing that Saudi women and American women don't differ significantly in this regard).

In the current study, the normal range for adenosine deaminase totalled 15.0 - 23.2, 14.8 - 23.6, 15.0 - 23.0 and 16.7 - 24.6 U/l for the overall population, all males, females, and children, respectively.
http://www.ncbi.nlm.nih.gov/m/pubmed/17587984/


Another study indicated that the average for healthy controls was 10.69. My value is at the very bottom, then, of this range as well.

The average (SD) of serum ADA in TB and non-TB patients were 20.88 (±5.97) and 10.69 (±2.98) U/L, respectively (P value < 0.05). The best cut-off point was 14 U/L.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732909/

This study got me thinking though because it seems that adenosine and consequently ADA levels are typicallyincreased in people with varying types of infection. The study above references TB and I found another study that examines measuring ADA as a way to assess treatment outcomes in brucellosis.
Serum ADA levels were found to be significantly higher in patients with brucellosis than in healthy individuals (43.45 ± 24.19 IU/l and 27.5 ± 9.3 IU/l, respectively) (P < 0.01). Serum ADA activity did not show any correlation between the Brucella agglutination titer and CRP level.
http://journals.tubitak.gov.tr/medical/issues/sag-04-34-5/sag-34-5-5-0404-3.pdf


So it seems that someone like me, with multiple chronic infections, would be more likely to have an elevated level of ADA as opposed to a low level.

This journal article tells us that there is a relationship between lymphocytes and serum ADA level. When lymphocytes are high, as mine consistently (see panel on labs dated 11/27), the ADA level should also be high, and mine is not.

Among lymphocytes, it is mainly associated with T-lymphocytes [1] and studies have shown increased serum ADA levels in diseases characterized by T cell proliferation or activation [2, 3].
http://www.jle.com/e-docs/00/01/8a/26/article.phtml


I think this is further evidence that my ADA level is too low to adequately manage the level of high level of adenosine. According to these studies, my labs should show a high level of ADA activity and they actually show a low level.

Technically speaking, adenosine deaminase deficiency causes an increase of dATP, which inhibits S-adenosyl-homocysteine hydrolase, causing an increase in S-adenosylhomocysteine. Both dATP and S-adenosylhomocysteine have toxic affects on lymphocytes, causing them to be functionally defective. The defective function is caused by a depletion of all of the dNTP pools. This causes a breakdown in DNA synthesis and repair of breaks occurring in the DNA. This makes for a very serious disease and that is why the presence of ICL in CFIDS/ME patients causes a severe immunodeficiency where patients become prone to repeated infections. In CFIDS/ME, this is an acquired condition due to the disease progression itself. I should point out that one treatment option for adenosine deaminase deficiency involves the replacement of the enzyme adenosine deaminase itself. The drug used for this is called Adagen by Enzon Pharmaceuticals and it has been used for the treatment of severe combined immunodeficiency disease, known also as SCID, due to adenosine deaminase deficiency.

I believe at this time that my chronic infections have induced a sort of hibernation syndrome caused by a high level of adenosine without a sufficient amount of adenosine deaminase enzyme to break it down. This high level of adenosine causes a vicious cycle that is devastating to the immune system and allows the infections to continue to gain ground.

This study has shown that adenosine is the "switch" that turns on hibernation.

Turns out, the hibernation switch in squirrels is a receptor on brain cells for the ‘drowsiness’ neurotransmitter adenosine, which sends us to sleep by building up gradually in the brain during the day, New Scientist explains.

By blocking it using a chemical called cyclopentyltheophylline, the researchers could wake hibernating squirrels up; stimulating it using a chemical called cyclohexyladenosine sent them back to sleep.

http://www.jneurosci.org/content/31/30/10752

Theoretically, at least, high levels of adenosine, as shown on my methylation panel, could cause a sort of hibernation syndrome that may be exacerbated by the fact that I am carry the recessive allele for ADA deaminase. This may account for the lowered levels of ADA and my inability to fight chronic infections normally.

Finally, I also found a pilot study that contends that Valtrex modulates adenosine levels.
Dr. Sid Baker, in cooperation with Jill James Ph.D., conducted a pilot study of 10 children with autism. Nine children were treated with acyclovir and one child was not treated.

Note: Valtex is quickly converted to acyclovir in the intestines and the liver5. From a viral treatment perspective many viruses that Valtrex can affect can also take up residence in the liver. Valtrex is also more bioavailable than oral acyclovir6 (more similar to IV acyclovir) and has what seems to be a safer side-effect profile.

In all the 9 children adenosine levels were seemingly improved. Some children had higher levels of adenosine and they were lowered. Some children had lower levels and they were raised. The untreated child’s level remained unchanged. This striking normalizing effect is not very common in medicine.


I wonder if this is actually why antivirals seem to help - they may not only be stopping the viral replication, but they are modulating adenosine levels. I know that I have found improvement from high doses of AVs.

Based on my high levels of adenosine, the demonstrated problems with my purinergic pathway from adenosine to uric acid, and my genetic predisposition concerning adenosine deaminase, I really think that this should be enough to convince the makers of Adagen that there is a solid clinical rationale supported by the available literature to try Adagen in my case. The shots are easily administered and I have not come across any significant side effects. There is significant room in my results to raise my level that would still not approach the top of the range observed in those with illness. I think it might only take a few months of therapy to "clear the backlog" of adenosine, so to speak. At that point, I might make *enough* ADA on my own to keep myself out of adenosine induced hibernation and infection.
 

Hope

Active Member
Remy forgive my ignorance, but do you know if that is that the same adenosine that's measured on the methylation panel by the Health diagnostics and research institute? I had elevated levels on that test and always wondered what it was about as could find no useful information.

Here's what Rich Van K said about adenosine:
"Adesnosine is a product of the reaction that converts SAH to homocysteine. It is also exported to the plasma when mitochondria develop a low energy charge, so that ATP drops down to ADP, AMP and eventually, adenosine. Adesnosine in the plasma is normally broken down to inosine by the enzyme adenosine deaminase.

In some pwME, adenosine is found to be high, in some it is low, and in some in the reference range. I don't yet understand what controls the adenosine level in these patients. In most pwME who started with abnormal values though, the adenosine level moves into the reference range with methylation cycle treatment, but more data are needed."

Later he writes:

"I think that the elevated adenosine is indicating that the SAHH reaction is proceeding faster than normal, which I think agrees with the high SAMe level and the inferred high rate of reaction of glycine N methyltransferase, converting SAMe to SAH at a higher than normal rate. I think it would be good to make sure there is enough B6 and magnesium available to support the enzymes of the transsulfuration pathway, so that the flow of homocysteine in that direction can be increased, hopefully draining more of the metabolites from the methylation cycle and lower SAMe to a normal level."

Not sure if this is helpful at all.
 

Remy

Administrator
Yes, @Hope, it's exactly the same adenosine...and my elevated level on the methylation panel was what first got me looking in this direction.

Especially this part about Valtrex..."In all the 9 children adenosine levels were seemingly improved. Some children had higher levels of adenosine and they were lowered. Some children had lower levels and they were raised. The untreated child’s level remained unchanged. This striking normalizing effect is not very common in medicine."

So that's basically exactly how the adenosine levels look in MECFS when RichvanK looked at the panels...

Then, Valentijn pointed out that I had this very rare SNP in the adenosine deaminase receptor gene and I was intrigued. If the SNP is responsible, then obviously this is not the answer for everyone (or maybe even anyone!) but there are enough weird things in common that I keep putting this idea out there in the hopes that someone more knowledgeable will say yes, this has merit or no, you've missed this totally simple thing that makes this theory completely unworkable.

I got in touch with Cheney about it but didn't pique his interest unfortunately. He just said, yes, the purine pathway was implicated in MECFS but suggested I take inosine instead of trying to get Adagen. Unfortunately, I'd already taken inosine and it successfully raised my uric acid level very quickly so I knew that the bottleneck was higher up the pathway...in the breakdown of adenosine to inosine. So while inosine may be helpful, it wasn't going to help me break down the adenosine causing the hibernation syndrome at the root cause.

I also have some propentofylline and pentoxifylline here and I always meant to try them because that may block the adenosine and is thought to be able to reverse the hibernation syndrome. Unfortunately, it can also cause anxiety so I was nervous. I am prone to panic attacks. (Propentofylline is a veterinary medicine here and the package says it is used to perk up aging bitches. LOLOLOL!! It should work on me then!!)

I have a whole 10 page document on this but I just posted the highlights here. I'm happy to share the whole thing but it's a very rough form of cuts and pastes of my notes and not completely thought out.
 

Hope

Active Member
So if adenosine is reduced by valtrex, high levels must be caused by a virus. And doesn't valtrex mainly target the herpes family? I do have CMV...

I'm confused by the uric acid and purine levels though as mine are often high, leading to gout attacks. Also inosine brought on a gout attack so I won't be taking that again.

Sounds like high adenosine means we should treat our viruses, yes?
 

Seanko

Well-Known Member
Adenosine is one of those multi-purpose hormones used all over the body. It slows down nerve activity when bound to nerve receptors

There is one simple way to reduce adenosine activity in the body drink: drink tea or coffee.

Caffeine works by taking the place of adenosine at nerve receptors, as adenosine normally dampens receptors, neurons start firing faster. The autonomic nervous system kicks in filling the blood with noradrenaline & you feel the caffeine buzz.

Source: Rough Guide to the Brain, Dr Barry J Gibb p193-194

PS caffeine is used as an insecticide by plants, it's a neurotoxin reducing hungry insects to gibbering, vulnerable wrecks!

[bimg=500|no-lightbox]http://uclu.org/sites/uclu.org/files/coffee-cup-bowl-with-grains-images.jpg[/bimg]
 

Veet

Well-Known Member
Very interesting re coffee. I'd quit coffee for 4 years, once I started GAPS diet and healing. Then I understood coffee to be gluten cross-reactive, but in fact, that's only instant coffee. So a few months ago I began cautiously drinking it again, organic. It turns out my body really likes it. And on bad days, I have not 2, but 3 cups, the 3rd even in the afternoon. With zero agitation or restlessness. In my way of assessing my symptoms, I've been assuming the benefit to be antioxidant, but maybe it's something else, or additional.
 

Seanko

Well-Known Member
@Veet if you drink a lot of coffee, your body produces more adenosine receptors so the chemical can still do its work to make up for the receptors blocked by caffeine. That's what gives coffee its addictive qualities.

However if you come off coffee, less receptors are produced so when you do drink caffeine again you get a really intense caffeine buzz.

I try to limit my intake of tea, so that I can get the more effective caffeine hit on the days I need it. :)
 
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Remy

Administrator
I also think caffeine is a pretty good test for whether or not high adenosine may be an issue.

Wikipedia says this:

Caffeine's stimulatory effects, on the other hand, are credited primarily (although not entirely) to its inhibition of adenosine by binding to the same receptors, and therefore effectively blocking adenosine receptors in the CNS. This reduction in adenosine activity leads to increased activity of the neurotransmitters dopamine and glutamate.
I use caffeine a lot, but have been trying to drink more green tea than Coke Zero lately. :)
 

IrisRV

Well-Known Member
I also think caffeine is a pretty good test for whether or not high adenosine may be an issue.
Expound, please. :) I may be foggy today, but it's not clear to me how one would do this informal test. Drink a lot of caffeine and look for.....?
 

Remy

Administrator
Expound, please. :) I may be foggy today, but it's not clear to me how one would do this informal test. Drink a lot of caffeine and look for.....?
Feeling better. :) More energy, less brain fog...basically does it wake you up or just leave you still tired but feeling jittery? Obviously some of this will be dose and form dependent so it's a rough test only.
 

Remy

Administrator
Also just putting this here so I can remember it later...pentoxifylline blocks adenosine receptors.

Pentoxifylline has some interesting effects on the immune system and looks to decrease TNF-a pretty substantially. It also works on the adenosine 2 receptors. It also decreases interferon gamma and reduces the innate immune response. I think that this would be a good thing possibly as being stuck in the initial immune response to a pathogen doesn't seem to be helpful. I've read some where people say that is the difference between developing chronic Lyme or not - whether or not the interferon gamma drops and one switches into adaptive immune responses.

One of the metabolites of pentoxifylline is lisofylline...which is also an interesting anti-inflammatory molecule.

From wikipedia:

As well, LSF improves cellular mitochondrial function and blocksinterleukin-12 (IL-12) signaling and STAT-4activation in target cells and tissues. IL-12 and STAT-4 activation are important pathways linked to inflammation and autoimmune damage to insulinproducing cells. Therefore, LSF and related analogs could provide a new therapeutic approach to prevent or reverse type 1 diabetes. LSF also directly reduces glucose-induced changes in human kidney cells suggesting that LSF and analogs have the potential to treat the complications associated with diabetes.​
Part of my theory is also that high adenosine concentrations will put mammals into a state of hibernation. It looks like high glutamate levels can also stimulate adenosine so that all fits together. I'm very curious if lowering glutamate would be sufficient to causee adenosine levels to drop as well and possibly reverse the hibernation effect.

I'm also curious to know if vinpocetine would work in this regard even though it is structurally different.

Differences in the anti-inflammatory effects of theophylline and pentoxifylline: important for the development of asthma therapy?
Authors
Entzian P, et al. Show all
Journal
Allergy. 1998 Aug;53(8):749-54.

Affiliation
Abstract
Antiasthma drugs are now being re-evaluated for their anti-inflammatory effects. Theophylline is an immunomodulator; however, weak effects and the narrow therapeutic window make it a controversial drug. We compared the immunomodulatory potencies of theophylline with those of the xanthines pentoxifylline (POF) and A802715. Using a whole-blood, cell-culture system, we studied the effects on the release of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and interleukin-6 (IL-6) in six healthy subjects, and, in granulocyte suspensions, the effects on the release of reactive oxygen species (ROS). We also studied the influence of a 14-day treatment with theophylline or POF on the release of the cytokines named above in 14 asthmatics. We found that equimolar concentrations of A802715 most effectively inhibit ROS generation, followed by POF; the effects of theophylline were weakest. A802715-inhibited release of TNF-alpha was four times as potent as that of theophylline, and POF two times as potent. Inhibition of IFN-gamma by A802715 was three times as potent, and by POF two times. Neither drug influenced IL-6 release. After a 14-day treatment of asthmatics, POF proved to inhibit TNF-alpha release more effectively (by 44.3%) than theophylline (7.5%). It is concluded that study of xanthine derivatives in asthmatics might help the development of asthma therapy. POF seems to be an especially promising candidate.​
 

Remy

Administrator
Here's more...tying together "stress" and dysregulation in the HPA axis.

I am going to assume that stress could be interpreted in a variety of ways given that we are also not rats including physical insults from viruses, bacteria, etc.

Adenosine A2A receptor blockade reverts hippocampal stress-induced deficits and restores corticosterone circadian oscillation

VL Batalha1 , JM Pego2,3, BM Fontinha1 , AR Costenla1 , JS Valadas1 , Y Baqi4 , H Radjainia4 , CE Mu¨ller4 , AM Sebastia˜o1 and LV Lopes1 1 Institute of Pharmacology and Neurosciences, Neurosciences Unit, Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; 2 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; 3 ICVS/3B’s—PT Government Associate Laboratory, Braga/Guimara˜es, Portugal and 4 PharmaCenter Bonn, Pharmazeutische Chemie I, Pharmazeutisches Institut, University of Bonn, Bonn, Germany

Maternal separation (MS) is an early life stress model that induces permanent changes in the central nervous system, impairing hippocampal long-term potentiation (LTP) and spatial working memory. There are compelling evidences for a role of hippocampal adenosine A2A receptors in stress-induced modifications related to cognition, thus opening a potential window for therapeutic intervention.

Here, we submitted rats to MS and evaluated the longlasting molecular, electrophysiological and behavioral impairments in adulthood. We then assessed the therapeutic potential of KW6002, a blocker of A2A receptors, in stress-impaired animals. We report that the blockade of A2A receptors was efficient in reverting the behavior, electrophysiological and morphological impairments induced by MS.

In addition, this effect is associated with restoration of the hypothalamic-pituitary-adrenal axis (HPA-axis) activity, as both the plasma corticosterone levels and hippocampal glucocorticoid receptor expression pattern returned to physiological-like status after the treatment.

These results reveal the involvement of A2A receptors in the stress-associated impairments and directly in the stress response system by showing that the dysfunction of the HPA-axis as well as the long-lasting synaptic and behavioral effects of MS can be reverted by targeting adenosine A2A receptors.

These findings provide a novel evidence for the use of adenosine A2A receptor antagonists as potential therapy against psychopathologies.


Molecular Psychiatry (2013) 18, 320–331; doi:10.1038/mp.2012.8; published online 28 February 2012 Keywords: adenosine A2A receptors; corticosterone; hippocampus; HPA-axis; maternal separation; stress
 

Seanko

Well-Known Member
@Remy in the Sonnenburg's book the Good Gut they mention maternal separation in a different context...that it changes the gut biome in lab mice...

Given that they also bring up stress & the microbiome...The plot thickens (& gets more complicated.)
 

Remy

Administrator
@ZeroGravitas, I'm going to cross post your last post in the Naviaux thread here and try my best to answer some of your questions! (And never apologize for asking questions! We are all trying to work things out together. If anyone had the "right" answers, this forum would cease to exist because we would all be well and out enjoying life!).

Ooh. I think I might also have caught that New Scientist article too (about squirrel brain adenosine receptor stimulation putting them (back) into hibernation). I certainly looked up adenosine after this other 2010 New Scientist article on how adenosine in the brain builds sleep pressure (and astrocytes appear to be the source). Anyway, that's quite a lot of interesting information! The years of expertise on here are quite intimidating, so please excuse me noobing in with my half arsed thinking now...

If we take Naviaux and these results at face value ("Plasma adenosine was decreased in females[...]"), then does this seem to contradict most of the previous thinking on adenosine? Like this tiny study in 2011 that found raised serum levels in CFSers. Remy's (and other's) raised test results, and theories (that I won't risk mincing via attempting to paraphrase). Also, the natural assumption that we must have too much as it's known to create tiredness. But then:
Yes, it does seem to me to contradict previous thinking on adenosine. I know from speaking to the late RichVanK that he often saw raised adenosine on the methylation panel, but not always by any means. So it's hard for me to know what to make of this, especially since it seems to vary from men to women.​
In many ways lowered adenosine, or lowered rate of production makes more sense here. One of our biggest certainties is mitochondria under-performing (either damaged, missing or inactivated). And if the primary source of adenosine accumulation is from our (diminished) "turnover (flux) of ATP and GTP" (Naviaux), then sleepiness inducing adenosine accumulation could well be muted and slowed, in line.
Does the Naviaux paper quantify the lowered adenosine level or just say it is lower?

I've read "Extracellular adenosine concentrations from normal cells are approximately 300 nM; however, in response to cellular damage (e.g. in inflammatory or ischemic tissue), these concentrations are quickly elevated (600–1,200 nM). Thus, in regard to stress or injury, the function of adenosine is primarily that of cytoprotection preventing tissue damage during instances of hypoxia, ischemia, and seizure activity. Activation of A2A receptors produces a constellation of responses that in general can be classified as anti-inflammatory.".

I wonder how fast adenosine levels can change??


If adenosine is broken down fairly rapidly in the blood (as I seem to be reading) then won't any variation in the activity of that degrading enzyme have a bigger effect on observed serum level than it's production rate (which can't vary tooo much, without the host dying?)? Isn't the issue, as with many quantities, where does it mostly come from and how much does actually cross over between areas? Would sampling the cerebrospinal fluid (CSF) give a different/more accurate/more relevant picture of adenosine build up? Or is even that going to be quite different to in-cell levels? Also, given the stated diurnal variation, won't the time of day a sample is taken also have a large effect? (Please excuse all the blathering, I imagine much like this must have already been discussed by better than me somewhere on one of the 'Rising forums...)
It's not blathering and it's not been discussed to my knowledge.

I don't know the answers but you have good questions.

@Remy, what was your adenosine deaminase (ADA) SNP? Was it either of: the one mentioned in this different 2012 paper, causing stronger sleep pressure, depth and reduced alerness - Rs73598374 (which my 23andMe data shows a 'no call' on, frustratingly). Or even full on ADA deficiency (Wikipedia - 1 in 100k births). Also, sorry, I should probably have posted much of this in your thread on this topic.
OK, so the SNP mentioned in the 2012 paper is rs73598374, risk allele T. I'm CC so it looks like that one is OK in me.

My mutations are in AMPD1...

"rs17602729, a SNP located in the AMPD1 gene and also known as 'C34T', has at times been called the "most prevalent genetic disease mutation", at least in Caucasians. [PMID 11331279] Perhaps up to 10% of Caucasians and African-American carry one C34T allele (i.e. carry one rs17602729(A) allele) - and actually, most of them are unaware of any medically related issues since they don't typically have any particular symptoms that would warrant a trip to the doctor.
So what's the issue? The AMPD1 gene encodes the enzyme adenosine monophosphate deaminase, which is one of the key enzymes used to process the energy source ATP. The C34T variation causes a premature stop in the protein, leading to a nonfunctional AMPD1 enzyme. Some individuals - but by no means all or even a majority apparently - who are AMPD1 deficient get muscle cramps and pains when they exert themselves. The most common genotype bringing this about is rs17602729(A;A), i.e. the individuals who carry two copies of the C34T allele and therefore have no functioning AMPD1 allele. It is not known why only some of C34T homozygotes experience muscle myalgia."

Beyond that mutation, which is apparently very common, I have this very rare mutation on USP4 (rs17595410) which deubiquinates ADORA2A and could cause a functional deficiency in those receptors. "ADORA2A is an adenosine receptor, which "plays an important role in many biological functions, such as cardiac rhythm and circulation, cerebral and renal blood flow, immune function, pain regulation, and sleep. It has been implicated in pathophysiological conditions such as inflammatory diseases and neurodegenerative disorders."

I think people should be looking into adenosine and it's receptors very, very carefully as there clearly seems to be some sort of connection.
 

Remy

Administrator
From that excellent Scientific American article:

In this case, the authors of this study were looking at adenosine 2A receptors.

Adenosine is a neurotransmitter, a chemical messenger between neurons, that plays a role in promoting sleep as one of its functions.

But the role of adenosine really relies on what receptors it hits, and where those receptors are. In the hippocampus, for example, adenosine 2A receptors can increase transmission of glutamate, another neurotransmitter, and can contribute to disorders and dysfunction.

For example, high adenosine 2A receptors can be seen in response to acute stress, or in Alzheimer's. If adenosine 2A receptors in the hippocampus are altered in acute stress, and the hippocampus is altered by chronic stress in early life, does this mean that adenosine 2A receptors could have anything to do with chronic stress?
So it looks like it REALLY matters where the adenosine is and if the receptors are altered.

In my case, I wonder if theoretically having fewer ADORA2A or A2A receptors should theoretically *lower* glutamate transmission in the hippocampus and maybe this rare mutation is not deleterious but yet protective.

So many questions, where is my own research lab? :)
 
Does the Naviaux paper quantify the lowered adenosine level or just say it is lower?

I've read "Extracellular adenosine concentrations from normal cells are approximately 300 nM
Ok, so 300nM would fit with what I see listed for blood levels: ~0.3uM (on the Human Metabolome DataBase page for adenosine http://www.hmdb.ca/metabolites/HMDB00050).

On page 16 of Naviaux's Supporting Information (SI) Appendix report PDF, top 25 diagnostic metabolites for females, it lists adenosine as: "0.49" in the "fold change" column. This would presumably mean levels were about half normal, at ~150nM.
http://m.pnas.org/content/suppl/2016/08/24/1607571113.DCSupplemental/pnas.1607571113.sapp.pdf

Do you have your actual numerical value to hand for your methylation panel result that was high?

I wonder how fast adenosine levels can change??
Wikipidea's adenosine article states the Pharmacokinetics in the right side panel. It appears to be saying that it has a (serum?) half-life of <10 seconds (!), "cleared plasma <30s", rapidly converted to inosine and AMP, rapidly cleared from circulation via cellular uptake.

So, to be honest, I don't fully understand why it's possible to detect *any* in serum, at all if the ADA breakdown enzyme is in the blood sampled itself.... Ah: "Requires elevated adenosine levels for optimal enzyme activity. Binds to cell surfaces via proteoglycans and may play a role in the regulation of cell proliferation and differentiation, independently of its enzyme activity."
http://www.hmdb.ca/proteins/HMDBP11629

So the enzyme will presumably stop working below a certain concentration of adenosine(?), depending on the concentration of the enzyme itself(?) and perhaps other factors (like ph, temperature?). It's zinc dependent (so a deficiency there might be an issue?).

I've no idea if this serum enzymatic base level is what determines the actual serum level observed, though, since adenosine is also 'rapidly cleared' into cells by the plasma membrane monoamine transporter, PMAT (AKA hENT4):
This protein is an integral membrane protein that transports the monoamine neurotransmitters (serotonin, dopamine, norepinephrine) as well as adenosine,[4] from synaptic spaces into presynaptic neurons or neighboring glial cells. It is abundantly expressed in the human brain,[5] heart tissue, and skeletal muscle, as well as in the kidneys. It is relatively insensitive to the high affinity inhibitors (such as SSRIs) of the SLC6A monoamine transporters (SERT, DAT, NET), as well being only weakly sensitive to the adenosine transport inhibitor, dipyridamole. Its transport of monoamines, unlike for adenosine, is pH-insensitive. At low pH, (5.5-6.5 range, as occurs under ischemic conditions) however, its transport efficiency for adenosine becomes greater than for serotonin.
https://en.wikipedia.org/wiki/Plasma_membrane_monoamine_transporter

And this is all just in serum. What happens in the cell cytosol? Presumably there's no ADA activity there (since adenosine's kinda useful for a lot of essential things...?).

I don't know were to even start with the adenosine (and other purinergic) receptors... Which type is responsible for the sleep pressure effect? And within or outside the cell (intra/extra-cellular)? I.e. where does the daily adenosine accumulate (must be protected from blood, so inside the BBB, in the CSF, or actually in the cells)?

So many different contexts for purinergic signalling... https://en.wikipedia.org/wiki/Purinergic_signalling
[bimg=no-lightbox]https://upload.wikimedia.org/wikipedia/commons/f/f6/Purinergic_signalling.jpg[/bimg]
... even before considering the role of purinergic signalling Naviaux introduces with the cell danger response (although, not sure adenosine itself is part of that, just ATP, ADP, etc?): http://www.sciencedirect.com/science/article/pii/S1567724913002390

...

Anyway, a couple of adenosine tid-bits:

1 - serum adenosine is raised via endotoxemia (E. Coli Lipopolysaccharides - AKA simulated Herx): http://www.ncbi.nlm.nih.gov/pubmed/21211004 but is not the mediator of immune response/damage (so perhaps opposes it?).

2 - Adenosine receptor 'nanoagonists' can apparently be used to open up the blood brain barrier (for a carefully tuneable amount of time, for administering drugs to the CNS): http://www.ncbi.nlm.nih.gov/pubmed/24673594

Which is interesting/odd, right(?), because adenosine is normally anti-imflamatory, but here it's allowing large molecules into the brain, proper, which is neuro-inflamatory, yes(?), allowing the body's main immune system access to normally immune privaledged area. = Brain fog...?


Sorry it's taken a couple days to reply here (been reading up on Naviaux's work and such), I'm sure I've not said all I've thought of along the way and it's not exactly very insightful... This whole process of trying to infer meaning from internet resources, study abstracts and such I kinda feel is near utterly purile, really, sorry. I mean, at best it's like trying to spot the night sky constellations with one's eye permanently glued to a powerful telescope. Or doing a difficult jigsaw puzzle (without a box picture) while exclusively looking at the pieces down a meter length of narrow tubing. That is: one keeps stumbling over intriguing tid-bits, but there's no hope of grasping the overall context, or even the relative feature scales. Which is a critical problem, because you can sometimes tell that a thing will have an effect in this direction, but without the magnitude it may well be made irrelevant by another factor one's not even looking at, or might well end up working in reverse, or just it's meaning is just completely different in context, in vivo. And personally, I've never had the declarative memory (working, or long term) to handle all the names and terminology in chemistry or biology (let alone biochemistry). They're pretty much just arbitrary human-language-friendly handles for opaque dynamic nano-machinery. I'm much more of a systems engineer (by education). Really I can't see making progress on things as complex as manipulating metabolic networks without either having at least continuous empirical feedback (e.g. testing) or preferably a full bio-informatics simulation of all the metabolic nodes and weightings, across the different biological compartments and tissues, to allow one to poke at it and really get a *feel* for it's dynamic behaviour responses to inputs or alterations. Otherwise, adding in supplements is like trying to reverse a triple trailer articulated lorry out of a long, narrow alley, while blindfolded.

Sorry. I'm diverging a fair bit here. I guess this is more my frustration with the whole Yasko/Freddd/even RichVK protocol procedure - they always sound compelling, in theory, especially with diagrams, but inevitably go wrong almost immediately, leaving me to pull back and start all over, not seeing how it would be possible for anyone to realistically execute anything like that without a fortune to blow on continuous retesting and expert advice (even if it's fully correct and appropriate, which it won't be entirely). "Where is my own lab", indeed?! End moan.
 

Remy

Administrator
Do you have your actual numerical value to hand for your methylation panel result that was high?
24.5 x 10^8 M range (16.8-21.4). That doesn't seem to fit?

It seems like *if* adenosine was building up, it could conceivable decrease ATP production as well to slow further accumulation of adenosine.

I'll need to have a think about the rest you wrote. It's all very complicated. :)

(Try not to get frustrated...even though it is SO frustrating. We're all blind men feeling the elephant.)
 

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