Anti-purinergic therapy restores itaconate/IFNa (Dr. Phair's theory) and Dr. Prusty's proposed abnormalities in ME/CFS

[serg1942]

@serg1942 and all,



We know that the inflammation/cytokines lead to the negative symptoms and so first thought was to reduce them via inhibiting the NLRP3 inflammasome at minimum in earlier phases which would therefore stop all the subsequent downstream cascade of effects by blocking the cytokines. That is where palmitoylethanolamide, doxycycline, and colchicine which all inhibit the NLRP3 inflammasome that have shown benefits may be effective before all the major downstream issues set in. Suramin happens to be another NLRP3 inhibitor and why its helpful in inflammatory conditions including autism and likely ME/CFS in earlier phases. I have lists of dozens of them, but those also happen to have potential additional effects on other areas known to be related to ME/CFS and some have reported benefits.

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/ The NLRP3 inflammasome is present primarily in immune and inflammatory cells, including mast cells, neutrophils, and macrophages, following activation by inflammatory stimuli and is a good target to stop downstream effects that can lead to ME/CFS.

Consistently, apyrase (extracellular ATP scavenger), suramin (P2 receptor inhibitor), TNP-ATP (P2X receptor antagonist), and 5-BDBD (P2X4 inhibitor) downregulate NLRP3 expression https://www.nature.com/articles/s41401-022-00886-7

Viruses can trigger a biochemical pathway, known as the immune complement system...Complement activation then elicits secretion of both IL-1β and IL-18 via activation of the NLRP3 inflammasome https://pubmed.ncbi.nlm.nih.gov/23817414/

These articles were discussing the activation of the NLRP3 inflammasome in regard to COVID-19 which is not the same
https://www.sciencedirect.com/science/article/pii/S0024320520308651
Palmitoylethanolamide inhibits NLRP3 inflammasome expression (such as mentioned here expressed by sars-cov-2 spike protein). However it also helped with the gut barrier, restructuring the gut bacteria and short chain fatty acid profile, and inhibits STING so that was my first thought over some of the other options that appear to help from their NLRP3 inhibition which I can provide a list I started awhile ago.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472716/ And of course sodium butyrate in later stages should help with the pem and energy as another thought I've mentioned so far in addition to inflammation and perhaps helping to restore TH1.

Regarding Dr Phairs latest video about IL-1a, which they suggested as a potential target:

This article confirms IL-1 can induce production and release of more IL-1, a process described as an autoinflammatory loop. Anakinra is a bio-engineered form of the naturally occurring interleukin-1 receptor antagonist (IL-1ra) that blocks the action of interleukin-1. It is routinely used in patients with autoimmune and inflammatory disorders and MAS. Within the IL-1 family of cytokines, several inhibitory mechanisms are in place to prevent runaway inflammation induced by IL-1α or IL-1β. The main mechanism is the IL-1 receptor antagonist (IL-1Ra), which blocks the IL-1R1 and prevents binding of IL-1α and IL-1β. In contrast to JAKinibs, anakinra will not directly block the IFN-STAT1/STAT2 pathway critical for host defense against viral infections. Third, in contrast to tocilizumab (an IL-6 inhibitor), it targets and inhibits the core mechanism in the pathogenesis of MAS, namely the hyperactive inflammasome loop https://ccforum.biomedcentral.com/articles/10.1186/s13054-020-03166-0

This one metions neutralization of IL-1α inhibits the antiviral activity of IFN-γ by 90%, whereas no inhibition of type I IFN activity was observed. Indeed, the antiviral activity of IFN-γ depends largely on the basal level of NF-κB, which is maintained by constitutively expressed IL-1α. https://www.sciencedirect.com/science/article/pii/S1568997221000227#s0070

Thanks @bob800 The paper says Several studies in inflammatory and noninflammatory illnesses have assessed the effect of IL-1 inhibition on fatigue severity, and most have found positive effects. Studies using daily anakinra injections (100 mg) found decreased fatigue within 4 weeks of treatment. To investigate the role of proinflammatory activity in CFS, we conducted a randomized, placebo controlled trial in female patients with CFS using the IL-1 receptor antagonist anakinra. All patients had severe fatigue leading to functional impairment. a decision was made to exclude patients with illness lasting more than 10 years - Median illness duration (range), mo 44 (7–109).

So its possible here that this treatment can work on earlier states of ME/CFS where the inflammation level is still currently high as would things like NLRP3 inflammation inhibition to a greater degree which would help prevent further deterioration. However in the later phase it does not appear that IL-1 inhibition alone at that point ( at least via anakinra that may not be able to reach the brain) can recover the subsequent lasting alterations that happen from the chronic inflammatory state and requires a different treatment approach as expected, which is important to note the two phases patients can be in.

Hi @datadragon,

Thank you for your message, it's really interesting.

Perhaps the IL-1 receptor is too downstream to reverse the cell danger response cascade. I prefer to inhibit the purinergic system from the very top, so that not only the inflammasome is inhibited, but also the rest of the inflammatory response, including IFNs I secretion and Janus Kinase activation. And most importantly, it does so without suppressing the immune system (This fits with the review you've quoted where it's explained that IL-1a neutralization inhibits IFN gamma activity, but not IFNI).

I have actually been taking an anti-purinergic combo for a month, including lidocaine (anti-p2x7), probenecid (anti-pannexin-1), glycyrrhizic acid (anti-pannexin-1 and anti-connexin 43) and brilliant blue FCF (anti-pannexin-1), and my IL1beta secreted by PBMCs ex vivo, after stimulation with LPS and ATP has decreased to half of the baseline level.

Another problem with the study is that it is too short. One month won't be enough to heal a long term body with CFS. I have actually experienced a hard flare from the anti-purinergic drugs for about 20 days or so, and now that I have recovered my baseline, I don't think I'll be seeing any improvement for the next months. This happens with most successful treatments for ME/CFS, such as GcMAF, LDN, antibiotics, antivirals, etc. There are cross-reactive "inflammation-producing" antibodies and memory cells which will live for months. Also, there are many intracellular infections and accumulated toxins which will have to be dealt with once the immune system starts to connect better with itsself and the CNS.

I had read about palmitoylethanolamide time ago, but I didn't remember it to inhibit the inflammasome assembly or STING expresson. I will take a look at it!

As for butyrate, yes, I like it, and that's why I am following a very strict ketogenic diet, because I think that beta-hydroxy-butyrate can behave identically to luminal butyrate in the gut.

Thanks again,
Sergio

 

[Violeta]

Just some notes I found when looking up adenosine and glutamate.


Adenosine has several functions in the central nervous system (CNS) that are critical for proper brain function. As a neuromodulator, one of the main functions of adenosine is to inhibit glutamate release via presynaptic A1 receptors in the nucleus accumbens.

Adenosine inhibits the action potential-dependent excitatory inputs to large Ih GABAergic neurons via A1 receptors and a presynaptic mechanism, but has no effect on their inhibitory inputs.

Studies have also shown that adenosine is released [3] from cortical slices and inhibits acetylcholine (ACh) release from cholinergic terminals evoked by axonal stimulation via activation of theophylline-sensitive receptors.

Adenosine and glutamate signaling are interrelated, with adenosine decreasing glutamate neurotransmission but glutamate, and receptor agonists, increasing cellular release of adenosine.

Adenosine and Glutamate Signaling in Neuron-Glial interactions: Implications in Alcoholism and Sleep Disorders​

https://www.ncbi.nlm.nih.gov/pmc/ar... are,increasing cellular release of adenosine.

 

[Thebirdman333]

Just some notes I found when looking up adenosine and glutamate.


Adenosine has several functions in the central nervous system (CNS) that are critical for proper brain function. As a neuromodulator, one of the main functions of adenosine is to inhibit glutamate release via presynaptic A1 receptors in the nucleus accumbens.

Adenosine inhibits the action potential-dependent excitatory inputs to large Ih GABAergic neurons via A1 receptors and a presynaptic mechanism, but has no effect on their inhibitory inputs.

Studies have also shown that adenosine is released [3] from cortical slices and inhibits acetylcholine (ACh) release from cholinergic terminals evoked by axonal stimulation via activation of theophylline-sensitive receptors.

Adenosine and glutamate signaling are interrelated, with adenosine decreasing glutamate neurotransmission but glutamate, and receptor agonists, increasing cellular release of adenosine.

Adenosine and Glutamate Signaling in Neuron-Glial interactions: Implications in Alcoholism and Sleep Disorders​

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3349794/#:~:text=Adenosine and glutamate signaling are,increasing cellular release of adenosine.

Probably why GABA drugs like Pregabalin, Ativan, etc. Have been known to help a large portion of us sick people.