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Xenon, potential applications for me/cfs and other diseases

C

copium7777

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Apr 26, 2020
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I have been curious about dissociative anaesthetics for ME/CFS for awhile. But in reading about xenon, I’m more excited by the potential applications than by ketamine, nitrous oxide, etc. The only downside seems to be cost and difficulty obtaining it.

“Xenon interacts with many different receptors and ion channels, and like many theoretically multi-modal inhalation anesthetics, these interactions are likely complementary. Xenon is a high-affinity glycine-site NMDA receptor antagonist.[136]However, xenon is different from certain other NMDA receptor antagonists in that it is not neurotoxic and it inhibits the neurotoxicity of ketamine and nitrous oxide, while actually producing neuroprotective effects.[137][138] Unlike ketamine and nitrous oxide, xenon does not stimulate a dopamine efflux in the nucleus accumbens.[139] Like nitrous oxide and cyclopropane, xenon activates the two-pore domain potassium channel TREK-1. A related channel TASK-3 also implicated in the actions of inhalation anesthetics is insensitive to xenon.[140] Xenon inhibits nicotinic acetylcholine α4β2 receptors which contribute to spinally mediated analgesia.[141][142] Xenon is an effective inhibitor of plasma membrane Ca2+ATPase. Xenon inhibits Ca2+ ATPase by binding to a hydrophobic pore within the enzyme and preventing the enzyme from assuming active conformations.[143]
Xenon is a competitive inhibitor of the serotonin 5-HT3 receptor. While neither anesthetic nor antinociceptive, this reduces anesthesia-emergent nausea and vomiting.[144]

Xenon has a minimum alveolar concentration (MAC) of 72% at age 40, making it 44% more potent than N2O as an anesthetic.[145] Thus, it can be used with oxygen in concentrations that have a lower risk of hypoxia.
...
Xenon induces robust cardioprotectionand neuroprotection through a variety of mechanisms. Through its influence on Ca2+, K+, KATP\HIF, and NMDA antagonism, xenon is neuroprotective when administered before, during and after ischemic insults.[147][148] Xenon is a high affinity antagonist at the NMDA receptor glycine site.[136] Xenon is cardioprotective in ischemia-reperfusion conditions by inducing pharmacologicnon-ischemic preconditioning. Xenon is cardioprotective by activating PKC-epsilon and downstream p38-MAPK.[149] Xenon mimics neuronal ischemic preconditioning by activating ATP sensitive potassium channels.[150]Xenon allosterically reduces ATP mediated channel activation inhibition independently of the sulfonylurea receptor1 subunit, increasing KATP open-channel time and frequency.[151]

Sports dopingEdit
Inhaling a xenon/oxygen mixture activates production of the transcription factor HIF-1-alpha, which may lead to increased production of erythropoietin. The latter hormone is known to increase red blood cell production and athletic performance. Reportedly, doping with xenon inhalation has been used in Russia since 2004 and perhaps earlier.[152] On August 31, 2014, the World Anti Doping Agency (WADA) added xenon (and argon) to the list of prohibited substances and methods, although no reliable doping tests for these gases have yet been developed.[153”
So we have an nmda antagonist with some direct effects on ion channels, increases blood volume, antagonist of 5ht3 (like zofran) , neuro and cardioprotective , and I have heard from people in the industry that it’s bejng experimented with to protect from brain damage in premature babies. I also have found some info on its use in cancer. Will post below.

The ONLY real downside seems to be cost and availability.
 
Xenon and breast cancer cell function in-vitro : 9AP6-7
Ash, S. A.1; Valchev, G.1; Crowley, P.2; Gallagher, H. G.3; Buggy, D. J.1
European Journal of Anaesthesiology: June 2014 - Volume 31 - Issue - p 160
Pharmacology
Background and Goal of Study: Breast cancer is one of the most common causes of cancer death among women, usually from metastasis. Several perioperative factors may influence the development of metastasis. Volatile agents have been implicated in metastasis-enhancing effects on cancer cell biology. The noble gas Xenon is an anaesthetic with many desirable properties, but its effects on cancer cell biology are unknown. Therefore, we investigated the effect of Xenon and Sevoflurane on proliferation, migration and expression of angiogenesis biomarkers in breast adenocarcinoma cell cultures in-vitro.
Materials and methods: MDA-MB-231 (estrogen receptor negative, ER-) and MCF-7 (estrogen and progesterone receptor positive, ER+) breast cancer cells were seeded in 96-well plates and exposed to experimental or control gas concurrently in two hermetic chambers. The Xenon cylinder contained O2 25 %, CO2 5% and Xenon 70%. The Control gas cylinder contained O2 25 %, CO2 5% and N2 75%. Sevoflurane 2.5% was administered in control gas. Methylthaizolyldiphenyl-tetrazolium-bromide (MTT) assay evaluated the effect of Xenon on cell viability. Cancer cell migration was determined using the Oris™ Cell Migration Assay, its mechanism with addition of glycine or glipizide. Human Angiogensis Array C1 quantified the expression of angiogenesis markers in the cellular supernatant.
Results: Cell exposure to each gas mixtures for 1, 3 or 5 hr had no effect on cell viability in either cell. Xenon reduced ER- migration to 59±13% following 1 hr exposure, P=0.02; to 64±10% at 3 hr, P=0.01; and 71±9% at 5 hr, P=0.04. Similar results were observed in ER+ cells. Sevoflurane had no effect on migration. Glycine, a NMDA receptor agonist, competitively reversed Xenon inhibition of migration, increasing ER- migration to 190±44%, P=0.02 and ER+ migration to 173±17%, P=0.02. No effect was observed with addition of glipizide. Examination of the angiogenisis array film in Xenon exposed media showed decreased RANTES cytokine compared with Sevoflurane and Control (mean dot density 2.05±0.20 vs 2.95±0.07 and 3.1±0.28 respectively, P=0.02).
Conclusion: Xenon inhibits breast cancer cell migration in both ER+ and ER- breast cancer cells by an NMDA receptor mediated mechanism, whereas Sevoflurane does not. Xenon decreases expression of breast cancer angiogenesis factor RANTES compared with Sevoflurane.
Acknowledgements: Funded by an unrestricted research grant from Air Liquide, manufacturers of xenon.
 
Reason I think it may be helpful in me/cfs and fibro, besides the broad Neuro and cardio protection , is increase in blood volume, and nmda antagonism in an illness that may involve disturbed gaba/glutamate balance.
 
Thinking of ketamine as an extreme and far-flung but efficient anti-depressant, I wonder how the binding in Xenon differs in not resulting in dopamine influx. Reminds me of all the allosteric binding sites tentatively found on the DAT, I wonder how far they've mapped the NMDA binding site.
 
Nagelfar said:
Thinking of ketamine as an extreme and far-flung but efficient anti-depressant, I wonder how the binding in Xenon differs in not resulting in dopamine influx. Reminds me of all the allosteric binding sites tentatively found on the DAT, I wonder how far they've mapped the NMDA binding site.
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Xenon is really odd in terms of binding. It is listed as having all of these specific affinities but i have also read that with the structure of noble gases they dont bind to any specific receptor but dissolve in tbe cell membrane and alter the structure /function, leading to their anesthetic properties. Its all a little bit over my head and hard to reconcile with reading that the gas binds to such and such receptor
 
Isn't xenon incredibly expensive? Xenon is present in the atmosphere at levels of only 87 parts per billion and must be seperated by multi-stage cryogenic fractional distillation of liquified air. Global production is 5 million liters per year. I think I remember people going to great extents to develop closed-loop systems to recirculate xenon in a person's air supply. A review on xenon as an anesthetic gives figures of 15 to 36 liters of xenon being used per session. Praxair, my local supplier of compressed gases, gave a price quote of $24 CAD per liter of pure Xe circa 2014. Aldrich wants $35 CAD per liter. I've also heard pricings of $10 USD/L, or as far gone as $275 a liter (for a single liter of xenon in New Zealand, ref) This all adds up to a potential cost of $1,260 CAD for xenon alone (36 liters at $35/L CAD) - a little too high for comfort!

For comparison, compressed oxygen is about 0.2 cents per liter. Compressed nitrous oxide is around once cent per liter. Sevoflurane theapy works out to $18 per hour or so and is "50% the cost" of xenon.
 
sekio said:
Isn't xenon incredibly expensive? Xenon is present in the atmosphere at levels of only 87 parts per billion and must be seperated by multi-stage cryogenic fractional distillation of liquified air. Global production is 5 million liters per year. I think I remember people going to great extents to develop closed-loop systems to recirculate xenon in a person's air supply. A review on xenon as an anesthetic gives figures of 15 to 36 liters of xenon being used per session. Praxair, my local supplier of compressed gases, gave a price quote of $24 CAD per liter of pure Xe circa 2014. Aldrich wants $35 CAD per liter. I've also heard pricings of $10 USD/L, or as far gone as $275 a liter (for a single liter of xenon in New Zealand, ref) This all adds up to a potential cost of $1,260 CAD for xenon alone (36 liters at $35/L CAD) - a little too high for comfort!

For comparison, compressed oxygen is about 0.2 cents per liter. Compressed nitrous oxide is around once cent per liter. Sevoflurane theapy works out to $18 per hour or so and is "50% the cost" of xenon.
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It is expensive. That is basically the only downside. If one is buying in large bulk quantities the price becomes a little more reasonable but for those quantities were definitely talking at least a few thousand--got a quote from a local noble gas supply company.

Yes, the name xenon refers to how rare it is in atmosphere
 
I think it is fairly potent and i found one source saying an anesthetic dose might be around a liter an hour so for smaller doses ,it seems like one could get decent bang for buck, if one could do a bulk purchase , maybe split it with friends. Etc
 
Neuroprotective and neurorestorative potential of xenon
J Lavaur, M Lemaire, [...], and P P Michel

Additional article information

Xenon is a monatomic gas that belongs to the family of noble gases. Like other noble gases, it is characterized by a filled valence shell and therefore exhibits low chemical reactivity. Paradoxically, xenon possesses a remarkable spectrum of biological effects that are of potential clinical interest. Xenon is an approved anesthetic drug with analgesic properties.1, 2 In addition to that xenon is neuroprotective in preclinical models of focal and global brain ischemia, spinal cord ischemia and traumatic brain injury.1, 2 These neuroprotective effects are generally observed at concentrations of xenon ranging from 35 to 75%.1, 2, 3 Although the activation of ATP-sensitive potassium channels or of two-pore potassium channels may explain some of the neuroprotective effects of xenon, the noble gas appears to work primarily by limiting the overstimulation of N-methyl-d-aspartate (NMDA) glutamate receptors under excitotoxic stress conditions.1, 4 More specifically, xenon has been reported to compete with glycine, a co-agonist for NMDA receptor activation.1
Excitotoxic stress mediated through NMDA receptors is most generally associated to acute central nervous system insults such as ischemia and traumatic brain injury, but chronic, low-level overexcitation of these receptors is also a possible contributor to neuronal death in a number of chronic neurodegenerative conditions, including amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease (AD).5, 6 The implication of excitotoxic stress in AD-mediated neurodegeneration is specifically supported by studies reporting the benefits of treatments with NMDA receptor antagonists in preclinical models of the disease.7 Of interest, one of these antagonists memantine has also a small beneficial effect on cognitive impairment in AD patients.7, 8
In our work published in Cell Death Discovery,9 we explored for the first time the neuroprotective potential of xenon in experimental settings that mimic sustained, low-level excitotoxic stress as it may occur in the AD pathology. For that, we established cultures of neurons typically affected in this disorder, that is, cortical neurons and basal forebrain cholinergic neurons,10, 11 and exposed them to l-trans-pyrrolidine-2,4-dicarboxylic acid (PDC), a synthetic glutamate analog that provokes an increase in ambient glutamate through the blockade of glutamate uptake and the stimulation of its release.
When the conventional cell culture atmosphere was substituted with a gas combination, including the same amount of oxygen (20%) and carbon dioxide (5%) but 75% xenon instead of nitrogen, we observed a substantial reduction of neuronal loss induced by PDC. The noble gas argon remained inactive against PDC, pointing to the specificity of the effects of xenon in the present paradigm. Neuroprotection by xenon was mimicked by two noncompetitive antagonists of NMDA glutamate receptors memantine and ketamine, indicating that xenon might work itself by antagonizing NMDA receptors. Coherent with this view, we found that xenon remained strongly protective when NMDA, a specific agonist for NMDA receptors was used instead of PDC to trigger the death of cortical neurons. Note that we failed to demonstrate a competitive inhibition of xenon at the glycine-binding site of NMDA receptors, which is in apparent contradiction with previous reports.1 Yet, molecular dynamic simulation studies predict different sites of action for xenon on the NMDA receptor.4
Most interestingly, we found that memantine and ketamine potentiated xenon-mediated neuroprotection when each of these compounds was used at concentrations providing suboptimal rescue to cortical neurons and, most surprisingly, no rescue at all. The nature of this cooperative interaction needs to be further characterized. Yet, we may assume that it was due to the fact that xenon on one hand, and memantine and ketamine on the other hand, acted through distinct binding sites to modulate NMDA receptor activity. This type of cooperative effect is of potential clinical interest in the context of AD, as memantine is an approved drug for the treatment of this disorder.7, 8
Basal forebrain cholinergic neurons represent another type of neurons particularly vulnerable in the AD pathology.11, 12 Besides exerting true neuroprotective effects for cholinergic neurons, we established that xenon was providing trophic support for these neurons as well. This trophic effect that was most prominent in control cultures remained observable in PDC-treated cultures. The analysis of the trophic effects of xenon, revealed that the noble gas increased the size of cholinergic cell bodies and stimulated the cellular expression of the cholinergic marker protein, choline acetyltransferase transferase (ChAT). A subset of dormant cholinergic neurons was also probably the target of xenon effects as the gaseous treatment increased the number of ChAT+ neurons in cultures not exposed to PDC. Memantine amplified some of the effects of xenon on cholinergic neurons but was generally less efficacious than the noble gas when applied alone to the cultures. In relation with these observations, NMDA receptor blockade was reported to promote the expression of cholinergic traits during development in subsets of forebrain glutamatergic neurons.13 Thus, it is reasonable to believe that NMDA receptor antagonism accounted for both the trophic and restorative effects of xenon. These data are of interest as there is evidence from experimental lesions in animals and post-mortem human studies that phenotypic markers disappear early from basal forebrain cholinergic neurons vulnerable to AD pathology.12
In summary, present data demonstrate that the noble gas xenon has the ability to provide protection and to exert trophic or restorative effects for AD vulnerable neurons (Figure 1). Noticeably, some of the effects of xenon were improved by the AD medication memantine. Altogether, these observations are an indication that the noble gas may have potential utility for AD treatment.
 
I have a friend in Germany who runs a roaring trade in xenon blood doping for professional/semi-pro athletes. FWIW the xenon is added into blood outside the body with some funky machinery before being returned to circulation.
 
Have been interested in Xenon ever since I read about (well, it's a dissociative at last, and I gotta try them all) but I guess my chances are somewhat higher to get rich by playing bets than I ever will hold enough xenon in my hands to do anything meaningful with it.. so my interest wandered away to other molecules with interesting properties ...

What you write @CFC sounds strangely interesting though. Guess the right dissociative in the right dosage can make a decent doping agent, yeah. Remember when I was on Malta and somewhat happened to hurt my knee, could barely walk but then sky-high on ketamine I joined a tour with heavy bagpack straight through the iland and couldn't have cared less ...
 
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I wonder if xenon has any affinity for the sigma receptors. Although the function of the receptor itself is still largely a mystery a lot of dissociatives are known to be sigma agonists. Sigma agonism has been consistently implicated in altering basic motor functions in various ways, which could make sense given the use of it in athletics
 
dopamimetic said:
What you write @CFC sounds strangely interesting though. Guess the right dissociative in the right dosage can make a decent doping agent, yeah. Remember when I was on Malta and somewhat happened to hurt my knee, could barely walk but then sky-high on ketamine I joined a tour with heavy bagpack straight through the iland and couldn't have cared less ...
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Not sure about the dissociative effect being beneficial, but xenon has some direct PED qualities, in particular increasing oxygen transport capacity, but is harder to catch than many other substances known to boost EPO > RBCs, hence its popularity among some tested athletes.
 
Well my experiences with N2O were pretty disappointing, maybe my tolerance was too high but yeah if it's just about the dissociation youll be better off with arylcyclohexylamines but if xenon should have independent benefits like memantine or selegiline, then it becomes interesting again..
 
Trying to get a quote but I don't have any idea what size bottle to ask for
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Ask them what sizes they can supply? You probably want a lecture bottle, which i think is 25L, unless you need insane amounts. I think they supply Xe in a K size tank, that's 5000 L.



Well my experiences with N2O were pretty disappointing
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How so? N2O is pretty fun for me. Where did you get it from, whippets or a tank?
 
sekio said:
Ask them what sizes they can supply? You probably want a lecture bottle, which i think is 25L, unless you need insane amounts. I think they supply Xe in a K size tank, that's 5000 L.
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Yeah a lecture cylinder seems like plenty butthe price per liter seems wayyyy better in bulk so ideally I'd like to get a bigger cylinder and split it with others, however I can't find anyone who wants to split, or manage the logistics of transferring a gas to separate containers.
 
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