Xe and Thee

The six elements in the far-right column of the periodic table (1), a table first constructed by my maternal great-granduncle Dmitry, are the noble gases. They are termed ‘noble’ because they hardly react to anything; they display a chemically aristocratic amalgam of hauteur and froideur. 

Unruly life forms like us fret at the opposite end of the table, far below the salt. We react and adapt constantly to almost everything, although most reactions occur deep inside our cells and tissues and their effects may not become noticeable for decades, if ever.

We do this because surviving and procreating in an infinitely dynamic world requires continuous adaptative change. 

Anthropologists and historians know that humans are highly adaptable, and so do life scientists. In 1865 Claude Bernard discovered the stability of le milieu intérieur (2), and in 1932 Walter Cannon revealed that this stability was maintained via the balancing act of homeostasis. Their work explains why evolution engineered redundancy and many other types of buffering systems into us (ie 3-7), allowing us to handle continuous change while remaining, mostly, the same.

Classic examples of homeostatic systems include the maintenance of body temperature and blood pressure, but it is hard to find any life process where the principles of homeostasis do not prevail. 

We are buffered six hundred ways from Sunday; from the shock absorbing qualities of CSF to the calorific reserve functions of adipose tissue, selective filtering by the placenta and blood brain barrier, the modification of gene expression by epigenetic markers (7), the relationship between genome and microbiome, proteostasis (8), immune function (ie 9), our ability to rationalise …

This enables sophisticated life forms like us to think of ourselves as la plus haute d’haute couture. The design, however, is not as exclusive as we used to think.  

There is a good argument to be made that every aspect of who and what we are is fashioned to support a homeostasis that preserves the hologenome (the totality of host and microbiomal genes) (10); with apparently defining human traits such as self-awareness little more than emergent accidents. If this is accurate, evolutionary biologist Lynn Margulis joins Copernicus and Darwin at the top table of deflators of human self-importance.

Returning to more pragmatic ground, the sensory, buffering and feedback elements of homeostasis utilise and require a large number of macro-, micro- and phytonutrients, which are present at relatively high levels in traditional diets. These are the diets we co-evolved with, and abandoned only very recently. 

In contrast, the modern diet and lifestyle leave us multiply depleted (11) and calorifically overloaded. Our ability to maintain the milieu interieur is thus degraded and simultaneously overwhelmed, leaving us more systemically fragile than our ancestors and more vulnerable to stressors of all kinds.

Increasing numbers of intra- and extra-cellular parameters shift beyond their safety margins, homeostatic elements fail and cells are forced to activate the Integrated Stress Response and the more encompassing Cell Danger Response (12). The acute activation of these responses is entirely positive (13, 14), but the chronic activation caused by our post-modern lifestyles degrades the homeostatic control of mitochondrial function and intracellular protein quality, eventually proceeding via a series of checkpoints to programmed cell death (15, 16). 

Tissues become inflamed, disorganised and dysfunctional (17), and we set out on the long and largely unnecessary road to chronic non-communicable disease.

That so many of us follow this path is manifest in our failing public health, referred to in many previous posts. Health services everywhere are failing to stem the rising tides of non-communicable chronic degenerative disease, a category which now includes the neuro-psychological and neuroprogressive pathologies of anxiety and depression (18). The Chronic Integrated Stress and Cell Danger Responses create inter alia neuroinflammation (19), explaining the increasing case load of psychopathology and neurodegenerative disease (20-22).

All of which makes the latest candidate treatment for these conditions very odd indeed. It is the noble gas, Xenon, which has shown clear and specific pharmacological activity in pre-clinical and clinical models.

Hold on. How can a famously non-reactive element interact with a dynamically homeostatic mouse or man?

Xenon does not form covalent bonds with other elements except under extreme duress, such as fluorination. However, its large outer electron shell can be deformed and polarised by nearby charged molecules, thus creating the possibility of dipole or electrostatic interactions. In the body it binds in this way to proteins (23). It also binds to the polar headgroups of the phosphatidyl phospholipids that make up the bulk of the cell membrane (24), thereby blocking the N-methyl-d-aspartate (NMDA) receptor. 

As glutamate is a major excitatory neurotransmitter, blocking NDMA receptors induces anaesthesia. The anaesthetic properties of xenon were first glimpsed in 1939 (25), when navy scientists found it induced the “martini effect’ in deep sea divers. They were clinically proven in 1951 (26) and are now integrated into specialised clinical anaesthesiology (27, 28).

Excess glutamate is cytotoxic, so NDMA receptor blockade would also be expected to be neuroprotective. Xenon combines its anaesthetic effects with neuroprotective effects in stroke (29) and trauma (30, 31) and excellent safety data, constituting a very useful therapeutic profile (32, 33). Xenon’s noble cousin argon confers similar but subtly different benefits (34-38).

But the NDMA receptor blocking effect opens some other interesting avenues. NDMA blockade is one of the ways ketamine works to degrade maladaptive reward memories, the kind that fuel addiction, addictive behaviours and unhappiness (39). A quick sniff of xenon may therefore help re-wire a bad brain if co-presented with the object of addiction, and break or at least weaken the self-destructive impulse to give in (40).

Because this is related to impulse control and resilience (41), it is not surprising that NDMA receptor blocking drugs such as ketamine also have anti-depressant and anxiolytic effects (42-45); as do natural NDMA blockers including xenon (40, 46-47), saffron (48), the curcuminoids (49, 50) and doubtless other polyphenols.

Which brings us back to where we started.

More and more adults and children are presenting with depression and anxiety disorders (20-22, 51, 52), due in part to our increasingly neuro-inflammatory diets.

As medics are trained to think in terms of pharmaceutical medicine, most patients end up with prescriptions for psychotropic drugs, which come with multiple problems. Natural and safer alternatives include xenon, which provides an interesting but expensive alternative – mini-tanks of the stuff start at $200 (53) – and my personal favourite, a validated saffron extract.

Saffron is superior in every way to the current drugs of choice (54), but in a sense, we are still fiddling as Rome burns. It would be better if we could repair the foundations.

The multiple feedback and control systems that maintain homeostasis and underpin our health developed in an age when our ancestors ate an unprocessed diet, and depend on the presence of dietary catalysts and damping agents that have been abstracted from today’s industrial foods.

We should put them back. Only in this way can good health be expected to flow, once again, through the control systems and feedback loops of individual health. 

Public health requires a complementary approach.

To achieve that we must remove the clots who have accumulated in the arteries of office. Hopefully, as lighting and hot water systems are switched off all over Europe, as cold and hunger grow and the full horror of force de-industrialisation sets in, thrombolytic therapy will be administered. I prefer the ballot and jury boxes, but if they are sealed a third box may be needed.

People are beginning to fight back against governmental incompetence and the over-reach of undemocratic place-holders such as Macron, von der Leyen, Rutte, Baerbock and Habeck. Restoring local autonomy, enforcing term limits and switching to de-centralised digital currencies (as opposed to government-issued and enforced central bank digital currency), will do a great deal to increase the sum total of human happiness.

Until that glorious new dawn, we must endure and renounce. Until then, Xenon and saffron may help. 

Next week: Growing Pains

References: 

References 2 and 4 are particularly worth reading. Billman’s paper is elegant and Bernard’s book is beautiful. I cannot do it justice here, or anywhere else for that matter.

1. There is a semi-theoretical 7^th columnist now. Helium (He), neon (Ne) argon (Ar), krypton (Kr) xenon (Xe) and radon (Rn) have been joined by oganesson (Og). A very few atoms of transuranic oganesson were created by Russian physicists at the Joint Institute for Nuclear Research in Dubna, 2002. 
2. Bernard C. An Introduction to the Study of Experimental Medicine. 1865
3. Schmitt BM. The concept of “buffering” in systems and control theory: from metaphor to math. Chembiochem. 2004 Oct 4;5(10):1384-92.
4. Billman GE. Homeostasis: The Underappreciated and Far Too Often Ignored Central Organizing Principle of Physiology. Front Physiol. 2020 Mar 10;11:200.
5. https://whitesmoke-heron-286383.hostingersite.com/blog/eloi-and-morlocks/
6. https://whitesmoke-heron-286383.hostingersite.com/blog/turn-fat-into-muscle/
7. https://whitesmoke-heron-286383.hostingersite.com/blog/the-meth(yl)-lab
8. https://whitesmoke-heron-286383.hostingersite.com/blog/know-when-to-fold-em/
9. Liston A, Gray DH. Homeostatic control of regulatory T cell diversity. Nat Rev Immunol. 2014 Mar;14(3):154-65.
10. van de Guchte M, Blottière HM, Doré J. Humans as holobionts: implications for prevention and therapy. Microbiome. 2018 May 1;6(1):81.
11. https://whitesmoke-heron-286383.hostingersite.com/blog/the-fear-of-food/
12. Naviaux RK. Perspective: Cell danger response Biology-The new science that connects environmental health with mitochondria and the rising tide of chronic illness. Mitochondrion. 2020 Mar;51:40-45.
13. Romero-Ramírez L, Nieto-Sampedro M, Barreda-Manso MA. Integrated Stress Response as a Therapeutic Target for CNS Injuries. Biomed Res Int. 2017;2017:6953156.
14. Huang TC, Luo L, Jiang SH, Chen C, He HY, Liang CF, Li WS, Wang H, Zhu L, Wang K, Guo Y. Targeting integrated stress response regulates microglial M1/M2 polarization and attenuates neuroinflammation following surgical brain injury in rat. Cell Signal. 2021 Sep;85:110048.
15. Hetz C, Papa FR. The unfolded protein response and cell fate control. Mol. Cell 69, 169–181 (2018).13.
16. Hetz C, Chevet E, Oakes SA. Proteostasis control by the unfolded protein response. Nat. Cell Biol. 17, 829–838 (2015).
17. Costa-Mattioli M, Walter P. The integrated stress response: From mechanism to disease. Science. 2020 Apr 24;368(6489):eaat5314.
18. Stein DJ, Benjet C, Gureje O, Lund C, Scott KM, Poznyak V, van Ommeren M. Integrating mental health with other non-communicable diseases. BMJ. 2019 Jan 28;364:l295.
19. Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Martin MG, Halliday M, Morgan J, Dinsdale D, Ortori CA, Barrett DA, Tsaytler P, Bertolotti A, Willis AE, Bushell M, Mallucci GR. Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature. 2012 May 6;485(7399):507-11
20. Operation Freedom’s Sentinel, Operation Inherent Resolve, Operation New Dawn, Operation Iraqi Freedom, and Operation Enduring Freedom. August 7, 2015. www.crs.gov, http://news.usni.org/tag/oef.
21. https://adaa.org/understanding-anxiety/facts-statistics
22. Proudman D, Greenberg P, Nellesen D. The Growing Burden of Major Depressive Disorders (MDD): Implications for Researchers and Policy Makers. Pharmacoeconomics. 2021 Jun;39(6):619-625. 
23. Trudell JR, Koblin DD, Eger IE II: A molecular description of how noble gases and nitrogen bind to a model site of anesthetic action. Anesth Analg 1998; 87:411–8
24. Xu Y, Tang P. Amphiphilic sites for general anesthetic action? Evidence from ¹²⁹Xe-[1H] intermolecular nuclear Overhauser effects. Biochim Biophys Acta 1997; 1323:154–62
25. Behnke AR, Yarborough OD: Respiratory resistance, oil water solubility and mental effects of argon compared with helium and nitrogen. Am J Physiol 1939, 126(2),409-415
26. Cullen SC, Gross EG. The anesthetic properties of xenon in animals and human beings, with additional observations on krypton. Science 1951; 113:580–2
27. Franks NP, Dickinson R, de Sousa SLM, Hall AC, Lieb WR. How does xenon produce anaesthesia? Nature. 1998;396:324–324.
28. Esencan E, Yuksel S, Tosun YB, Robinot A, Solaroglu I, Zhang JH. XENON in medical area: emphasis on neuroprotection in hypoxia and anesthesia. Med Gas Res. 2013 Feb 1;3(1):4.
29. Koziakova M, Harris K, Edge CJ, Franks NP, White IL, Dickinson R. Noble gas neuroprotection: xenon and argon protect against hypoxic-ischaemic injury in rat hippocampus in vitro via distinct mechanisms. Br J Anaesth. 2019 Nov;123(5):601-609.
30. Campos-Pires R, Onggradito H, Ujvari E, Karimi S, Valeo F, Aldhoun J, Edge CJ, Franks NP, Dickinson R. Xenon treatment after severe traumatic brain injury improves locomotor outcome, reduces acute neuronal loss and enhances early beneficial neuroinflammation: a randomized, blinded, controlled animal study. Crit Care. 2020 Nov 27;24(1):667.
31. Campos-Pires R, Koziakova M, Yonis A, Pau A, Macdonald W, Harris K, Edge CJ, Franks NP, Mahoney PF, Dickinson R. Xenon Protects against Blast-Induced Traumatic Brain Injury in an In Vitro Model. J Neurotrauma. 2018 Apr 15;35(8):1037-1044.  
32. Baumert J-H. Xenon-based anesthesia: theory and practice. Open Access Surgery. 2009;2:5–13.
33. Jin Z, Piazza O, Ma D, Scarpati G, De Robertis E. Xenon anesthesia and beyond: pros and cons. Minerva Anestesiol. 2019 Jan;85(1):83-89.
34. Qi H, Zhang J, Shang Y, Yuan S, Meng C. Argon inhibits reactive oxygen species oxidative stress via the miR-21-mediated PDCD4/PTEN pathway to prevent myocardial ischemia/reperfusion injury. Bioengineered. 2021 Dec;12(1):5529-5539. 
35. Liang M, Ahmad F, Dickinson R. Neuroprotection by the noble gases argon and xenon as treatments for acquired brain injury: a preclinical systematic review and meta-analysis. Br J Anaesth. 2022 Aug;129(2):200-218.
36. Harris K, Armstrong SP, Campos-Pires R, Kiru L, Franks NP, Dickinson R. Neuroprotection against traumatic brain injury by xenon, but not argon, is mediated by inhibition at the N-methyl-D-aspartate receptor glycine site. Anesthesiology. 2013 Nov;119(5):1137-48.
37. Koziakova M, Harris K, Edge CJ, Franks NP, White IL, Dickinson R. Noble gas neuroprotection: xenon and argon protect against hypoxic-ischaemic injury in rat hippocampus in vitro via distinct mechanisms. Br J Anaesth. 2019 Nov;123(5):601-609. 
38. Li X, Zhang ZW, Wang Z, Li JQ, Chen G. The role of argon in stroke. Med Gas Res. 2018 Jul 3;8(2):64-66.  
39. https://whitesmoke-heron-286383.hostingersite.com/blog/through-the-k-hole/
40. David HN, Ansseau M, Lemaire M, Abraini JH. Nitrous oxide and xenon prevent amphetamine-induced carrier-mediated dopamine release in a memantine-like fashion and protect against behavioral sensitization. Biol Psychiatry. 2006 Jul 1;60(1):49-57.
41. Russo SJ, Nestler EJ. The brain reward circuitry in mood disorders. Nat Rev Neurosci. 2013 Sep;14(9):609-25.
42. Ates-Alagoz Z, Adejare A. NMDA Receptor Antagonists for Treatment of Depression. Pharmaceuticals (Basel). 2013 Apr 3;6(4):480-99.
43. Chen BK, Le Pen G, Eckmier A, Rubinstenn G, Jay TM, Denny CA. Fluoroethylnormemantine, A Novel Derivative of Memantine, Facilitates Extinction Learning Without Sensorimotor Deficits. Int J Neuropsychopharmacol. 2021 Jul 14;24(6):519-531.
44. Highland JN, Zanos P, Georgiou P, Gould TD (2019) Group II metabotropic glutamate receptor blockade promotes stress resilience in mice. Neuropsychopharm 44:1788–1796.
45. Sattar Y, Wilson J, Khan AM, Adnan M, Azzopardi Larios D, Shrestha S, Rahman Q, Mansuri Z, Hassan A, Patel NB, Tariq N, Latchana S, Lopez Pantoja SC, Vargas S, Shaikh NA, Syed F, Mittal D, Rumesa F. A Review of the Mechanism of Antagonism of N-methyl-D-aspartate Receptor by Ketamine in Treatment-resistant Depression. Cureus. 2018 May 18;10(5):e2652.
46. Shao J, Meng L, Yang Z, Yu P, Song L, Gao Y, Gong M, Meng C, Shi H. Xenon produces rapid antidepressant- and anxiolytic-like effects in lipopolysaccharide-induced depression mice model. Neuroreport. 2020 Mar 25;31(5):387-393.
47. Aftanas L, Akhmetova O, Brack I, Danilenko K, Khabarov A, Nikolenko E. Xenon in Sub-Anesthetic Doses for Treatment of Major Depression: A Proof-of-Concept Placebo-Controlled Pilot Study. Biol Psychiat 2017. 81(10), S319–S320
48. Lechtenberg M, Schepmann D, Niehues M, Hellenbrand N, Wünsch B, Hensel A. Quality and functionality of saffron: quality control, species assortment and affinity of extract and isolated saffron compounds to NMDA and sigma1 (sigma-1) receptors. Planta Med. 2008 Jun;74(7):764-72.
49. Mallozzi C, Parravano M, Gaddini L, Villa M, Pricci F, Malchiodi-Albedi F, Matteucci A. Curcumin Modulates the NMDA Receptor Subunit Composition Through a Mechanism Involving CaMKII and Ser/Thr Protein Phosphatases. Cell Mol Neurobiol. 2018 Aug;38(6):1315-1320.
50. Lopresti AL. Potential Role of Curcumin for the Treatment of Major Depressive Disorder. CNS Drugs. 2022 Feb;36(2):123-141.
51. Moreno-Agostino D, Wu YT, Daskalopoulou C, Hasan MT, Huisman M, Prina M. Global trends in the prevalence and incidence of depression:a systematic review and meta-analysis. J Affect Disord. 2021 Feb 15;281:235-243.
52. Xiong P, Liu M, Liu B, Hall BJ. Trends in the incidence and DALYs of anxiety disorders at the global, regional, and national levels: Estimates from the Global Burden of Disease Study 2019. J Affect Disord. 2022 Jan 15;297:83-93.
53. https://www.ebay.com/itm/313009233925
54. Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry. 2022 Jul 20. doi: 10.1038/s41380-022-01661-0.