Xenon ameliorates chronic post-surgical pain by regulating mitophagy in microglia and rats mediated by PINK1/Parkin pathway.

Background: Chronic post-surgical pain (CPSP) is one of the important causes of poor postoperative outcomes, the activation of microglia in the spinal cord is closely related to the generation, transmission and maintenance of CPSP. Xenon (Xe), an anesthetic gas, has been reported to be able to significantly reduce intraoperative analgesia and postoperative pain sensation at low doses. However, the mechanism of the regulatory effect of xenon on activated microglia after CPSP remains unclear. Methods: In this study, CPSP model rats were treated with 50% Xe inhalation for 1 h following skin/muscle incision and retraction (SMIR), once a day for 5 consecutive days, and then the painbehavioraltests (pain behavior indexes paw withdrawal mechanical threshold, PWMT and thermal withdrawal latency, TWL), microglial activation, oxidative stress-related indexes (malondialdehyde, MDA; superoxide dismutase, SOD; hydrogen peroxide, H2O2; and catalase, CAT), mitophagy and PINK1/Parkin pathway were examined. Results: The present results showed that a single dose of Xe treatment in SMIR rat model could significantly improve PWMT and TWL in the short-term at a single treatment and long-term at multiple treatments. Xe treatment inhibited microglia activation and oxidative stress in the spinal dorsal horn of SMIR rats, as indicated by the decrease of Iba1 and MDA/H2O2 levels and the increase of SOD/CAT levels. Compared with the control group, Xe further increased the CPSP promoted Mito-Tracker (a mitochondrial marker) and LC3 (an autophagy marker) co-localization positive spots and PINK1/Parkin/ATG5/BECN1 (autophagy-related proteins) protein expression levels, and inhibited the Mito-SOX (a mitochondrial reactive oxygen species marker) positive signal, indicating that Xe promoted microglia mitophagy and inhibited oxidative stress in CPSP. Mechanistically, we verified that Xe promoted PINK1/Parkin signaling pathway activation. Conclusion: Xe plays a role in ameliorating chronic post-surgical pain by regulating the PINK1/Parkin pathway mediated microglial mitophagy and provide new ideas and targets for the prevention and treatment of CPSP.

Combining a noble gas with radiotherapy: glutamate receptor antagonist xenon may act as a radiosensitizer in glioblastoma.

BACKGROUND: Ionotropic glutamate receptors α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) modulate proliferation, invasion and radioresistance in glioblastoma (GB). Pharmacological targeting is difficult as many in vitro-effective agents are not suitable for in patient applications. We aimed to develop a method to test the well tolerated AMPAR- and NMDAR-antagonist xenon gas as a radiosensitizer in GB. METHODS: We designed a diffusion-based system to perform the colony formation assay (CFA), the radiobiological gold standard, under xenon exposure. Stable and reproducible gas atmosphere was validated with oxygen and carbon dioxide as tracer gases. After checking for AMPAR and NMDAR expression via immunofluorescence staining we performed the CFA with the glioblastoma cell lines U87 and U251 as well as the non-glioblastoma derived cell line HeLa. Xenon was applied after irradiation and additionally tested in combination with NMDAR antagonist memantine. RESULTS: The gas exposure system proved compatible with the CFA and resulted in a stable atmosphere of 50% xenon. Indications for the presence of glutamate receptor subunits were present in glioblastoma-derived and HeLa cells. Significantly reduced clonogenic survival by xenon was shown in U87 and U251 at irradiation doses of 4-8 Gy and 2, 6 and 8 Gy, respectively (p < 0.05). Clonogenic survival was further reduced by the addition of memantine, showing a significant effect at 2-8 Gy for both glioblastoma cell lines (p < 0.05). Xenon did not significantly reduce the surviving fraction of HeLa cells until a radiation dose of 8 Gy. CONCLUSION: The developed system allows for testing of gaseous agents with CFA. As a proof of concept, we have, for the first time, unveiled indications of radiosensitizing properties of xenon gas in glioblastoma.

Effects of xenon anesthesia on postoperative neurocognitive disorders: a systematic review and meta-analysis.

The latest clinical trials have reported conflicting outcomes regarding the effectiveness of xenon anesthesia in preventing postoperative neurocognitive dysfunction; thus, this study assessed the existing evidence. We searched the PubMed, Embase, Cochrane Library, and Web of Science databases from inception to April 9, 2023, for randomized controlled trials of xenon anesthesia in postoperative patients. We included English-language randomized controlled studies of adult patients undergoing surgery with xenon anesthesia that compared its effects to those of other anesthetics. Duplicate studies, pediatric studies, and ongoing clinical trials were excluded. Nine studies with 754 participants were identified. A forest plot revealed that the incidence of postoperative neurocognitive dysfunction did not differ between the xenon anesthesia and control groups (P = 0.43). Additionally, xenon anesthesia significantly shortened the emergence time for time to opening eyes (P < 0.001), time to extubation (P < 0.001), time to react on demand (P = 0.01), and time to time and spatial orientation (P = 0.04). However, the Aldrete score significantly increased with xenon anesthesia (P = 0.005). Postoperative complications did not differ between the anesthesia groups. Egger's test for bias showed no small-study effect, and a trim-and-fill analysis showed no apparent publication bias. In conclusion, xenon anesthesia probably did not affect the occurrence of postoperative neurocognitive dysfunction. However, xenon anesthesia may effectively shorten the emergence time of certain parameters without adverse effects.

Protein Kinase A Is Responsible for the Presynaptic Inhibition of Glycinergic and Glutamatergic Transmissions by Xenon in Rat Spinal Cord and Hippocampal CA3 Neurons.

The effects of a general anesthetic xenon (Xe) on spontaneous, miniature, electrically evoked synaptic transmissions were examined using the "synapse bouton preparation," with which we can clearly evaluate pure synaptic responses and accurately quantify pre- and postsynaptic transmissions. Glycinergic and glutamatergic transmissions were investigated in rat spinal sacral dorsal commissural nucleus and hippocampal CA3 neurons, respectively. Xe presynaptically inhibited spontaneous glycinergic transmission, the effect of which was resistant to tetrodotoxin, Cd2+, extracellular Ca2+, thapsigargin (a selective sarcoplasmic/endoplasmic reticulum Ca2+-ATPase inhibitor), SQ22536 (an adenylate cyclase inhibitor), 8-Br-cAMP (membrane-permeable cAMP analog), ZD7288 (an hyperpolarization-activated cyclic nucleotide-gated channel blocker), chelerythrine (a PKC inhibitor), and KN-93 (a CaMKII inhibitor) while being sensitive to PKA inhibitors (H-89, KT5720, and Rp-cAMPS). Moreover, Xe inhibited evoked glycinergic transmission, which was canceled by KT5720. Like glycinergic transmission, spontaneous and evoked glutamatergic transmissions were also inhibited by Xe in a KT5720-sensitive manner. Our results suggest that Xe decreases glycinergic and glutamatergic spontaneous and evoked transmissions at the presynaptic level in a PKA-dependent manner. These presynaptic responses are independent of Ca2+ dynamics. We conclude that PKA can be the main molecular target of Xe in the inhibitory effects on both inhibitory and excitatory neurotransmitter release. SIGNIFICANCE STATEMENT: Spontaneous and evoked glycinergic and glutamatergic transmissions were investigated using the whole-cell patch clamp technique in rat spinal sacral dorsal commissural nucleus and hippocampal CA3 neurons, respectively. Xenon (Xe) significantly inhibited glycinergic and glutamatergic transmission presynaptically. As a signaling mechanism, protein kinase A was responsible for the inhibitory effects of Xe on both glycine and glutamate release. These results may help understand how Xe modulates neurotransmitter release and exerts its excellent anesthetic properties.

Xenon's Sedative Effect Is Mediated by Interaction with the Cyclic Nucleotide-Binding Domain (CNBD) of HCN2 Channels Expressed by Thalamocortical Neurons of the Ventrobasal Nucleus in Mice.

Previous studies have shown that xenon reduces hyperpolarization-activated cyclic nucleotide-gated channels type-2 (HCN2) channel-mediated current (Ih) amplitude and shifts the half-maximal activation voltage (V1/2) in thalamocortical circuits of acute brain slices to more hyperpolarized potentials. HCN2 channels are dually gated by the membrane voltage and via cyclic nucleotides binding to the cyclic nucleotide-binding domain (CNBD) on the channel. In this study, we hypothesize that xenon interferes with the HCN2 CNBD to mediate its effect. Using the transgenic mice model HCN2EA, in which the binding of cAMP to HCN2 was abolished by two amino acid mutations (R591E, T592A), we performed ex-vivo patch-clamp recordings and in-vivo open-field test to prove this hypothesis. Our data showed that xenon (1.9 mM) application to brain slices shifts the V1/2 of Ih to more hyperpolarized potentials in wild-type thalamocortical neurons (TC) (V1/2: -97.09 [-99.56--95.04] mV compared to control -85.67 [-94.47--82.10] mV; p = 0.0005). These effects were abolished in HCN2EA neurons (TC), whereby the V1/2 reached only -92.56 [-93.16- -89.68] mV with xenon compared to -90.03 [-98.99--84.59] mV in the control (p = 0.84). After application of a xenon mixture (70% xenon, 30% O2), wild-type mice activity in the open-field test decreased to 5 [2-10] while in HCN2EA mice it remained at 30 [15-42]%, (p = 0.0006). In conclusion, we show that xenon impairs HCN2 channel function by interfering with the HCN2 CNBD site and provide in-vivo evidence that this mechanism contributes to xenon-mediated hypnotic properties.

Xenon attenuates hypoxic-ischemic brain damage by inhibiting autophagy in neonatal rats.

Xenon (Xe) is an inert, colorless and odorless heavy gas and has many biological functions. However, little is known about whether and how Xe can modulate hypoxic-ischemic brain damage (HIBD) in neonatal rats. This study employed a neonatal rat model to explore the potential effect of Xe on neuron autophagy and the severity of HIBD. Neonatal Sprague-Dawley rats were subjected to HIBD, randomized and treated with Xe or mild hypothermia (at 32 °C) for 3 h. The degrees of HIBD, neuron autophagy and the neuronal functions in some neonates from each group were tested by histopathology, immunochemistry, transmission electron microscopy, western blot, open-field and Trapeze tests at 3 and 28 days post-induction of HIBD, respectively. Compared with the Sham group, hypoxic-ischemia caused larger volumes of cerebral infarction and severe brain damage, and increased autophagosome formation and Beclin-1 and microtubule-associated protein 1A/1B-light chain 3 class II (LC3-II) expression in the brain of rats, accompanied by the defect in neuronal functions. In contrast, treatment with Xe and/or hypothermia significantly reduced infarct volumes and ameliorated neurological defects in the HIBD rats, particularly for the combination of Xe and hypothermia. Xe significantly mitigated the relative levels of Beclin-1 and LC3-II expression and autophagosome formation induced by HIBD in rats. Xe acted as a neuroprotective factor against HIBD, possibly by inhibiting the hypoxia-induced neuron autophagy in rats.

Injury Site Specific Xenon Delivered by Platelet Membrane-Mimicking Hybrid Microbubbles to Protect Against Acute Kidney Injury via Inhibition of Cellular Senescence.

Inhalation of xenon gas improves acute kidney injury (AKI). However, xenon can only be delivered through inhalation, which causes non-specific distribution and low bioavailability of xenon, thus limiting its clinical application. In this study, xenon is loaded into platelet membrane-mimicking hybrid microbubbles (Xe-Pla-MBs). In ischemia-reperfusion-induced AKI, intravenously injected Xe-Pla-MBs adhere to the endothelial injury site in the kidney. Xe-Pla-MBs are then disrupted by ultrasound, and xenon is released to the injured site. This release of xenon reduced ischemia-reperfusion-induced renal fibrosis and improved renal function, which are associated with decreased protein expression of cellular senescence markers p53 and p16, as well as reduced beta-galactosidase in renal tubular epithelial cells. Together, platelet membrane-mimicking hybrid microbubble-delivered xenon to the injred site protects against ischemia-reperfusion-induced AKI, which likely reduces renal senescence. Thus, the delivery of xenon by platelet membrane-mimicking hybrid microbubbles is a potential therapeutic approach for AKI.

The Anaesthetics Isoflurane and Xenon Reverse the Synaptotoxic Effects of Aß1-42 on Megf10-Dependent Astrocytic Synapse Elimination and Spine Density in Ex Vivo Hippocampal Brain Slices.

It has been hypothesised that inhalational anaesthetics such as isoflurane (Iso) may trigger the pathogenesis of Alzheimer's disease (AD), while the gaseous anaesthetic xenon (Xe) exhibits many features of a putative neuroprotective agent. Loss of synapses is regarded as one key cause of dementia in AD. Multiple EGF-like domains 10 (MEGF10) is one of the phagocytic receptors which assists the elimination of synapses by astrocytes. Here, we investigated how ß-amyloid peptide 1-42 (Aß1-42), Iso and Xe interact with MEGF10-dependent synapse elimination. Murine cultured astrocytes as well as cortical and hippocampal ex vivo brain slices were treated with either Aß1-42, Iso or Xe and the combination of Aß1-42 with either Iso or Xe. We quantified MEGF10 expression in astrocytes and dendritic spine density (DSD) in slices. In brain slices of wild type and AAV-induced MEGF10 knock-down mice, antibodies against astrocytes (GFAP), pre- (synaptophysin) and postsynaptic (PSD95) components were used for co-localization analyses by means of immunofluorescence-imaging and 3D rendering techniques. Aß1-42 elevated pre- and postsynaptic components inside astrocytes and decreased DSD. The combined application with either Iso or Xe reversed these effects. In the presence of Aß1-42 both anaesthetics decreased MEGF10 expression. AAV-induced knock-down of MEGF10 reduced the pre- and postsynaptic marker inside astrocytes. The presented data suggest Iso and Xe are able to reverse the Aß1-42-induced enhancement of synaptic elimination in ex vivo hippocampal brain slices, presumably through MEGF10 downregulation.

Depression of Synaptic N-methyl-D-Aspartate Responses by Xenon and Nitrous Oxide.

In "synapse bouton preparation" of rat hippocampal CA3 neurons, we examined how Xe and N2O modulate N-methyl-D-aspartate (NMDA) receptor-mediated spontaneous and evoked excitatory post-synaptic currents (sEPSCNMDA and eEPSCNMDA). This preparation is a mechanically isolated single neuron attached with nerve endings (boutons) preserving normal physiologic function and promoting the exact evaluation of sEPSCNMDA and eEPSCNMDA responses without influence of extrasynaptic, glial, and other neuronal tonic currents. These sEPSCs and eEPSCs are elicited by spontaneous glutamate release from many homologous glutamatergic boutons and by focal paired-pulse electric stimulation of a single bouton, respectively. The s/eEPSCAMPA/KA and s/eEPSCNMDA were isolated pharmacologically by their specific antagonists. Thus, independent contributions of pre- and postsynaptic responses could also be quantified. All kinetic properties of s/eEPSCAMPA/KA and s/eEPSCNMDA were detected clearly. The s/eEPSCNMDA showed smaller amplitude and slower rise and 1/e decay time constant (τ Decay) than s/eEPSCAMPA/KA Xe (70%) and N2O (70%) significantly decreased the frequency and amplitude without altering the τ Decay of sEPSCNMDA They also decreased the amplitude but increased the Rf and PPR without altering the τ Decay of the eEPSCNMDA These data show clearly that "synapse bouton preparation" can be an accurate model for evaluating s/eEPSCNMDA Such inhibitory effects of gas anesthetics are primarily due to presynaptic mechanisms. Present results may explain partially the powerful analgesic effects of Xe and N2O. SIGNIFICANCE STATEMENT: We could record pharmacologically isolated NMDA receptor-mediated spontaneous and (action potential-evoked) excitatory postsynaptic currents (sEPSCNMDA and eEPSCNMDA) and clearly detect all kinetic parameters of sEPSCNMDA and eEPSCNMDA at synaptic levels by using "synapse bouton preparation" of rat hippocampal CA3 neurons. We found that Xe and N2O clearly suppressed both sEPSCNMDA and eEPSCNMDA. Different from previous studies, present results suggest that Xe and N2O predominantly inhibit the NMDA responses by presynaptic mechanisms.

Identifying medically relevant xenon protein targets by in silico screening of the structural proteome.

In a previous study, in silico screening of the binding of almost all proteins in the Protein Data Bank to each of the five noble gases xenon, krypton, argon, neon, and helium was reported. This massive and rich data set requires analysis to identify the gas-protein interactions that have the best binding strengths, those where the binding of the noble gas occurs at a site that can modulate the function of the protein, and where this modulation might generate clinically relevant effects. Here, we report a preliminary analysis of this data set using a rational, heuristic score based on binding strength and location. We report a partial prioritized list of xenon protein targets and describe how these data can be analyzed, using arginase and carbonic anhydrase as examples. Our aim is to make the scientific community aware of this massive, rich data set and how it can be analyzed to accelerate future discoveries of xenon-induced biological activity and, ultimately, the development of new "atomic" drugs.

Xenon-Induced Recovery of Functional Activity of Pulmonary Surfactant (In Silico Study).

To understand the nature of xenon-induced recovery of the functional activity of pulmonary surfactant during inhalation of a gas mixture of Xe/O2, the mechanisms of the ongoing processes were studied in silico. Impaired ability of pulmonary surfactant to maintain low surface tension preventing alveolar atelectasis occurs due to formation of aggregates of its phospholipids and a decrease in their lateral mobility. Aggregated lipid systems, whose structure can explain the loss of lateral mobility of surfactant phospholipids, were modeled in silico at the molecular level. Changes in the Gibbs energy and enthalpy in the reactions of the formation and decomposition of xenon intermediates with model systems of various compositions/structures were calculated. The simulation was carried out for atomic xenon and for xenon polarized by molecular oxygen in the gas phase and taking into account solvation with water. The loss of lateral mobility of phospholipids can be explained by specific features of electronic structure of hydrophobic hydrocarbon molecules (acyl chains), which, under certain conditions, are capable of forming structured common regions of the electrostatic potential, to which xenon has an affinity. In this case, inclusion coordination compounds of the "guest-host" type are formed, which subsequently decompose due to the nature of the polarization of the Xe atoms. The formation and decomposition of xenon intermediates in these systems lead to recovery of the lateral mobility (fluidity) of phospholipids, which restores functional activity of surfactant films.

[Xenon post-conditioning protects against spinal cord ischemia-reperfusion injury in rats by downregulating mTOR pathway and inhibiting endoplasmic reticulum stress-induced neuronal apoptosis].

OBJECTIVE: The purpose of this study was to determine whether xenon post-conditioning affects mTOR signaling as well as endoplasmic reticulum stress (ERS)-apoptosis pathway in rats with spinal cord ischemia/reperfusion injury. METHODS: Fifty male rats were randomized equally into sham-operated group (Sham group), I/R model group (I/R group), I/R model+ xenon post-conditioning group (Xe group), I/R model+rapamycin (a mTOR signaling pathway inhibitor) treatment group (I/R+ Rapa group), and I/R model + xenon post- conditioning with rapamycin treatment group (Xe + Rapa group).. In the latter 4 groups, SCIRI was induced by clamping the abdominal aorta for 85 min followed by reperfusion for 4 h. Rapamycin (or vehicle) was administered by daily intraperitoneal injection (4 mg/kg) for 3 days before SCIRI, and xenon post-conditioning by inhalation of 1∶1 mixture of xenon and oxygen for 1 h at 1 h after initiation of reperfusion; the rats without xenon post-conditioning were given inhalation of nitrogen and oxygen (1∶ 1). After the reperfusion, motor function and histopathologic changes in the rats were examined. Western blotting and real-time PCR were used to detect the protein and mRNA expressions of GRP78, ATF6, IRE1α, PERK, mTOR, p-mTOR, Bax, Bcl-2 and caspase-3 in the spinal cord. RESULTS: The rats showed significantly lowered hind limb motor function following SCIRI (P < 0.01) with a decreased count of normal neurons, increased mRNA and protein expressions of GRP78, ATF6, IRE1α, PERK, and caspase-3, and elevated p-mTOR/mTOR ratio and Bax/Bcl-2 ratio (P < 0.01). Xenon post-conditioning significantly decreased the mRNA and protein levels of GRP78, ATF6, IRE1α, PERK and caspase-3 (P < 0.05 or 0.01) and reduced p-mTOR/mTOR and Bax/Bcl-2 ratios (P < 0.01) in rats with SCIRI; the mRNA contents and protein levels of GRP78 and ATF6 were significantly decreased in I/R+Rapa group (P < 0.01). Compared with those in Xe group, the rats in I/R+Rapa group and Xe+Rapa had significantly lowered BBB and Tarlov scores of the hind legs (P < 0.01), and caspase-3 protein level and Bax/Bcl-2 ratio were significantly lowered in Xe+Rapa group (P < 0.05 or 0.01). CONCLUSION: By inhibiting ERS and neuronal apoptosis, xenon post- conditioning may have protective effects against SCIRI in rats. The mTOR signaling pathway is partially involved in this process.

Hyperbaric treatment of platelets extends in vitro storage to 14 days.

BACKGROUND: Platelets for transfusion have a storage time of 5-7 days at 22°C-24°C, which results in a strain on the supply chain and supply shortages. We describe a novel method to extend platelet storage using xenon (Xe) gas under high pressure and refrigeration. STUDY DESIGN AND METHODS: Apheresis platelets (APU) prepared in 65% platelet additive solution (PAS) were stored under standard conditions (SC) at 20°C-24°C to Day 5. Paired APUs were prepared with Xe and stored to Day 14 at 2°C-6°C under hyperbaric conditions (XHC). A standard panel of in vitro assays was conducted. RESULTS: XHC platelets were viable out to Day 14. The average pH of Day 14 platelets was 6.58, and 86% maintained some degree of swirl compared with 7.02 and 100% swirl for Day 5 SC platelets. The rate of glycolysis was reduced under XHC storage with less glucose consumption and lactate generation. Activation levels for Day 14 platelets, while increased, did not prevent response to agonists in vitro, including epinephrine + Adenosine 5-Diphosphate (EPI/ADP) and thrombin receptor-activating peptide (TRAP) aggregation. Thromboelastogram (TEG) assessment showed 80% or greater conservation of platelet function for Day 14 xenon stored platelets compared with Day 5 SC platelets. DISCUSSION: Platelet storage with the Xe/hyperbaric/cold method is a feasible candidate for extension of storage to 14 days based on in vitro characteristics. In vivo recovery and survival studies are indicated. The capability to extend platelet storage to 14 days would make large strides toward resolving issues of platelet outdating for prophylactic use.

Beta-Site Amyloid Precursor Protein-Cleaving Enzyme Inhibition Partly Restores Sevoflurane-Induced Deficits on Synaptic Plasticity and Spine Loss.

Evidence indicates that inhalative anesthetics enhance the ß-site amyloid precursor protein (APP)-cleaving enzyme (BACE) activity, increase amyloid beta 1-42 (Aß1-42) aggregation, and modulate dendritic spine dynamics. However, the mechanisms of inhalative anesthetics on hippocampal dendritic spine plasticity and BACE-dependent APP processing remain unclear. In this study, hippocampal slices were incubated with equipotent isoflurane (iso), sevoflurane (sevo), or xenon (Xe) with/without pretreatment of the BACE inhibitor LY2886721 (LY). Thereafter, CA1 dendritic spine density, APP processing-related molecule expressions, nectin-3 levels, and long-term potentiation (LTP) were tested. The nectin-3 downregulation on LTP and dendritic spines were evaluated. Sevo treatment increased hippocampal mouse Aß1-42 (mAß1-42), abolished CA1-LTP, and decreased spine density and nectin-3 expressions in the CA1 region. Furthermore, CA1-nectin-3 knockdown blocked LTP and reduced spine density. Iso treatment decreased spine density and attenuated LTP. Although Xe blocked LTP, it did not affect spine density, mAß1-42, or nectin-3. Finally, antagonizing BACE activity partly restored sevo-induced deficits. Taken together, our study suggests that sevo partly elevates BACE activity and interferes with synaptic remodeling, whereas iso mildly modulates synaptic changes in the CA1 region of the hippocampus. On the other hand, Xe does not alternate dendritic spine remodeling.

Neuroprotection by the noble gases argon and xenon as treatments for acquired brain injury: a preclinical systematic review and meta-analysis.

BACKGROUND: The noble gases argon and xenon are potential novel neuroprotective treatments for acquired brain injuries. Xenon has already undergone early-stage clinical trials in the treatment of ischaemic brain injuries, with mixed results. Argon has yet to progress to clinical trials as a treatment for brain injury. Here, we aim to synthesise the results of preclinical studies evaluating argon and xenon as neuroprotective therapies for brain injuries. METHODS: After a systematic review of the MEDLINE and Embase databases, we carried out a pairwise and stratified meta-analysis. Heterogeneity was examined by subgroup analysis, funnel plot asymmetry, and Egger's regression. RESULTS: A total of 32 studies were identified, 14 for argon and 18 for xenon, involving measurements from 1384 animals, including murine, rat, and porcine models. Brain injury models included ischaemic brain injury after cardiac arrest (CA), neurological injury after cardiopulmonary bypass (CPB), traumatic brain injury (TBI), and ischaemic stroke. Both argon and xenon had significant (P<0.001), positive neuroprotective effect sizes. The overall effect size for argon (CA, TBI, stroke) was 18.1% (95% confidence interval [CI], 8.1-28.1%), and for xenon (CA, TBI, stroke) was 34.1% (95% CI, 24.7-43.6%). Including the CPB model, only present for xenon, the xenon effect size (CPB, CA, TBI, stroke) was 27.4% (95% CI, 11.5-43.3%). Xenon, both with and without the CPB model, was significantly (P<0.001) more protective than argon. CONCLUSIONS: These findings provide evidence to support the use of xenon and argon as neuroprotective treatments for acquired brain injuries. Current evidence suggests that xenon is more efficacious than argon overall.

Behavior of Stimulus Response Signals in a Rat Cortical Neuronal Network Under Xe Pressure.

Neurons cultured on a multi-electrode array show not only spontaneous firing, but also network-specific burst firing, the latter of which develops into synchronous bursting. Such synchronous bursting can be suppressed by exposure to xenon (Xe) gas. To better understand such suppression of bursting by Xe, we investigate here whether signal transmission between neurons is also suppressed under these conditions. In these experiments, we apply a pulse electrical-stimulus to one electrode and observe the response signals within 10 ms at other active electrodes. When put under a sufficient Xe pressure, some response signals become delayed or vanish after disappearance of synchronous-bursts, particularly signals passing through multiple synaptic bonds. Such bonds have a high probability of having delayed or vanishing signals when the Xe pressure is above 0.3 MPa. The pressure dependence of the response ratio to the stimulus suggests that Xe suppresses multiple points of action simultaneously when suppressing synaptic signal transduction, as observed in the suppression of the synchronized bursting. In addition, we find that the signal that transmits not via synaptic bonding (axon conduction) is also suppressed under Xe gas pressures over 0.3 MPa. Therefore, we conclude that Xe-induced suppression of synchronized bursting is caused mainly by a decrease in the apparent number of active neurons that contribute to the neuronal network, a decrease due to inhibition of signal transmission via synaptic connections.

At least three xenon binding sites in the glycine binding domain of the N-methyl D-aspartate receptor.

Xenon can produce general anesthesia. Its main protein target is the N-methyl-D-aspartate receptor, a ionotropic channel playing a pivotal role in the function of the central nervous system. The molecular mechanisms allowing this noble gas to have such a specific effect remain obscure, probably as a consequence of the lack of structural data at the atomic level of detail. As a result of five independent molecular dynamics simulations, three different binding sites were found for xenon in the glycine binding domain of the N-methyl-D-aspartate receptor, the xenon binding constant being of the order of 2 108 s-1⋅M-1. On the other hand, the absolute binding free energy of xenon in these sites ranges between -3 and -14 kJ⋅mole-1. Noteworthy, it depends significantly upon the protein conformer chosen for performing the calculation, suggesting that larger values could be obtained, if other conformers were considered. These three sites are next to each other, one of them being next to the glycine site. This could noteworthy explain why the F758W and F758Y mutations can prevent competitive inhibition by xenon without affecting glycine binding.

Medical Gas Therapy for Tissue, Organ, and CNS Protection: A Systematic Review of Effects, Mechanisms, and Challenges.

Gaseous molecules have been increasingly explored for therapeutic development. Here, following an analytical background introduction, a systematic review of medical gas research is presented, focusing on tissue protections, mechanisms, data tangibility, and translational challenges. The pharmacological efficacies of carbon monoxide (CO) and xenon (Xe) are further examined with emphasis on intracellular messengers associated with cytoprotection and functional improvement for the CNS, heart, retina, liver, kidneys, lungs, etc. Overall, the outcome supports the hypothesis that readily deliverable "biological gas" (CO, H2 , H2 S, NO, O2 , O3 , and N2 O) or "noble gas" (He, Ar, and Xe) treatment may preserve cells against common pathologies by regulating oxidative, inflammatory, apoptotic, survival, and/or repair processes. Specifically, CO, in safe dosages, elicits neurorestoration via igniting sGC/cGMP/MAPK signaling and crosstalk between HO-CO, HIF-1α/VEGF, and NOS pathways. Xe rescues neurons through NMDA antagonism and PI3K/Akt/HIF-1α/ERK activation. Primary findings also reveal that the need to utilize cutting-edge molecular and genetic tactics to validate mechanistic targets and optimize outcome consistency remains urgent; the number of neurotherapeutic investigations is limited, without published results from large in vivo models. Lastly, the broad-spectrum, concurrent multimodal homeostatic actions of medical gases may represent a novel pharmaceutical approach to treating critical organ failure and neurotrauma.

Repetitive xenon treatment improves post-stroke sensorimotor and neuropsychiatric dysfunction.

Stroke is a life-changing event as stroke survivors experience changes in personality, emotions and mood. We investigated the effect of xenon gas encapsulated in liposomes on stroke-generated sensorimotor impairments, and anxiety- and depression-like phenotypes. Ischemic stroke was created by the intraluminal middle cerebral artery occlusion (MCAO) for 6 h followed by reperfusion in rats. Xenon-liposome (6 mg/kg, intravenous) treatment was given multiple times starting at 2 h post-ischemia through 6 h (5X), and once-daily for next 3 days. Rats underwent ischemic injury displayed sensorimotor deficits in the adhesive removal, vibrissae-evoked forelimb placement and rotarod tests. These animals also made lesser entries and spent less time on open arms of the elevated-plus maze and swam more in passive mode in the forced swimming test, indicating anxiety- and depression-like behaviors at 28- and 35-days post-injury, respectively. Repeated intravenous treatment with xenon-liposomes ameliorated these behavioral aberrations (p < 0.05). Gut microbiome analysis (16S ribosomal-RNA gene sequencing) showed a decrease in the Clostridium clusters XI, XIVa, XVIII and Lactobacillus bacterium, and increase of the Prevotella in the xenon-liposome group. No microbiota communities were majorly affected across the treatments. Moreover, xenon treatment group showed augmented plasma levels of IL-6 cytokines (∼5 fold) on day-35 post-ischemia, while no change was noticed in the IL-1ß, IL-4, IL-10, IL-13 and MCP-1 levels. Our data highlights the safety, behavioral recovery and reversal of post-stroke brain injury following xenon-liposome treatment in an extended ischemic model. These results show the potential for this treatment strategy to be translated to patients with stroke.

Influence of Xenon on Survival of Sperm of Common Frog Rana temporaria during Slow Freezing.

We studied the effect of xenon on the survival rate of the spermatozoa of the common frog Rana temporaria during slow freezing with saturation of the suspension with xenon at a pressure of up to 1.2 bar. The cryoprotective properties of xenon were analyzed in comparison with nitrogen. No specific cryoprotective effect of xenon was revealed. Viability of spermatozoa pretreated with xenon at atmospheric pressure (0 bar) or under excess pressure of 0.6 bar and frozen in a cryoprotective medium with dimethylformamide, sucrose, and BSA did not differ significantly. The use of overpressure of xenon of 1.0 or 1.2 bar in the pretreatment and freezing process significantly impaired viability of the biomaterial.