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Haloperidol, a dopamine D2 receptor antagonist, blocks nitrous oxide and ketamine-induced neurotoxicity. Data show the number of c-Fos positive neurones in the posterior cingulate and retrosplenial cortices following exposure to 75% nitrous oxide or s.c. injection of ketamine (50 mg kg ±1 ) compared with control. Results are means ( SEM ). ** P <0.01 relative to control.
Source publication
Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors have been shown not only to have neuroprotective effects but also to exhibit neurotoxic properties. In this study, we used c-Fos, a protein product of an immediate early gene, as a marker of neuronal injury to compare the neuroprotective effects of xenon and the neurotoxi...
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Context 1
... extent to which the neurotoxicity produced by nitrous oxide and ketamine could be blocked by the dopamine D2 receptor antagonist haloperidol was investigated. Pretreatment with haloperidol greatly decreased the number of c-Fos positive neurones induced by either nitrous oxide or ketamine alone (Fig. 5), and for both agents haloperidol pretreatment reduced the induction of c-Fos positive neurones to a level comparable with that found in control animals (Fig. ...
Context 2
... receptor antagonist haloperidol was investigated. Pretreatment with haloperidol greatly decreased the number of c-Fos positive neurones induced by either nitrous oxide or ketamine alone (Fig. 5), and for both agents haloperidol pretreatment reduced the induction of c-Fos positive neurones to a level comparable with that found in control animals (Fig. ...
Context 3
... contrast, xenon does not increase dopamine release in PC12 cells. 19 It is noteworthy that, of the neurotransmitters in cortical afferent neurones, only dopa- mine is distributed to frontal and cingulate areas. 34 All of the above argue for a possible role of dopamine in the neurotoxic effects of NMDA receptor antagonists. The data presented here (Fig. 5), showing that the dopamine D2 receptor antagonist haloperidol blocks the toxicity produced by both nitrous oxide and ketamine, provides supporting evidence for this ...
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Citations
... Zenon is a noble gas with an excellent safety profile in animal studies (117). Its use was investigated in combination with TH and in a rat model showed that there was functional improvements that were greater than in the TH alone group and that this was sustained over time (118). ...
Neonatal brain injury and associated inflammation is more common in males. There is a well-recognised difference in incidence and outcome of neonatal encephalopathy according to sex with a pronounced male disadvantage. Neurodevelopmental differences manifest from an early age in infancy with females having a lower incidence of developmental delay and learning difficulties in comparison with males and male sex has consistently been identified as a risk factor for cerebral palsy in epidemiological studies. Important neurobiological differences exist between the sexes with respect to neuronal injury which are especially pronounced in preterm neonates. There are many potential reasons for these sex differences including genetic, immunological and hormonal differences but there are limited studies of neonatal immune response. Animal models with induced neonatal hypoxia have shown various sex differences including an upregulated immune response and increased microglial activation in males. Male sex is recognized to be a risk factor for neonatal hypoxic ischemic encephalopathy (HIE) during the perinatal period and this review discusses in detail the sex differences in brain injury in preterm and term neonates and some of the potential new therapies with possible sex affects.
... Dopamine is also thought to play a role in NMDAinduced neurotoxicity (Ma et al., 2002). A reduction in dopamine release in brain slices, in both oxygen-glucose deprived and noninjured brain tissue slices, was attributed to the action of xenon in Table 5. ...
Introduction
Xenon exhibits significant neuroprotection against a wide range of neurological insults in animal models. However, clinical evidence that xenon improves outcomes in human studies of neurological injury remains elusive. Previous reviews of xenon's method of action have not been performed in a systematic manner. The aim of this review is to provide a comprehensive summary of the evidence underlying the cellular interactions responsible for two phenomena associated with xenon administration: anesthesia and neuroprotection.
Methods
A systematic review of the preclinical literature was carried out according to the PRISMA guidelines and a review protocol was registered with PROSPERO. The review included both in vitro models of the central nervous system and mammalian in vivo studies. The search was performed on 27th May 2022 in the following databases: Ovid Medline, Ovid Embase, Ovid Emcare, APA PsycInfo, and Web of Science. A risk of bias assessment was performed utilizing the Office of Health Assessment and Translation tool. Given the heterogeneity of the outcome data, a narrative synthesis was performed.
Results
The review identified 69 articles describing 638 individual experiments in which a hypothesis was tested regarding the interaction of xenon with cellular targets including: membrane bound proteins, intracellular signaling cascades and transcription factors. Xenon has both common and subtype specific interactions with ionotropic glutamate receptors. Xenon also influences the release of inhibitory neurotransmitters and influences multiple other ligand gated and non-ligand gated membrane bound proteins. The review identified several intracellular signaling pathways and gene transcription factors that are influenced by xenon administration and might contribute to anesthesia and neuroprotection.
Discussion
The nature of xenon NMDA receptor antagonism, and its range of additional cellular targets, distinguishes it from other NMDA antagonists such as ketamine and nitrous oxide. This is reflected in the distinct behavioral and electrophysiological characteristics of xenon. Xenon influences multiple overlapping cellular processes, both at the cell membrane and within the cell, that promote cell survival. It is hoped that identification of the underlying cellular targets of xenon might aid the development of potential therapeutics for neurological injury and improve the clinical utilization of xenon.
Systematic review registration
https://www.crd.york.ac.uk/prospero/, identifier: 336871.
... After the pivotal discovery that xenon is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor, numerous preclinical studies in three different species of animals and in various models of acute neuronal injury have confirmed that xenon confers neuroprotection [20]. There are many experimental models in which the beneficial effects of xenon have been evident, e.g., administration of excitotoxins or oxygen deprivation in rats [21][22][23], cardiopulmonary bypass (CBP) in rats [24], middle cerebral artery occlusion in mice [25,26], cardiac arrest in pigs [27,28], hypoxicischemic insult in rats [29,30], TBI in mice [31][32][33], and SAH in rats. Neuroprotection has been demonstrated by a reduction in the infarct volume after focal ischemia [25,26], attenuated short-and long-term neurologic and neurocognitive dysfunction [27,28,[34][35][36][37], and a reduction in the extent of the neurohistopathological damage [20,29,[31][32][33][34][35][36][37]. ...
... Trials (2023) 24:417 ischemia-reperfusion injury, and oxidant injury [9,12,16,30,[64][65][66][67][68][69]. Secondly, multiple experimental animal models have demonstrated xenon's neuroprotective effect on global ischemia, focal occlusive stroke, TBI, and SAH with functional and histopathological longterm benefits on the outcome [20][21][22][23][24][26][27][28][29][30][31][32][33][34][35][36][37]. Furthermore, Laitio et al. showed that xenon was able to decrease the global and regional cerebral metabolic rate of glucose (MRGlu) using positron emission tomography (PET) in healthy human volunteers [70,71]. ...
Background
Aneurysmal subarachnoid hemorrhage (aSAH) is a neurological emergency, affecting a younger population than individuals experiencing an ischemic stroke; aSAH is associated with a high risk of mortality and permanent disability. The noble gas xenon has been shown to possess neuroprotective properties as demonstrated in numerous preclinical animal studies. In addition, a recent study demonstrated that xenon could attenuate a white matter injury after out-of-hospital cardiac arrest.
Methods
The study is a prospective, multicenter phase II clinical drug trial. The study design is a single-blind, prospective superiority randomized two-armed parallel follow-up study. The primary objective of the study is to explore the potential neuroprotective effects of inhaled xenon, when administered within 6 h after the onset of symptoms of aSAH. The primary endpoint is the extent of the global white matter injury assessed with magnetic resonance diffusion tensor imaging of the brain.
Discussion
Despite improvements in medical technology and advancements in medical science, aSAH mortality and disability rates have remained nearly unchanged for the past 10 years. Therefore, new neuroprotective strategies to attenuate the early and delayed brain injuries after aSAH are needed to reduce morbidity and mortality.
Trial registration
ClinicalTrials.gov NCT04696523. Registered on 6 January 2021.
EudraCT, EudraCT Number: 2019-001542-17. Registered on 8 July 2020.
... Xenon is obtained by a complex air separation process, and its cost of production may unfortunately limit its use clinically. However, it does seem to have neuroprotective properties [182], especially in the context of cerebral ischemia [183]. Its action is not thought to be mediated by GABA receptors but rather by inhibition of NMDA receptors [184], thus reducing trauma-related excitotoxicity. ...
Head trauma is the most common cause of disability in young adults. Known as a silent epidemic, it can cause a mosaic of symptoms, whether neurological (sensory-motor deficits), psychiatric (depressive and anxiety symptoms), or somatic (vertigo, tinnitus, phosphenes). Furthermore, cranial trauma (CT) in children presents several particularities in terms of epidemiology, mechanism, and physiopathology-notably linked to the attack of an immature organ. As in adults, head trauma in children can have lifelong repercussions and can cause social and family isolation, difficulties at school, and, later, socio-professional adversity. Improving management of the pre-hospital and rehabilitation course of these patients reduces secondary morbidity and mortality, but often not without long-term disability. One hypothesized contributor to this process is chronic neuroinflammation, which could accompany primary lesions and facilitate their development into tertiary lesions. Neuroinflammation is a complex process involving different actors such as glial cells (astrocytes, microglia, oligodendrocytes), the permeability of the blood-brain barrier, excitotoxicity, production of oxygen derivatives, cytokine release, tissue damage, and neuronal death. Several studies have investigated the effect of various treatments on the neuroinflammatory response in traumatic brain injury in vitro and in animal and human models. The aim of this review is to examine the various anti-inflammatory therapies that have been implemented.
... The previous studies indicate the potential, wide therapeutic application of xenon in neurological diseases (Azzopardi et al., 2013(Azzopardi et al., , 2016 (David et al., 2003;Ma et al., 2002;Zhang, Zhang, Liu, et al., 2019;. Inappropriate treatment with xenon may have no therapeutic effect or even lead to local brain injury (Schmidt et al., 2001). ...
Xenon is an inert gas with stable chemical properties which is used as an anesthetic. Recent in vitro and in vivo findings indicate that xenon also elicits an excellent neuroprotective effect in subanesthetic concentrations. The mechanisms underlying this primarily involve the attenuation of excitotoxicity and the inhibition of N‐methyl‐d‐aspartic acid (NMDA) receptors and NMDA receptor‐related effects, such as antioxidative effects, reduced activation of microglia, and Ca2+‐dependent mechanisms, as well as the interaction with certain ion channels and glial cells. Based on this strong neuroprotective role, a large number of experimental and clinical studies have confirmed the significant therapeutic effect of xenon in the treatment of neurological diseases. This review summarizes the reported neuroprotective mechanisms of xenon and discusses its possible therapeutic application in the treatment of various neurological diseases.
... Xenon, an approved and safe anesthetic drug [98], is a non-competitive antagonist of the NMDA subtype of the glutamate receptor. Other neuroprotective actions include activation of the two-pore K + -channel, inhibition of the calcium/calmodulin dependent protein kinase II, activation of anti-apoptotic effectors Bcl-XL and Bcl-2 and induced expression of hypoxia-inducible factor 1 alpha and its downstream effectors Epo and vascular endothelial growth factor, which can interrupt the apoptotic pathway [99]. ...
Intrapartum-related hypoxia-ischemia (HI) leading to neonatal encephalopathy (NE) is the second commonest preventable cause of childhood neurodisability worldwide (1) with profound psychosocial and economic consequences for families and society. The incidence of NE varies across the world, affecting 1–3.5/1000 live births in high-resource settings and ∼26/1000 in low-resource settings (2). NE is a global health priority as 0.7 million affected newborns die, and 1.15 million develop NE each year (2). Therapeutic hypothermia (HT) with intracorporeal temperature monitoring is standard care in the National Health Service, United Kingdom, and developed countries worldwide (3). Long-term follow-up has now assessed neurodevelopmental outcomes, health-related quality of life, and economic costs, confirming a persistent beneficial effect (4). With the current practice of HT, mortality due to NE has reduced from 25% in the clinical trials to 9% and disability from 20% to around 16% with a reduction in the rate of cerebral palsy. However, not all children benefit from treatment, and some level of intellectual impairment may remain even in the absence of cerebral palsy (5).
... Xenon, an approved and safe anesthetic drug [98], is a non-competitive antagonist of the NMDA subtype of the glutamate receptor. Other neuroprotective actions include activation of the two-pore K + -channel, inhibition of the calcium/calmodulin dependent protein kinase II, activation of antiapoptotic effectors Bcl-XL and Bcl-2 and induced expression of hypoxia-inducible factor 1 alpha and its downstream effectors Epo and vascular endothelial growth factor, which can interrupt the apoptotic pathway [99]. Argon, being a cost-efficient alternative to xenon, is not an anesthetic. ...
In term and near-term neonates with neonatal encephalopathy, therapeutic hypothermia protocols are well established. The current focus is on how to improve outcomes further and the challenge is to find safe and complementary therapies that confer additional protection, regeneration or repair in addition to cooling. Following hypoxia-ischemia, brain injury evolves over three main phases (latent, secondary and tertiary), each with a different brain energy, perfusion, neurochemical and inflammatory milieu. While therapeutic hypothermia has targeted the latent and secondary phase, we now need therapies that cover the continuum of brain injury that spans hours, days, weeks and months after the initial event. Most agents have several therapeutic actions but can be broadly classified under a predominant action (e.g., free radical scavenging, anti-apoptotic, anti-inflammatory, neuroregeneration, and vascular effects). Promising early/secondary phase therapies include Allopurinol, Azithromycin, Exendin-4, Magnesium, Melatonin, Noble gases and Sildenafil. Tertiary phase agents include Erythropoietin, Stem cells and others. We review a selection of promising therapeutic agents on the translational pipeline and suggest a framework for neuroprotection and neurorestoration that targets the evolving injury.
... A nearly linear plot results between the potency and oil:gas partition coefficient. Anesthetics range from simple gases N 2 O, Ar and Xe to the more complex molecules, including certain alcohols, alkanes, and amines, and more complex organic compounds (Yamamura, Harada et al. 1990;Allada and Nash, 1993;Fang, Ionescu et al. 1997;Wong, Fong et al. 1997;Ma, Wilhelm et al. 2002;Emmanouil and Quock, 2007;Zhuang, Yang et al. 2012). Despite the wide structural variation of known anesthetics, lipid solubility is seen empirically to play a role in determining their anesthetic effect (Janoff, Pringle et al. 1981). ...
The interactions of molecules such as short-chain alcohols with the mammalian plasma membrane are thought to play a role in anesthetic effects. We have examined the concentration-dependent effects of ethanol and n-butanol on the fluidity of planar model lipid bilayer structures supported on mica. The supported model bilayer was composed of 1,2-dioleoyl-sn-phosphatidylcholine (DOPC), cholesterol, and sphingomyelin, and the bilayers were formed by vesicle fusion from extruded unilamellar vesicles (133 nm diameter, polydispersity index of 0.17). Controlled amounts of ethanol and n-butanol were added during vesicle deposition. Translational diffusion constants were obtained utilizing fluorescence recovery after photobleaching (FRAP) measurements on the micrometer scale with perylene as the fluorophore. The translational diffusion constants increased and then decreased with increasing ethanol concentration, with the bilayer structure degrading at ca. 0.8 M ethanol. A similar trend was observed for n-butanol at lower alcohol concentrations owing to greater interactions with phospholipid bilayer constituents. For n-butanol, the integrity of the planar bilayer structure deteriorated at ca. 0.4 M n-butanol. The results are consistent with bilayer interdigitation.
... Various in vitro and animal studies showed beneficial effects of noble gases on hypoxic-ischemic brain damage (78,79). This resulted in feasibility and safety studies on xenon, helium, and hydrogen in patients with postanoxic encephalopathy after cardiac arrest (80)(81)(82). ...
Postanoxic encephalopathy is the key determinant of death or disability after successful cardiopulmonary resuscitation. Animal studies have provided proof-of-principle evidence of efficacy of divergent classes of neuroprotective treatments to promote brain recovery. However, apart from targeted temperature management (TTM), neuroprotective treatments are not included in current care of patients with postanoxic encephalopathy after cardiac arrest. We aimed to review the clinical evidence of efficacy of neuroprotective strategies to improve recovery of comatose patients after cardiac arrest and to propose future directions. We performed a systematic search of the literature to identify prospective, comparative clinical trials on interventions to improve neurological outcome of comatose patients after cardiac arrest. We included 53 studies on 21 interventions. None showed unequivocal benefit. TTM at 33 or 36°C and adrenaline (epinephrine) are studied most, followed by xenon, erythropoietin, and calcium antagonists. Lack of efficacy is associated with heterogeneity of patient groups and limited specificity of outcome measures. Ongoing and future trials will benefit from systematic collection of measures of baseline encephalopathy and sufficiently powered predefined subgroup analyses. Outcome measurement should include comprehensive neuropsychological follow-up, to show treatment effects that are not detectable by gross measures of functional recovery. To enhance translation from animal models to patients, studies under experimental conditions should adhere to strict methodological and publication guidelines.
... In contrast to most general anesthetics whose primary effect is on the GABAergic system or act as NMDA channel blockers (e.g., ketamine) [22], xenon inhibits the NMDARs via both competitive inhibition of the glycine co-agonist binding site and noncompetitive inhibition of other domains in the subunits of the NMDA receptors [23]. The noncompetitive inhibition of the NMDARs might confer the neuroprotective feature of xenon [24,25]. Xenon has also been reported to have neuroprotective effects in models of hypoxic-ischemic injury [26][27][28]. ...
Early life exposure to general anesthetics can have neurotoxic consequences. Evidence indicates that xenon, a rare noble gas with anesthetic properties, may lessen neuronal damage under certain conditions. However, its potential neuroprotective properties, when used alone or in combination with other anesthetics, remain largely unknown. While it is difficult to verify the adverse effects of long duration anesthetic exposure in infants and children, the utilization of relevant non-clinical models (i.e., human-derived neural stem cells) may serve as a “bridging” model for evaluating the vulnerability of the nervous system. Neural stem cells, purchased from PhoenixSongs Biologicals, Inc., were guided to differentiate into neurons, astrocytes, and oligodendrocytes, which were then exposed to propofol (50 μM) for 16 h in the presence or absence of xenon (33%). Differentiation into cells of the neural lineage was confirmed by labelling with cell-specific markers, β-tubulin for neurons, glial fibrillary acidic protein (GFAP) for astrocytes, and galactocerebroside (GALC) for oligodendrocytes after 5 days of differentiation. The presence and severity of neural damage induced by anesthetic exposures were assessed by several methods, including the TUNEL assay, and immuno-histochemical measurements. Our data demonstrate that prolonged exposure to propofol results in a significant increase in the number of TUNEL-positive cells, indicating increased neural apoptosis. No significant changes were detected in the number of GFAP-positive astrocytes or GALC-positive oligodendrocytes. However, the number of β-tubulin-positive neurons was substantially reduced in the propofol-exposed cultures. Co-administration of xenon effectively blocked the propofol-induced neuronal damage/loss. No significant effects were observed when xenon was administered alone. The data indicate that prolonged exposure to propofol during development produces elevated levels of neuronal apoptosis in a human neural stem cell-derived model. However, sub-clinical, non-anesthetic concentrations of xenon, when used in combination with propofol, can prevent or ameliorate the toxic effects associated with prolonged anesthetic exposure. This is important as a more complete understanding of the neurotoxic mechanisms associated with a variety of clinically relevant anesthetic combinations becomes available. Protective approaches are critical for developing sound guidance on best practices for the use of these agents in the pediatric setting.
