Jan Pype

Antiapoptotic activity of argon and xenon.

Although chemically non-reactive, inert noble gases may influence multiple physiological and pathological processes via hitherto uncharacterized physical effects. Here we report a cell-based detection system for assessing the effects of pre-defined gas mixtures on the induction of apoptotic cell death. In this setting, the conventional atmosphere for cell culture was substituted with gas combinations, including the same amount of oxygen (20%) and carbon dioxide (5%) but 75% helium, neon, argon, krypton, or xenon instead of nitrogen. The replacement of nitrogen with noble gases per se had no effects on the viability of cultured human osteosarcoma cells in vitro. Conversely, argon and xenon (but not helium, neon, and krypton) significantly limited cell loss induced by the broad-spectrum tyrosine kinase inhibitor staurosporine, the DNA-damaging agent mitoxantrone and several mitochondrial toxins. Such cytoprotective effects were coupled to the maintenance of mitochondrial integrity, as demonstrated by means of a mitochondrial transmembrane potential-sensitive dye and by assessing the release of cytochrome c into the cytosol. In line with this notion, argon and xenon inhibited the apoptotic activation of caspase-3, as determined by immunofluorescence microscopy coupled to automated image analysis. The antiapoptotic activity of argon and xenon may explain their clinically relevant cytoprotective effects.

Pharmacokinetic analysis of the chronic administration of the inert gases Xe and Ar using a physiological based model.

BackgroundNew gas therapies using inert gases such as xenon and argon are being studied, which would require chronically administered repeating doses. The pharmacokinetics of this type of administration has not been addressed in the literature.MethodsA physiologically based pharmacokinetics (PBPK) model for humans, pigs, mice, and rats has been developed to investigate the unique aspects of the chronic administration of inert gas therapies. The absorption, distribution, metabolism and excretion (ADME) models are as follows: absorption in all compartments is assumed to be perfusion limited, no metabolism of the gases occurs, and excretion is only the reverse process of absorption through the lungs and exhaled.ResultsThe model has shown that there can be a residual dose, equivalent to constant administration, for chronic repeated dosing of xenon in humans. However, this is not necessarily the case for small animals used in pre-clinical studies.ConclusionsThe use of standard pharmacokinetics parameters such as area under the curve would be more appropriate to assess the delivered dose of chronic gas administration than the gas concentration in the delivery system that is typically reported in the scientific literature because species and gas differences can result in very different delivered doses.

Argon and xenon ventilation during prolonged ex vivo lung perfusion.

BACKGROUND Evidence supports the use of ex vivo lung perfusion (EVLP) as a platform for active reconditioning before transplantation to increase the potential donor pool and to reduce the incidence of primary graft dysfunction. A promising reconditioning strategy is the administration of inhaled noble gases based on their organoprotective effects. Our aim was to validate a porcine warm ischemic lung injury model and investigate postconditioning with argon (Ar) or xenon (Xe) during prolonged EVLP. METHODS Domestic pigs were divided in four groups (n = 5 per group). In the negative control group, lungs were flushed immediately. In the positive control (PC) and treatment (Ar, Xe) groups, lungs were flushed after a warm ischemic interval of 2-h in situ. All grafts were evaluated and treated during normothermic EVLP for 6 h. In the control groups, lungs were ventilated with 70% N2/30% O2 and in the treatment groups with 70% Ar/30% O2 or 70% Xe/30% O2, respectively. Outcome parameters were physiological variables (pulmonary vascular resistance, peak airway pressures, and PaO2/FiO2), histology, wet-to-dry weight ratio, bronchoalveolar lavage, and computed tomography scan. RESULTS A significant difference between negative control and PC for pulmonary vascular resistance, peak airway pressures, PaO2/FiO2, wet-to-dry weight ratio, histology, and computed tomography-imaging was observed. No significant differences between the injury group (PC) and the treatment groups (Ar, Xe) were found. CONCLUSIONS We validated a reproducible prolonged 6-h EVLP model with 2 h of warm ischemia and described the physiological changes over time. In this model, ventilation during EVLP with Ar or Xe administered postinjury did not improve graft function.

Neuroprotective and neurorestorative potential of xenon

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. In addition to that xenon is neuroprotective in preclinical models of focal and global brain ischemia, spinal cord ischemia and traumatic brain injury. These neuroprotective effects are generally observed at concentrations of xenon ranging from 35 to 75%. 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. More specifically, xenon has been reported to compete with glycine, a co-agonist for NMDA receptor activation. 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, Parkinsons disease and Alzheimers disease (AD). 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. Of interest, one of these antagonists memantine has also a small beneficial effect on cognitive impairment in AD patients.

Xenon-mediated neuroprotection in response to sustained, low-level excitotoxic stress

Noble gases such as xenon and argon have been reported to provide neuroprotection against acute brain ischemic/anoxic injuries. Herein, we wished to evaluate the protective potential of these two gases under conditions relevant to the pathogenesis of chronic neurodegenerative disorders. For that, we established cultures of neurons typically affected in Alzheimers disease (AD) pathology, that is, cortical neurons and basal forebrain cholinergic neurons and exposed them to L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) to generate sustained, low-level excitotoxic stress. Over a period of 4 days, PDC caused a progressive loss of cortical neurons which was prevented substantially when xenon replaced nitrogen in the cell culture atmosphere. Unlike xenon, argon remained inactive. Xenon acted downstream of the inhibitory and stimulatory effects elicited by PDC on glutamate uptake and efflux, respectively. Neuroprotection by xenon was mimicked by two noncompetitive antagonists of NMDA glutamate receptors, memantine and ketamine. Each of them potentiated xenon-mediated neuroprotection when used at concentrations providing suboptimal rescue to cortical neurons but most surprisingly, no rescue at all. The survival-promoting effects of xenon persisted when NMDA was used instead of PDC to trigger neuronal death, indicating that NMDA receptor antagonism was probably accountable for xenon’s effects. An excess of glycine failed to reverse xenon neuroprotection, thus excluding a competitive interaction of xenon with the glycine-binding site of NMDA receptors. Noticeably, antioxidants such as Trolox and N-acetylcysteine reduced PDC-induced neuronal death but xenon itself lacked free radical-scavenging activity. Cholinergic neurons were also rescued efficaciously by xenon in basal forebrain cultures. Unexpectedly, however, xenon stimulated cholinergic traits and promoted the morphological differentiation of cholinergic neurons in these cultures. Memantine reproduced some of these neurotrophic effects, albeit with less efficacy than xenon. In conclusion, we demonstrate for the first time that xenon may have a therapeutic potential in AD.

The noble gas xenon provides protection and trophic stimulation to midbrain dopamine neurons

Despite its low chemical reactivity, the noble gas xenon possesses a remarkable spectrum of biological effects. In particular, xenon is a strong neuroprotectant in preclinical models of hypoxic‐ischemic brain injury. In this study, we wished to determine whether xenon retained its neuroprotective potential in experimental settings that model the progressive loss of midbrain dopamine (DA) neurons in Parkinsons disease. Using rat midbrain cultures, we established that xenon was partially protective for DA neurons through either direct or indirect effects on these neurons. So, when DA neurons were exposed to l‐trans‐pyrrolidine‐2,4‐dicarboxylic acid so as to increase ambient glutamate levels and generate slow and sustained excitotoxicity, the effect of xenon on DA neurons was direct. The vitamin E analog Trolox also partially rescued DA neurons in this setting and enhanced neuroprotection by xenon. However, in the situation where DA cell death was spontaneous, the protection of DA neurons by xenon appeared indirect as it occurred through the repression of a mechanism mediated by proliferating glial cells, presumably astrocytes and their precursor cells. Xenon also exerted trophic effects for DA neurons in this paradigm. The effects of xenon were mimicked and improved by the N‐methyl‐d‐aspartate glutamate receptor antagonist memantine and xenon itself appeared to work by antagonizing N‐methyl‐d‐aspartate receptors. Note that another noble gas argon could not reproduce xenon effects. Overall, present data indicate that xenon can provide protection and trophic support to DA neurons that are vulnerable in Parkinsons disease. This suggests that xenon might have some therapeutic value for this disorder.

Inhaling xenon ameliorates l-dopa-induced dyskinesia in experimental parkinsonism: Xenon Ameliorates Dyskinesia

Parkinsons disease motor symptoms are treated with levodopa, but long‐term treatment leads to disabling dyskinesia. Altered synaptic transmission and maladaptive plasticity of corticostriatal glutamatergic projections play a critical role in the pathophysiology of dyskinesia. Because the noble gas xenon inhibits excitatory glutamatergic signaling, primarily through allosteric antagonism of the N‐methyl‐d‐aspartate receptors, we aimed to test its putative antidyskinetic capabilities. We first studied the direct effect of xenon gas exposure on corticostriatal plasticity in a murine model of levodopa‐induced dyskinesia We then studied the impact of xenon inhalation on behavioral dyskinetic manifestations in the gold‐standard rat and primate models of PD and levodopa‐induced dyskinesia. Last, we studied the effect of xenon inhalation on axial gait and posture deficits in a primate model of PD with levodopa‐induced dyskinesia. This study shows that xenon gas exposure (1) normalized synaptic transmission and reversed maladaptive plasticity of corticostriatal glutamatergic projections associated with levodopa‐induced dyskinesia, (2) ameliorated dyskinesia in rat and nonhuman primate models of PD and dyskinesia, and (3) improved gait performance in a nonhuman primate model of PD. These results pave the way for clinical testing of this unconventional but safe approach.