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

Abstract : 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 Alzheimer's 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. INTRODUCTION Noble gases such as xenon and argon have little propensity to participate in chemical reactions because of a filled valence shell. However, both xenon and argon possess interesting biological properties. Xenon is an approved anesthetic drug 1,2 with organoprotective properties when administered alone 3,4 or in combination with hypothermia. 5,6 Xenon has been described as neuroprotectant in preclinical models of focal and global brain ischemia, 7–11 spinal cord ischemia 12 and traumatic brain injury. 13,14 Some of the organoprotective and neuroprotective properties of xenon are also shared by argon. 14–16 For example, argon can provide neuroprotection in acute brain slices subjected to oxygen and glucose deprivation, 16 in rats subjected to intra-striatal injection of N-methyl-D-aspartate (NMDA) 16 or to transient occlusion of the middle cerebral artery. 17 Most recently, argon was also reported to reduce apoptosis of retinal ganglion cells after ischemia/reperfusion injury of the rat's eye. 18
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J Lavaur, J Pype, D Le Nogue, E C Hirsch, Patrick Pierre Michel. Xenon-mediated neuroprotection in response to sustained, low-level excitotoxic stress. Cell Death Discovery, 2016, 2, ⟨10.1038/cddiscovery.2016.18⟩. ⟨hal-01319283⟩



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