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.

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

“…The technical set‐up used for the supply of the pre‐defined gas atmospheres (20% O 2 , 5% CO 2 and 75% of the test gas) has been previously described in detail (Lavaur et al . ). The incubation chambers were maintained at 37°C in a conventional cell culture incubator for time periods indicated in the manuscript.…”

“…In particular, we showed for the first time that a sustained exposure to xenon provides neuronal rescue in culture settings that are relevant to the pathogenesis of Alzheimer's disease (Lavaur et al . ). Interestingly, we found that xenon also worked as a trophic factor toward basal forebrain cholinergic neurons, a neuronal population at risk in this disorder (Lavaur et al .…”

“…Interestingly, we found that xenon also worked as a trophic factor toward basal forebrain cholinergic neurons, a neuronal population at risk in this disorder (Lavaur et al . ,b).…”

Neuroprotection of dopamine neurons by xenon against low-level excitotoxic insults is not reproduced by other noble gases

“…Consistent with this view, DA cell death induced by PDC was also efficiently reduced by antagonizing NMDA receptors with memantine, in cultures maintained under 75% nitrogen. Note that the site to which xenon binds on NMDA receptors appears distinct from that of memantine (Kotermanski and Johnson 2009;Liu et al 2010) and unrelated to the glycine binding site of the receptor in the present setting (Lavaur et al 2016a). Indeed, glycine is inherently present in Neurobasal culture medium at a concentration of 400 μM, which is sufficient to saturate the NMDA receptor glycine-binding site (Dickinson et al 2007).…”

“…Specific gas concentrations were produced with a gas mixing system (GasMix, Alytech, Juvisy/Orge, France) supplied by compressed gas cylinders of individual pure gases. The description of the technical procedure used to fill up incubation chambers with gas atmospheres has been previously described in detail (Lavaur et al 2016a(Lavaur et al , 2017. The control cell culture atmosphere contained 20% O 2 , 5% CO 2 and 75% N 2 and test atmospheres adequate percentages of noble gases in replacement of an equivalent amount of nitrogen.…”