title: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U 1127, CNRS, Unité Mixte de Recherche (UMR) 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM , Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Lavaur
authors.affiliation: Air Liquide Santé International Medical R&D Paris, Saclay Research Center , Jouy-en Josas, France.
authors.forename: M
authors.initials: M
authors.lastname: Lemaire
authors.affiliation: Air Liquide Santé International Medical R&D Paris, Saclay Research Center , Jouy-en Josas, France.
authors.forename: J
authors.initials: J
authors.lastname: Pype
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U 1127, CNRS, Unité Mixte de Recherche (UMR) 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM , Paris, France.
authors.forename: D
authors.initials: D
authors.lastname: Le Nogue
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U 1127, CNRS, Unité Mixte de Recherche (UMR) 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM , Paris, France.
authors.forename: E C
authors.initials: EC
authors.lastname: Hirsch
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U 1127, CNRS, Unité Mixte de Recherche (UMR) 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM , Paris, France.
authors.forename: P P
authors.initials: PP
authors.lastname: Michel