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

Déborah Le Nogue,Ira Katz,Jérémie Lavaur,Etienne C Hirsch,Juan Fernando Ramirez-Gil,Patrick Pierre Michel,Aude Milet,Marc Lemaire,Géraldine Farjot

doi:10.1007/s00702-019-02112-x

Abstract

Using midbrain cultures, we previously demonstrated that the noble gas xenon is robustly protective for dopamine (DA) neurons exposed to l-trans-pyrrolidine-2,4-dicarboxylate (PDC), an inhibitor of glutamate uptake used to generate sustained, low-level excitotoxic insults. DA cell rescue was observed in conditions where the control atmosphere for cell culture was substituted with a gas mix, comprising the same amount of oxygen (20%) and carbon dioxide (5%) but 75% of xenon instead of nitrogen. In the present study, we first aimed to determine whether DA cell rescue against PDC remains detectable when concentrations of xenon are progressively reduced in the cell culture atmosphere. Besides, we also sought to compare the effect of xenon to that of other noble gases, including helium, neon and krypton. Our results show that the protective effect of xenon for DA neurons was concentration-dependent with an IC50 estimated at about 44%. We also established that none of the other noble gases tested in this study protected DA neurons from PDC-mediated insults. Xenon’s effectiveness was most probably due to its unique capacity to block NMDA glutamate receptors. Besides, mathematical modeling of gas diffusion in the culture medium revealed that the concentration reached by xenon at the cell layer level is the highest of all noble gases when neurodegeneration is underway. Altogether, our data suggest that xenon may be of potential therapeutic value in Parkinson disease, a chronic neurodegenerative condition where DA neurons appear vulnerable to slow excitotoxicity.

Highlights

Noble gases are monatomic gases with very low chemical reactivity, which explains why they are referred as inert gases (Selig et al 1964; Khriachtchev et al 2000)
We used the synthetic analog of glutamate PDC to generate, in vitro, low-level excitotoxicity as it may occur in Parkinson disease (PD) (Wallace et al 2007; Ambrosi et al 2014; Michel et al 2016)
When nitrogen was substituted with 75% xenon, DA cell death was virtually absent from the cultures (Fig. 1a, b)

Summary

Introduction

Noble gases are monatomic gases with very low chemical reactivity, which explains why they are referred as inert gases (Selig et al 1964; Khriachtchev et al 2000). An excessive excitatory drive from subthalamic nucleus glutamatergic neurons is thought to contribute to the vulnerability of substantia nigra DA neurons in this disorder (Wallace et al 2007; Ambrosi et al 2014) This slow excitotoxic process was mimicked by treating midbrain dopaminergic cultures with l-transpyrrolidine-2,4-dicarboxylate (PDC), a synthetic analog of glutamate that operates as a transportable inhibitor of inward glutamate transport (Blitzblau et al 1996; Grewer et al 2014). In such paradigm, DA neurons were protected when 75% nitrogen contained in the control atmosphere was substituted with 75% xenon (Lavaur et al 2017) but we did not explore the neuroprotective potential of lower concentrations of xenon in this setting. These cultures which contained about 2–3% of tyrosine hydroxylase (TH) positive neurons, at the time of plating, were maintained in Neurobasal medium (Gibco, Saint Aubin, France) supplemented with a B27 cocktail minus antioxidants (Gibco), a N2 mix (Gibco), 2 mM glutamine and 100 IU/ml penicillin/ streptomycin (Nafia et al 2008; Lavaur et al 2017)

Treatment procedures

Materials and methods

Results

Discussion

Compliance with ethical standards