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

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 IC 50 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.

Discovery of the Xenon–Protein Interactome Using Large-Scale Measurements of Protein Folding and Stability

“…Xenon's biological effects were studied previously in numerous animal models (rat, dog, rabbit, etc. ), 35−39 bacteria, 40 cancer cells, 41 kidney cells, 42 neurons, 43,44 and human volunteers. 45,46 Although carried out in a different model system, our studies find protein targets that overlap with previously established modes of action for xenon, specifically xenon's ability to inhibit or influence the activity of proteins with ATP-dependent activity.…”

Noble gas and neuroprotection: From bench to bedside

“…Overactivation of NMDA receptors leads to an unpredictable amount of calcium influx that triggers cellular cascades and, ultimately, kills brain cells. Xenon has been proven to exert neuroprotective properties in both in vivo and in vitro models, including HIE in neonates, TBI, stroke, cerebral ischemia following CA, AD, PD, and L-dopa-induced dyskinesia (LID) ( Thoresen et al, 2009 ; Chakkarapani et al, 2010 ; Arola et al, 2013 ; Campos-Pires, 2013 ; Campos-Pires et al, 2015 ; Azzopardi et al, 2016 ; Laitio et al, 2016 ; Lavaur et al, 2016 ; Campos-Pires et al, 2018 ; Campos-Pires et al, 2019 ; Le Nogue et al, 2020 ). The technique of applying moderate hypothermia (33°C–34°C) is widely adopted for the treatment of neonatal asphyxia, becoming a standard strategy in some countries ( Azzopardi et al, 2012 ).…”

“…An in vitro study using midbrain cultures found that xenon was a robustly neuroprotective agent for DA neurons ( Lavaur et al, 2017 ). The protective effect of xenon for DA neurons was concentration-dependent, as evidenced by optimal effects at concentrations ranging from 50% to 75% ( Le Nogue et al, 2020 ). These findings pave the way for future clinical studies and shine a light on applications of xenon for AD, PD, and LID.…”

“…To date, xenon is the best characterized noble gas used in biomedicine. In addition to producing an anesthetic effect, xenon elicited neuroprotective effects against various injuries in both preclinical and clinical models of neonatal hypoxic-ischemic encephalopathy (HIE), spinal cord ischemia, traumatic brain injury (TBI), and even neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) ( Lavaur et al, 2016 ; Winkler et al, 2016 ; Le Nogue et al, 2020 ). At present, the mechanism by which xenon yields neuroprotection is primarily attributed to its competitive inhibition at a glycine site of N-methyl-D-aspartate (NMDA) receptors, although activation of adenosine triphosphate -sensitive potassium (KATP) channels or two-pore potassium channels may also explain some of its neuroprotective effects ( Gruss et al, 2004 ; Bantel et al, 2010 ).…”

Organoprotective Properties of Argon (Review)

“…За несколько десятилетий были получены данные о кардио-, нейро-, нефропротективных свойствах аргона при различных патологических процессах в экспериментальных моделях in vivo и in vitro . Получены новые знания о молекулярных механизмах действия аргона, проведено сравнение защитных эффектов аргона и других благородных газов, в частности, ксенона [37][38][39].…”