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

• Published in: Journal of neurochemistry Vol. 142; no. 1; pp. 14 - 28
• Main Authors: Lavaur, Jérémie, Le Nogue, Déborah, Lemaire, Marc, Pype, Jan, Farjot, Géraldine, Hirsch, Etienne C., Michel, Patrick P.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.07.2017; Wiley; John Wiley and Sons Inc
• Subjects: Anesthetics, Inhalation - pharmacology; Animal models; Animals; Antioxidants - pharmacology; Argon; Astrocytes; astroglial cells; Biological effects; Brain; Brain injury; Cell death; Cell Death - drug effects; Cells, Cultured; Chemical reactions; Chromans - pharmacology; Dicarboxylic Acids - antagonists & inhibitors; Dicarboxylic Acids - toxicity; Dopamine; dopamine neurons; Dopaminergic Neurons - drug effects; Excitatory Amino Acid Antagonists - pharmacology; Excitotoxicity; Glial cells; glutamate; Glutamic acid receptors; Head injuries; Human health and pathology; Hypoxia; Ischemia; Life Sciences; Memantine; Memantine - pharmacology; Mesencephalon; Mesencephalon - drug effects; Movement disorders; N-Methyl-D-aspartic acid receptors; neurodegeneration; Neurodegenerative diseases; Neurons; Neuroprotection; Neuroprotective agents; Neuroprotective Agents - pharmacology; NMDA; Organ Culture Techniques; Original; ORIGINAL ARTICLES; Parkinson's disease; Pyrrolidine; Pyrrolidines - antagonists & inhibitors; Pyrrolidines - toxicity; Rare gases; Rats; Rats, Wistar; Receptors; Rodents; Stimulation; Tocopherol; Vitamin E; Xenon; Xenon - pharmacology; NMDA; neurodegeneration; dopamine neurons; xenon; glutamate; astroglial cells; dihydro-rhodamine-123; Parkinson's disease; N-methyl-D-aspartate PBS; glial cell line-derived neurotrophic factor HS; HS; PDC; xenon Ara-C; glial cell line-derived neurotrophic factor; horse serum NMDA; 4-dicarboxylic acid; L-trans-pyrrolidine-2; Dulbecco's phosphatebuffered saline; reactive oxygen species; fetal calf serum; N-methyl-D-aspartate; horse serum; PBS; reactive oxygen species TH; dihydro-rhodamine-123 DIV; cytosine b-D-arabinoside; DHR-123; dopamine DHR-123; tyrosine hydroxylase; fetal calf serum GDNF; Parkinson's disease ROS; DIV; GDNF; PD; TH; days in vitro FCS; FCS; ROS; days in vitro; cytosine b-D-arabinoside DA; DA; dopamine; 4-dicarboxylic acid PD; Dulbecco's phosphatebuffered saline PDC
• DOI: 10.1111/jnc.14041
• ISSN: 0022-3042

Despite its low chemical reactivity, the noble gas xenon possesses a remarkable spectrum of biological effects. In particular, xenon is a strong neuroprotectant in preclinical models of hypoxic‐ischemic brain injury. In this study, we wished to determine whether xenon retained its neuroprotective potential in experimental settings that model the progressive loss of midbrain dopamine (DA) neurons in Parkinson's disease. Using rat midbrain cultures, we established that xenon was partially protective for DA neurons through either direct or indirect effects on these neurons. So, when DA neurons were exposed to l‐trans‐pyrrolidine‐2,4‐dicarboxylic acid so as to increase ambient glutamate levels and generate slow and sustained excitotoxicity, the effect of xenon on DA neurons was direct. The vitamin E analog Trolox also partially rescued DA neurons in this setting and enhanced neuroprotection by xenon. However, in the situation where DA cell death was spontaneous, the protection of DA neurons by xenon appeared indirect as it occurred through the repression of a mechanism mediated by proliferating glial cells, presumably astrocytes and their precursor cells. Xenon also exerted trophic effects for DA neurons in this paradigm. The effects of xenon were mimicked and improved by the N‐methyl‐d‐aspartate glutamate receptor antagonist memantine and xenon itself appeared to work by antagonizing N‐methyl‐d‐aspartate receptors. Note that another noble gas argon could not reproduce xenon effects. Overall, present data indicate that xenon can provide protection and trophic support to DA neurons that are vulnerable in Parkinson's disease. This suggests that xenon might have some therapeutic value for this disorder. The noble gas xenon is neuroprotective in preclinical models of hypoxic‐ischemic brain injury. Here, we evaluated xenon effects in cell culture paradigms that model DA cell death in PD. We found that xenon partially protected DA neurons from low‐level excitotoxic insults or astrocyte‐mediated neurodegeneration. Xenon operated by means of direct or indirect effects toward DA neurons, in these two settings, respectively. Xenon worked by antagonizing NMDA receptors and its action was improved by blockade of these receptors with memantine.