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

Abstract

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-Daspartate glutamate receptor antagonist memantine and xenon itself appeared to work by antagonizing N-methyl-Daspartate 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.

Microglial glutamate release evoked by α‐synuclein aggregates is prevented by dopamine

“…The effects of DA and SKF are only partially mimicked with the cAMP-elevating agent FK nigra DA neurons in PD may not simply result from an increased excitatory drive from subthalamic glutamatergic neurons as suggested before (Lavaur et al, 2017;Wallace et al, 2007) but also from a local rise of the neurotransmitter. **p < .01 and ****p < .0001 vs. controls.…”

“…Here, we wished to evaluate the pro-inflammatory potential of amyloid fibrils of αS, using glutamate release as an activation marker of these cells. Our specific interest for this marker comes from the fact that glutamate has the potential to generate low-level excitotoxic insults (Lavaur et al, 2017) that may aggravate neurodegeneration in PD (Ambrosi et al, 2014). Using a model system of purified microglial cell cultures, we established that amyloid fibrils of αS had the capacity to stimulate FIGURE 5 Dopamine prevents glutamate release induced by αSa in microglial cells through D 1 receptor activation.…”

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

“…We reported previously that xenon promotes neuronal rescue not only against acute ischemic insults as initially demonstrated, but also in experimental situations where neurodegeneration is more slowly progressing (Lavaur et al 2016a, b). In particular, xenon was found to protect dopamine (DA) neurons in a culture setting where these neurons undergo sustained, low-level excitotoxicity mediated by glutamate (Lavaur et al 2017), i.e., experimental conditions that model Parkinson disease (PD) neurodegeneration (Nafia et al 2008). Indeed, 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).…”

“…Specifically, 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. Furthermore, even if we reported previously that argon was inactive against DA cell death induced by PDC, we have no information about the effects of other noble gases in the same experimental context.…”

Decoding the Rich Biological Properties of Noble Gases: How Well Can We Predict Noble Gas Binding to Diverse Proteins?

“…Heavier noble gases exhibit valuable properties in clinical and experimental settings—almost ideal anesthesia, neuroprotection, and analgesic qualities—and show beneficial effects on memory and addiction. They provide neuroprotection in in vitro and in vivo models of neurodegenerative conditions, potentially alleviating long‐term sequelae of stroke or other ischemic accidents . They exhibit little toxicity and wash out quickly, leading to rapid recovery.…”