Is Xenon a Future Neuroprotectant?

Pamela Sun; Jianteng Gu; Mervyn Maze; Daqing Ma


Future Neurology. 2009;14(4):483-492. 

In This Article


NMDA antagonists have displayed neuroprotective properties against brain injury, hence, the discovery's generation of such interest in the potential use of xenon as a neuroprotective agent.

Xenon against Excitotoxicity

Numerous animal experiments have demonstrated that key destructive processes of the neuroexcitatory cascade, such as Ca2+ influx,[71] accumulation of glutamate and the release of its coagonist glycine, can be prevented by application of xenon. Xenon provided protection against cellular damage and prevention of hypoxia-induced glutamate release in hypoxia-damaged, embryonic-rate, cortical neuron cultures.[72]

Recently, it has been shown that xenon, administered at subanesthetic doses, offered global neuroprotection from reduction of neurotransmitter release induced by ischemia and subsequent cell injury and neuronal death, in both in and ex vivo excitotoxic insults. Maximal neuroprotection has been obtained with 50% xenon at which it further exhibited significant neuroprotective effects in vivo even when administered up to 4 h after intrastriatal NMDA injection.[73] In addition, xenon may inhibit calcium/calodulin-dependent protein kinase II, conferring protection against excitotoxicity in vitro.[74]

Xenon against Apoptosis

As apoptosis is a relatively late-developing process, the opportunity to mitigate this after the injury favors the therapeutic use of xenon.

Xenon may interrupt the apoptotic process, thus, preventing cell injury leading to apoptosis – this can occur through inhibition of caspase enzymes and mitigation of mitochondrial dysfunction.[75] It has been demonstrated to prevent isoflurane-induced neonatal neuronal apoptosis with a reduction in cytosolic proapoptotic Bax protein expression and enhanced Bcl-xl expression,[76] which binds to Bax and is consequently antiapoptotic.[77] When combined with isoflurane, xenon has been shown to suppress, rather than augment, isoflurane's apoptogenic activity. However, on its own, it has been found to trigger neuroapoptosis.[78] Further investigations are therefore warranted.

Xenon against Inflammation

During the reperfusion period, inflammatory cells are recruited to the site of injury causing exaggerated immune response, which may be detrimental.

Xenon has been revealed to interact with the human immune system by preserving neutrophil and monocyte antibacterial capacity, or the modulation of inflammatory cytokines such as TNF-α and IL-6 in monocytes.[79,80]

The time interval before the inflammatory process begins and the time delay before the process becomes destructive, provides an opportunistic therapeutic window for xenon to interrupt or mitigate inflammatory injury.

Xenon Promotes Cell Signaling

Xenon has been demonstrated to protect against oxygen and glucose deprivation (OGD) in vitro and against hypoxia–ischemia (H/I) in neonatal rats by cyclic AMP response element-binding protein (CREB)-mediated alteration of gene expression of several molecules involved in the induction of neuronal ischemic tolerance.[81] Xenon's inhibition of the NMDA receptor activates various transducers within the neuron, one of which is PKC, which triggers phosphorylation of MAPK including p38 MAPK and extracellular signal-regulated kinase (ERK).[82,83] MAPK is able to phosphorylate CREB to phospho-CREB (pCREB) which then recruits CREB-binding protein (CBP). The CREB–CBP interaction induces transcription of several prosurvival genes including brain-derived neurotrophic factor (BDNF) and prosurvival protein Bcl2, which promote cell tolerance to ischemic insult.[81]