Excitotoxicity

Overactivation of glutamate receptors is involved in a number of pathological processes. Excessive entry of calcium, mediated by NMDA receptors, triggers biochemical cascades that ultimately lead to neuronal cell death. This neurotoxicity due to overactivation of NMDA receptors, termed excitotoxicity by Olney,20 is considered to underlie the acute neuronal injury observed following insults such as stroke, cardiac arrest, and traumatic brain injury (TBI). N-methyl-D-aspartate receptor antagonists are neuroprotective in in vitro and in vivo brain injury models.21

Following the discovery that xenon inhibits NMDA receptors,15 it was shown that xenon could protect neuronal cell cultures against injury induced by NMDA, glutamate, or oxygen-glucose deprivation.22 The same study showed xenon to be neuroprotective in vivo against neuronal injury caused by subcutaneous injection of N-methyl-D,L-aspartate in rats. Subsequently, Petzelt et al. corroborated this finding in an in vitro model of hypoxia23 and in an in vivo model of stroke.24 Several NMDA antagonists have been clinically evaluated for their putative neuroprotective properties. Gavestinel (with activity at the glycine co-agonist site) and magnesium sulfate (an open pore blocker) were among the more recent, but neither had sufficient efficacy, possibly on the basis of poor central nervous system (CNS) penetrability.25,26

Other NMDA receptor antagonists, such as nitrous oxide, ketamine, and dizocilpine (MK-801) have intrinsic neurotoxicity,27 but xenon not only appears to be devoid of these neurotoxic effects but also ameliorates the injury produced by other NMDA antagonists.28 Reasons for xenon’s relative lack of neurotoxicity may relate to both the site of its action on the NMDA receptor as well its neutral effect on spontaneous dopamine release that the other NMDA antagonists enhance.29

Existing data distinguish the actions of xenon as a competitive inhibitor of NMDA receptors from well-established open-channel blockers of NMDA receptors, such as ketamine and MK-801. Open-channel blockers of NMDA receptors invariably show changed kinetics following the application of the agonist in the presence of the inhibitor. For example, when NMDA is applied to NMDA receptors, the rate of closure of the channel is always much faster when an open-channel blocker, such as ketamine or MK-801, is present.30 In the presence of xenon, there is no increase in the rate of closure of the NMDA response.15,16 Also, open-channel blockers, such as ketamine, invariably increase the decay of excitatory postsynaptic currents,31 but this is not observed with xenon.32 Thus, with both heterologous expression systems and intact synapses, xenon does not behave as an open-channel blocker, which may be an additional reason why it lacks the neurotoxicity seen with other NMDA antagonists.

Further reasons for the lack of neurotoxicity are provided below in the description of xenon’s other mechanisms of neuroprotective action.

Modulation of background (“leak”) potassium conductance

Activation of the two-pore potassium channels (K 2p channels) tends to hyperpolarize the membrane potential, taking it farther from an activation threshold. Xenon was shown to activate a species of these channels (TREK-1),Footnote 2 with the activation being critically dependent on a specific amino acid residue (Glu306). These TREK-1 channels are the mediating mechanism whereby intracellular acidification as well as polyunsaturated fatty acids produce neuroprotection.33 Genetically modified mice that lack TREK-1 channels fare poorly in models of cerebral ischemia, highlighting the importance of this molecular species in the organism’s defence against acute neuronal injury.34 It is notable that other NMDA antagonists, including nitrous oxide and cyclopropane, also activate TREK-1.19

Modulation of neuroapoptosis

Acute neuronal ischemic injury provokes sequential waves of signalling mechanisms, which successively results in neuronal death at different times. While excitotoxicity features early in the processes, resulting in neuronal death, apoptosis (i.e., programmed cell death) follows later through signalling mechanisms that are well defined.35 Xenon reduces the expression of pro-apoptotic genes, such as BAX,36 and increases anti-apoptotic proteins, such as Bcl-x L 36 and Bcl-2,36 , 37 resulting in a significant decline in neuroapoptosis.36

Modulation of neuroinflammation

Several investigators have reported that circulating immune cells traverse the blood-brain barrier following acute injury;38 furthermore, the ischemic brain activates the resident microglia cells. These activated macrophages propagate the ongoing neuronal damage through several pathways, including through the elaboration of pro-inflammatory cytokines that further injures the penumbra around an infarcted core.39 This process selectively prevents neuroinflammation and attenuates brain ischemic injury.40-42 In several types of organ injury models, xenon has been shown to exert anti-inflammatory effects43,44 and decrease neuronal dysfunction associated with neuroinflammation.45,46

Induction of hypoxia-inducible factor 1alpha (HIF-1α)

Xenon potently increases the translational efficiency and upregulation of the oxygen sensor, HIF-1α, under normoxic conditions.47 Downstream effectors of HIF-1α, including erythropoietin (EPO), have been shown to exert important neuroprotective properties.48 Nevertheless, it should be emphasized that, when EPO was administered to patients with anemia due to diabetes-induced renal failure, there was a twofold increase in stroke.49 In the setting of organ injury, xenon-induced upregulation of HIF-1α has been shown to be cytoprotective in the kidney,47,50 lung,43 heart,51 and brain.52 The Russian Federation’s Biomedical Agency exploited xenon’s ability to induce EPO by pretreating its endurance athletes. Some have speculated that this may have contributed to the athletes’ superior performance at the Sochi 2014 Winter Olympics. Since September 1, 2014, xenon has been banned for use in competitive athletics.Footnote 3

Modulation of adenosine triphosphate (ATP)-sensitive potassium channels (K ATP channels)