Potentially Neuroprotective and Therapeutic Properties of Nitrous Oxide and Xenon

Abstract

Despite the beneficial effects of prototypical glutamatergic receptor antagonists in animal models, the pharmacological attempts by the use of such agents have met with very limited clinical success because these compounds produce adverse side effects and possess an intrinsic neurotoxicity at neuroprotective and therapeutic concentrations. Interestingly, nitrous oxide and xenon, which are anesthetic gases with a remarkably safe clinical profile, have been shown to be effective inhibitors of the NMDA receptor. We briefly review accumulating evidence that nitrous oxide and xenon at subanesthetic concentrations may have potentially neuroprotective and therapeutic properties, with a particular focus on their beneficial effects on ischemia-induced neuronal death and amphetamine-induced sensitization. Nitrous oxide at 75-vol% and xenon up to 70-vol% reduce ischemia-induced neuronal death induced by occlusion of the middle cerebral artery in rodents, and decrease NMDA-induced Ca2+ influx in neuronal cell cultures, a critical event involved in excitotoxicity. Nitrous oxide at 75-vol% and xenon at 50-vol% further reduced amphetamine-induced locomotor sensitization in rodents. However, at a higher concentration of 75-vol%, xenon shows potentially neurotoxic properties and adverse side effects. Because both agents are rapidly eliminated from the body, it is plausible that their administration at appropriate subanesthetic neuroprotective and therapeutic concentrations may not be associated, in contrast with prototypical NMDA receptor antagonists, with adverse side effects and potentially neurotoxicity. Finally, the possible therapeutic implications in humans are discussed.

Antiapoptotic activity of argon and xenon

“…Xenon has been shown to mediate prominent neuroprotective, 8 , 11 - 15 cardioprotective 16 - 18 and nephroprotective 4 , 19 , 20 effects in vivo. Thus, xenon protects the fetal brain in rat and piglet models of intrauterine perinatal asphyxia, a process that is accompanied by a significant reduction in neuronal apoptosis, 11 , 12 , 14 , 15 inhibits nitrous oxide- and isoflurane-induced neuronal death (and the consequent cognitive impairment) in newborn rats 13 and blunts the death of neurons triggered by the occlusion of the middle cerebral artery in rodents 8 .…”

“…Thus, xenon protects the fetal brain in rat and piglet models of intrauterine perinatal asphyxia, a process that is accompanied by a significant reduction in neuronal apoptosis, 11 , 12 , 14 , 15 inhibits nitrous oxide- and isoflurane-induced neuronal death (and the consequent cognitive impairment) in newborn rats 13 and blunts the death of neurons triggered by the occlusion of the middle cerebral artery in rodents 8 . In addition, xenon reportedly reduces the lethal response to cold injury of organotypic cultures of rat hippocampus, 8 , 9 as well as the N -methyl- D -aspartate (NMDA)-induced influx of Ca 2+ ions in cultured neurons, 8 an event that is critically involved in excitotoxicity 29 . Xenon has also been shown to protect isolated rabbit hearts from ischemia/reperfusion injury, 16 an effect that was abolished by the specific mitoK ATP channel blocker 5-hydroxydecanoate 16 .…”

“…Nonetheless, at least some of these elements can interact in a stabilizing fashion with the active site of specific enzymes and receptors 6 , 7 . Of note, argon and xenon (but less so helium, krypton, neon, and radon) have been shown to mediate consistent neuroprotective, 8 - 15 cardioprotective, 16 - 18 and nephroprotective 4 , 19 , 20 effects in vitro, ex vivo, and in vivo. Though the molecular mechanisms underlying these observations remain largely undefined, it has been proposed that the cytoprotective effects of noble gases might result from the opening of the mitochondrial ATP-sensitive K (mitoK ATP ) channels 16 , 21 .…”

Bench-to-bedside review: Molecular pharmacology and clinical use of inert gases in anesthesia and neuroprotection

“…Other NMDA-receptor antagonists such as nitrous oxide, ketamine and dizocil-pine (MK801) have intrinsic neurotoxicity, but xenon appears devoid of neurotoxic effects [73,74]. Xenon has now been shown to afford neuroprotection in a variety of mammalian in vitro and in vivo models, including focal cerebral ischemia (mouse), neonatal asphyxia (mouse), neurocognitive deficit following cardiopulmonary bypass (rat and pig) and traumatic brain injury (mouse) [5,75-81] (Figure 3). …”

XENON in medical area: emphasis on neuroprotection in hypoxia and anesthesia

“…Additionally, increased calcium concentration results in activation of calpain, which in turn activates p38 (pro-death kinase), activation of stress-induced protein kinase (such as p38 and JNKs) and aggregation of proteins and nucleic acids that deteriorates lipid bilayer membrane [72] resulting in cell death. Xenon blocks NMDA receptor at the glycine binding site [73] and inhibits these excitotoxic pathways, thus establishes neuroprotection [74]. …”