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.

Inhalational Anesthetics as Neuroprotectants or Chemical Preconditioning Agents in Ischemic Brain

“…Furthermore, N 2 O (70% N 2 O/30% oxygen) failed to alter infarct size or behavioral outcomes as assessed at 3 or 14 days after transient middle cerebral artery occlusion (MCAO) and as compared with 70% nitrogen/30% oxygen treatment (Yokoo et al, 2004). While N 2 O administration (3 h) delivered after transient focal cerebral ischemia can improve cortical histopathology in rat (Abraini et al, 2005;David et al, 2003), N 2 O administered after global brain ischemia in paralyzed, ventilated primates failed to improve outcome even when administered for 48 h after the initial insult (Gisvold et al, 1984). These results are perhaps explained by the recent observation that even short-term high concentration (hyperbaric) N 2 O exposure (r3 h) in nonischemic, adult rat brain produces reversible neuronal injury, and prolonged N 2 O exposure ( > 3 h) causes neuronal cell death (Jetovic-Todorovic et al, 2003).…”

“…However, xenon exacerbated ischemic brain damage and aggravated neurological dysfunction in a rat model combining cardiopulmonary bypass and cerebral air emboli (Jungwirth et al, 2006). Post-MCAO treatment with xenon has also been reported to reduce cortical brain damage (Abraini et al, 2005;David et al, 2003). Another agent, enflurane, has been observed to have limited striatal protective effects in vitro (Toner et al, 2002).…”

“…For example, Bickler et al (1994) showed in rat cortical brain slices that the rate of glutamate and NMDA-mediated calcium influx was reduced during ischemia in the presence of isoflurane. Xenon and N 2 O decreased NMDAinduced calcium influx in cortical cell cultures when given 15 mins after transient focal cerebral ischemia (Abraini et al, 2005;David et al, 2003). In a gerbil model of forebrain ischemia, intra-ischemic halothane exposure did not alter the calcium reuptake rate as compared with sham operated animals or unanesthetized, nonischemic controls (Racay et al, 2000), suggesting another mechanism for decreasing the ischemia-induced upsurge in [Ca 2 + ] i .…”

Protein-Noble Gas Interactions Investigated by Crystallography on Three Enzymes - Implication on Anesthesia and Neuroprotection Mechanisms

“…When administrated after the reperfusion, xenon has beneficial effect by suppressing ischemic brain damage and tPA-induced brain hemorrhages Protein-Noble Gas Interactions Investigated by Crystallography on Three Enzymes -Implication on Anesthesia and Neuroprotection Mechanisms 287 (David et al, 2010) while nitrous oxide reduces ischemic brain damage but increases tPAinduced brain hemorrages (Haelewyn et al, 2011). Xenon is thus a very promising neuroprotective drug with few or no adverse side effects in models of acute ischemic stroke or perinatal hypoxia-ischemia (Homi et al, 2003;Ma et al, 2003;Abraini et al, 2005;David et al, 2008;Luo et al, 2008). Despite this, the widespread clinical use of xenon is limited by its scarceness and excessive cost of production, even if close xenon delivery systems are now being developed.…”

Transdermal delivery of xenon from lipophilic solution and water

“…Moreover, xenon is known as a medication for treatment of pain, insomnia, depression, and drug addiction [3,4]. Also, scientific literature presents evidence of the neuroprotective effects of xenon [5] in treatment of traumatic [6] and ischemic [7] brain injury.…”