Reduction of Ischemic Brain Damage by Nitrous Oxide and Xenon

Abstract

Neuronal death after ischemia-induced brain damage depends largely upon the activation of the N-methyl-D-aspartate (NMDA) excitatory glutamate receptor that is a target for many putative neuroprotective agents. Whereas the NMDA receptors mediate ischemic brain damage, blocking them is deleterious in humans. Here, the authors investigated whether nitrous oxide or xenon, which are gaseous anesthetics with a remarkably safe clinical profile that have been recently demonstrated as effective inhibitors of the NMDA receptor, may reduce the following: (1) ischemia-induced brain damage in vivo, when given after occlusion of the middle cerebral artery (MCAO), a condition needed to make these potentially neuroprotective agents therapeutically valuable; or (2) NMDA-induced Ca2+ influx in cortical cell cultures, a major critical event involved in excitotoxic neuronal death. The authors have shown that both nitrous oxide at 75 vol% and xenon at 50 vol% reduce ischemic neuronal death in the cortex by 70% and further decrease NMDA-induced Ca2+ influx by 30%. In addition, xenon at 50%, but not nitrous oxide at 75 vol%, further decreases ischemic brain damage in the striatum (a subcortical structure that is known to be resistant to neuroprotective interventions). However, at a higher concentration (75 vol%), xenon exhibits potentially neurotoxic effects. The mechanisms of the neuroprotective and potentially neurotoxic effects of nitrous oxide and xenon, as well as the possible therapeutic implications in humans, are discussed.

Adding 5 h delayed xenon to delayed hypothermia treatment improves long-term function in neonatal rats surviving to adulthood

“…Additionally, other studies have shown that xenon provides neuroprotection in different preclinical models. Xenon has shown protection in different types of models; an oxygen-glucose deprived neuronal-glial coculture cell model (35), a middle cerebral artery occlusion rat model (36) and a cardiac arrest pig model (37). Hence, our study findings may be transferable to wider clinical applications.…”

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

“…Gases have thus the great advantages to present a reducing risk of neurotoxic side effects, compared to chemical neuroprotective drugs, especially at the low concentrations used for neuroprotection. Nitrous oxide and xenon reduce ischemic neuronal death in an in-vivo model of transient cerebral ischemia in rats and decrease the NMDA-induced Ca 2+ influx on neuronal cell cultures studied by in-vitro calcium video microscopy (David et al, 2003). These two gases produce the same effect than memantine, a low-affinity antagonist of NMDA receptor which is already used in clinics for neurodegenerative disease treatments (David et al, 2006).…”

“…If we compared these data with in-vivo pharmacology studies, we noticed that this ratio corresponded to the ratio of the narcotic potency of xenon compared to nitrous oxide (about 1.38) as estimated by the concentration of gas necessary to induce loss of righting reflex in rodents (Koblin et al, 1998;David et al, 2003), considered to be a behavioural endpoint closely related to MAC-awake (Campagna et al, 2003). In comparison, the ratio of gas-induced volume expansion for xenon and nitrous oxide in annexin V, a protein which could be considered as a prototype of NMDA receptor for its properties of ion selectivity and voltage gating (Demange et al, 1994), did not correspond to the ratio of anesthetic potency of xenon and nitrous oxide.…”

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).…”