Reduction of ischemic brain damage by nitrous oxide and xenon.
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.
David
Helene N
HN
Université de Caen-Basse Normandie, Caen, France.
Leveille
Frederic
F
Chazalviel
Laurent
L
MacKenzie
Eric T
ET
Buisson
Alain
A
Lemaire
Marc
M
Abraini
Jacques H
JH
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D009609:Nitrous Oxide / Q000494:pharmacology*; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy; D014978:Xenon / Q000494:pharmacology*
D018685:Anesthetics, Inhalation; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D014978:Xenon; D016202:N-Methylaspartate; D009609:Nitrous Oxide; D002118:Calcium