Abstract
Purpose: Drugs that suppress neuronal activity, including all general anesthetics that have been tested thus far (ketamine, midazolam, isoflurane, propofol, and a cocktail of midazolam, nitrous oxide and isoflurane), trigger neuroapoptosis in the developing rodent brain. Combinations of nitrous oxide and isoflurane, or ketamine and propofol, cause more severe neuroapoptosis than any single agent by itself, which suggests a positive correlation between increased levels of anesthesia and increased severity of neuroapoptosis. In contrast, there is evidence that the rare gas, xenon, which has anesthetic properties, protects against isoflurane-induced neuroapoptosis in the infant rat brain, while not inducing neuroapoptosis by itself. The present study was undertaken to evaluate the potential of xenon to induce neuroapoptosis or to protect against neuroapoptosis induced by isoflurane in the infant mouse brain.
Methods: Seven-day-old C57BL/6 mice were exposed to one of four conditions: air (control); 0.75% isoflurane; 70% xenon; or 0.75% isoflurane +70% xenon for four hours. For histopathological evaluation of the brains, all pups were euthanized two hours later using activated caspase-3 immunohistochemical staining to detect apoptotic neurons. Under each condition, quantitative assessment of the number of apoptotic neurons in the cerebral cortex (CC) and in the caudate/putamen (C/P) was performed by unbiased stereology.
Results: The combination of xenon + isoflurane produced a deeper level of anesthesia than either agent alone. Both xenon alone (p<0.003 in CC;p<0.02 in C/P) and isoflurane alone (p<0.001 in both CC and C/P) induced a significant increase in neuroapoptosis compared to controls. The neuroapoptotic response to isoflurane was substantially more robust than the response to xenon. When xenon was administered together with isoflurane, the apoptotic response was reduced to a level lower than that for isoflurane alone (p<0.01 in CP; marginally non-significant in CC).
Conclusions: We conclude that xenon, in the infant mouse brain, has paradoxical properties. It triggers neuroapoptosis, and when combined with isoflurane, it increases the depth of anesthesia, and retains its own apoptogenic activity. However, it suppresses, rather than augments, isoflurane’s apoptogenic activity.
Résumé
Objectif: Les médicaments supprimant l’activité neuronale, y compris tous les anesthésiants généraux testés jusqu’à présent (kétamine, midazolam, isoflurane, propofol, et un cocktail de midazolam, de protoxyde d’azote et d’isoflurane) déclenchent la neuroapoptose dans le cerveau en développement des rongeurs. Des combinaisons de protoxyde d’azote de d’isoflurane, ou de kétamine et de propofol, provoquent une neuroapoptose plus grave que n’importe quel agent administré seul, ce qui suggère une corrélation positive entre des niveaux plus élevés d’anesthésie et une neuroapoptose plus grave. En revanche, il existe des données soutenant que le xénon, un gaz rare qui présente des propriétés anesthésiques, protège de la neuroapoptose induite par l’isoflurane dans le cerveau de rongeurs nourrissons, alors que seul, il n’induit pas de neuroapoptose. Cette étude a été menée dans le but d’évaluer le potentiel du xénon pour induire la neuroapoptose ou de protéger contre la neuroapoptose provoquée par l’isoflurance dans le cerveau de rongeurs nourrissons.
Méthode: Des souris C57BL/6 de sept jours ont été exposées à un de quatre états : air (témoin) ; 0,75 % isoflurane ; 70 % xénon ; ou 0,75 % isoflurane + 70 % xénon pendant quatre heures. Afin de réaliser une évaluation histopathologique du cerveau, tous les petits ont été euthanasiés deux heures plus tard à l’aide d’une technique de coloration immunohistochimique de caspase-3 activée pour permettre de détecter les neurones apoptotiques. Dans chaque état, une évaluation quantitative du nombre de neurones apoptotiques dans le cortex cérébral (CC) et dans le noyau caudé / putamen (C/P) a été réalisée par stéréologie non biaisée.
Résultats: La combinaison de xénon + isoflurane a provoqué un niveau d’anesthésie plus profond que lorsque les agents ont été administrés seuls. Le xénon seul (p<0,003 dans CC; p<0,02 dans C/P) et l’isoflurane seul (p<0,001 dans le CC et le C/P) ont provoqué une augmentation significative de neuroapoptose par rapport au groupe témoin. La réaction neuroapoptotique à l’isoflurane était considérablement plus puissante que la réaction au xénon. Lorsque le xénon a été administré avec l’isoflurane, la réaction apoptotique a diminué à un niveau plus bas que celui de l’isoflurane seul (p<0,01 dans CP; marginalement non significatif dans CC).
Conclusion: Nous concluons que le xénon, dans le cerveau de rongeurs nourrissons, possède des propriétés paradoxales. Il déclenche la neuroapoptose et, lorsqu’il est combiné à l’isoflurane, approfondit l’anesthésie, et retient sa propre activié apoptogène. Toutefois il supprime plutôt qu’augmente l’activité apoptogène de l’isoflurane.
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Financial support: Supported in part by NIH grant HD 37100 and a grant from the Department of Anesthesiology, Washington University.
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Cattano, D., Williamson, P., Fukui, K. et al. Potential of xenon to induce or to protect against neuroapoptosis in the developing mouse brain. Can J Anesth 55, 429–436 (2008). https://doi.org/10.1007/BF03016309
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DOI: https://doi.org/10.1007/BF03016309