Advertisement

Potential of xenon to induce or to protect against neuroapoptosis in the developing mouse brain

  • Davide Cattano
  • Peter Williamson
  • Kimiko Fukui
  • Michael Avidan
  • Alex S. Evers
  • John W. OlneyEmail author
  • Chainllie Young
Reports Of Original Investigations

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.

Keywords

Xenon NMDA Antagonist Infant Mouse Develop Mouse Brain Apoptotic Neurodegeneration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Le potentiel du xénon pour induire ou protéger contre la neuroapoptose dans le cerveau en développement de la souris

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.

References

  1. 1.
    Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999; 283: 70–4.PubMedCrossRefGoogle Scholar
  2. 2.
    Ikonomidou C, Bittigau P, Ishimaru MJ, et al. Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 2000; 287: 1056–60.PubMedCrossRefGoogle Scholar
  3. 3.
    Olney JW, Tenkova T, Dikranian K, Qin YQ, Labruyere J, Ikonomidou C. Ethanol-induced apoptotic neurodegeneration in the developing C57BL/6 mouse brain. Dev Brain Res 2002; 133: 115–26.CrossRefGoogle Scholar
  4. 4.
    Bittigau P, Sifringer M, Genz K, et al. Antiepileptic drugs and apoptotic neurodegeneration in the develop ing brain. Proc Natl Acad Sci USA 2002: 99: 15089–94.PubMedCrossRefGoogle Scholar
  5. 5.
    Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003; 23: 876–82.PubMedGoogle Scholar
  6. 6.
    Dobbing J, Sands J. Comparative aspects of the brain growth spurt. Early Hum Dev 1979; 3: 79–83.PubMedCrossRefGoogle Scholar
  7. 7.
    Dikranian K, Ishimaru MJ, Tenkova T, et al. Apoptosis in the in vivo mammalian forebrain. Neurobiol Dis 2001; 8: 359–79.PubMedCrossRefGoogle Scholar
  8. 8.
    Olney JW, Tenkova T, Dikranian K, et al. Ethanol-induced caspase-3 activation in the in vivo developing mouse brain. Neurobiol Dis 2002; 9: 205–19.PubMedCrossRefGoogle Scholar
  9. 9.
    Young C, Klocke BJ, Tenkova T, et al. Ethanol-induced neuronal apoptosis in vivo requires BAX in the developing mouse brain. Cell Death Differ 2003; 10: 1148–55.PubMedCrossRefGoogle Scholar
  10. 10.
    Young C, Roth KA, Klocke BJ, et al. Role of caspase-3 in ethanol-induced developmental neurodegeneration. Neurobiol Dis 2005; 20: 608–14.PubMedCrossRefGoogle Scholar
  11. 11.
    Franks NP, Lieb WR. Molecular and cellular mechanisms of general anaesthesia. Nature 1994; 367: 607–14.PubMedCrossRefGoogle Scholar
  12. 12.
    Jevtovic-Todorovic V, Todorovic SM, Mennerick S, et al. Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nat Med 1998; 4: 460–3.PubMedCrossRefGoogle Scholar
  13. 13.
    Jenkins A, Greenblatt EP, Faulkner HJ, et al. Evidence for a common binding cavity for three general anesthetics within the GABAA receptor. J Neurosci 2001; 21: RC136.Google Scholar
  14. 14.
    Fredriksson A, Ponten E, Gordh T, Eriksson P. Neonatal exposure to a combination of N-methyl-D-aspartate and gamma-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits. Anesthesiology 2007; 107: 427–36.PubMedCrossRefGoogle Scholar
  15. 15.
    Young C, Jevtovic-Todorovic V, Qin YO, et al. Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain. Br J Pharmacol 2005; 146: 189–97.PubMedCrossRefGoogle Scholar
  16. 16.
    Cattano D, Young C, Straiko M, Olney JW. Subanesthetic doses of propofol induce neuroapoptosis in the infant mouse brain. Anesth Analg 2008 (in press).Google Scholar
  17. 17.
    Winegar BD, Yost CS. Volatile anesthetics directly activate baseline S K+ channels in aplysia neurons. Brain Res 1998; 807: 255–62.PubMedCrossRefGoogle Scholar
  18. 18.
    Talley EM, Bayliss DA. Modulation of TASK-1 (Kcnk3) and TASK-3 (Kcnk9) potassium channels: volatile anesthetics and neurotransmitters share a molecular site of action. J Biol Chem 2002; 277: 17733–42.PubMedCrossRefGoogle Scholar
  19. 19.
    Grasshoff C, Rudolph U, Antkowiak B. Molecular and systemic mechanisms of general anaesthesia: the ‘multisite and multiple mechanisms’ concept. Curr Opin Anaesthesiol 2005; 18: 386–91.PubMedCrossRefGoogle Scholar
  20. 20.
    Franks NP. Molecular targets underlying general anesthesia. Br J Pharmacol 2006; 147: Suppl 1: S72–81.PubMedCrossRefGoogle Scholar
  21. 21.
    Bains R, Moe MC, Larsen GA, Berg-Johnsen J, Vinje ML. Volatile anaesthetics depolarize neural mitochondria by inhibition of the electron transport chain. Acta Anaesthesiol Scand 2006; 50: 572–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Loepke AW, Mccann JC, Kurth C, Mcauliffe JJ. The physiologic effects of isoflurane anesthesia in neonatal mice. Anesth Analg 2006; 102: 75–80.PubMedCrossRefGoogle Scholar
  23. 23.
    Johnson SA, Young C, Olney JW. Isoflurane-induced neuroapoptosis in the developing brain of nonhypoglycemic mice. J Neurosurg Anesthesiol 2008; 20: 21–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Franks NP, Dickinson R, De Sousa S, Hall AC, Lieb WR. How does xenon produce anaesthesia? Nature 1998; 396: 324.PubMedCrossRefGoogle Scholar
  25. 25.
    Jayasinghe D, Gill AB, Levene MI. CBF reactivity in hypotensive and normotensive preterm infants. Pediatr Res 2003; 54: 848–53.PubMedCrossRefGoogle Scholar
  26. 26.
    Lane GA, Nahrwold ML, Tait AR, Taylor-Busch M, Cohen P J, Beaudoin AR. Anesthetics as teratogens: nitrous oxide is fetotoxic, xenon is not. Science 1980; 210: 899–901.PubMedCrossRefGoogle Scholar
  27. 27.
    Ma D, Williamson P, Januszewski A, et al. Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain. Anesthesiology 2007; 106: 746–53.PubMedCrossRefGoogle Scholar
  28. 28.
    Gundersen HJ, Bendtsen TF, Korbo L, et al. Some new, simple and efficient stereological methods and their use in pathological research and diagnosis. APMIS 1988; 96: 379–94.PubMedGoogle Scholar
  29. 29.
    Goto T, Saito H, Shinkai M, Nakata Y, Ichinose F, Morita S. Xenon provides faster emergence from anesthesia than does nitrous oxide-sevoflurane or nitrous oxide-isoflurane. Anesthesiology 1997; 86: 1273–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Rossaint R, Reyle-Hahn M, Schulte Am Esch J, et al;Xenon Study Group. Multicenter randomized comparison of the efficacy and safety of xenon and isoflurane in patients undergoing elective surgery. Anesthesiology 2003; 98: 6–13.PubMedCrossRefGoogle Scholar
  31. 31.
    Young C, Olney JW. Rapid suppression of ERK and Akt phosphorylation by ethanolinduced neuroapoptosis in infant mouse brain. Soc Neurosci 2006; 89:1/MM95 (abstract).Google Scholar

Copyright information

© Canadian Anesthesiologists 2008

Authors and Affiliations

  • Davide Cattano
    • 2
    • 4
  • Peter Williamson
    • 3
  • Kimiko Fukui
    • 2
  • Michael Avidan
    • 2
  • Alex S. Evers
    • 2
  • John W. Olney
    • 1
    Email author
  • Chainllie Young
    • 1
  1. 1.Department of PsychiatryWashington University School of MedicineSt. LouisUSA
  2. 2.Department of AnesthesiologyWashington University School of MedicineSt. LouisUSA
  3. 3.Department of Anaesthetics, Intensive Care & Pain Medicine, Imperial College LondonChelsea & Westminster HospitalLondonUnited Kingdom
  4. 4.Departments of Anesthesiology Surgery, School of MedicineUniversity of PisaPisaItaly

Personalised recommendations