| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
,
* From the Departments of Psychiatry, and
Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA; the
Department of Anaesthetics, Intensive Care & Pain Medicine, Imperial College London, Chelsea & Westminster Hospital, London, United Kingdom; and the
Departments of Anesthesiology Surgery, School of Medicine, University of Pisa, Pisa, Italy.
Address correspondence to: Dr. John W. Olney, Department of Psychiatry, Washington University School of Medicine, 660 South Euclid, St. Louis, MO 63110, USA. Phone: 314-362-2479; Fax: 314-747-0346; E-mail: olneyj{at}psychiatry.wustl.edu
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.
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.
2 Ikonomidou C, Bittigau p, Ishimaru MJ, et al. Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 2000; 287: 1056–60.
3 Olney JW, Tenkova T, Dikranian K, Qin YQ, Labruyere J, Ikonomidou C. Ethanol-induced apoptotic neurode-generation in the developing C57BL/6 mouse brain. Dev Brain Res 2002; 133: 115–26.[Medline]
4 Bittigau p, Sifringer M, Genz K, et al. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci USA 2002: 99: 15089–94.
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.
6 Dobbing J, Sands J. Comparative aspects of the brain growth spurt. Early Hum Dev 1979; 3: 79–83.[Medline]
7 Dikranian K, Ishimaru MJ, Tenkova T, et al. Apoptosis in the in vivo mammalian forebrain. Neurobiol Dis 2001; 8: 359–79.[Medline]
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.[Medline]
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.[Medline]
10 Young C, Roth KA, Klocke BJ, et al. Role of caspase-3 in ethanol-induced developmental neurodegeneration. Neurobiol Dis 2005; 20: 608–14.[Medline]
11 Franks Np, Lieb WR. Molecular and cellular mechanisms of general anaesthesia. Nature 1994; 367: 607–14.[Medline]
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.[Medline]
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.
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.[Medline]
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.[Medline]
16 Cattano D, Young C, Straiko M, Olney JW. Sub-anesthetic doses of propofol induce neuroapoptosis in the infant mouse brain. Anesth Analg 2008 (in press).
17 Winegar BD, Yost CS. Volatile anesthetics directly activate baseline S K+ channels in aplysia neurons. Brain Res 1998; 807: 255–62.[Medline]
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.
19 Grasshoff C, Rudolph U, Antkowiak B. Molecular and systemic mechanisms of general anaesthesia: the ‘multi-site and multiple mechanisms’ concept. Curr Opin Anaesthesiol 2005; 18: 386–91.[Medline]
20 Franks Np. Molecular targets underlying general anesthesia. Br J Pharmacol 2006; 147: Suppl 1: S72–81.[Medline]
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.[Medline]
22 Loepke AW, Mccann JC, Kurth C, Mcauliffe JJ. The physiologic effects of isoflurane anesthesia in neonatal mice. Anesth Analg 2006; 102: 75–80.
23 Johnson SA, Young C, Olney JW. Isoflurane-induced neuroapoptosis in the developing brain of nonhypoglycemic mice. J Neurosurg Anesthesiol 2008; 20: 21–8.[Medline]
24 Franks Np, Dickinson R, De Sousa S, Hall AC, Lieb WR. How does xenon produce anaesthesia? Nature 1998; 396: 324.[Medline]
25 Jayasinghe D, Gill AB, Levene MI. CBF reactivity in hypotensive and normotensive preterm infants. Pediatr Res 2003; 54: 848–53.[Medline]
26 Lane GA, Nahrwold ML, Tait AR, Taylor-Busch M, Cohen pJ, Beaudoin AR. Anesthetics as teratogens: nitrous oxide is fetotoxic, xenon is not. Science 1980; 210: 899–901.
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.[Medline]
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.[Medline]
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.[Medline]
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.[Medline]
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).
Related articles in CJA:
This article has been cited by other articles:
 |
|
 |
|
  G. M.T. Hare Xenon anesthesia: safe, protective and neurotoxic?/L'anesthesie au xenon : securitaire, protectrice et neurotoxique ? Can J Anesth, July 1, 2008; 55(7): 403 - 407. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
