title: Xenon pretreatment attenuates anesthetic-induced apoptosis in the developing brain in comparison with nitrous oxide and hypoxia.
abstract: BACKGROUND
  Administration of certain general anesthetics to rodents during the synaptogenic phase of neurodevelopment produces neuronal injury. Preconditioning (pretreatment) can reduce tissue injury caused by a severe insult; the authors investigated whether pretreatment strategies can protect the developing brain from anesthetic-induced neurotoxicity.
  
  
  METHODS
  Seven-day-old Sprague-Dawley rats were pretreated with one of the following: 70% xenon, 70% nitrous oxide, or 8% hypoxia for 2 h; 24 h later, rats were exposed to the neurotoxic combination of 70% nitrous oxide and 0.75% isoflurane for 6 h. Cortical and hippocampal neuroapoptosis was assessed using caspase-3 immunostaining. Separate cohorts were maintained for 40 days at which time cognitive function with trace fear conditioning was performed. In other pretreated cohorts, rat cortices were isolated for immunoblotting of caspase-3, Bcl-2, cytochrome C, P53, and mitogen-activated protein kinases. To obviate physiologic influences, organotypic hippocampal slices harvested from postnatal rat pups were cultured for 5 days and exposed to the same conditions as obtained for the in vivo studies, and caspase-3 immunostaining was again the measured outcome.
  
  
  RESULTS
  Xenon pretreatment prevented nitrous oxide- and isoflurane-induced neuroapoptosis (in vivo and in vitro) and cognitive deterioration (in vivo). Contrastingly, nitrous oxide- and isoflurane-induced neuroapoptosis was exacerbated by hypoxic pretreatment. Nitrous oxide pretreatment had no effect. Xenon pretreatment increased Bcl-2 expression and decreased both cytochrome C release and P53 expression; conversely, the opposite was evident after hypoxic pretreatment.
  
  
  CONCLUSIONS
  Although xenon pretreatment protects against nitrous oxide- and isoflurane-induced neuroapoptosis, hypoxic pretreatment exacerbates anesthetic-induced neonatal neurodegeneration.
authors.affiliation: Division of Surgery, Department of Surgery, Imperial College London, London, United Kingdom.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shu
authors.forename: Shivali M
authors.initials: SM
authors.lastname: Patel
authors.forename: Chen
authors.initials: C
authors.lastname: Pac-Soo
authors.forename: António Rei
authors.initials: AR
authors.lastname: Fidalgo
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Wan
authors.forename: Mervyn
authors.initials: M
authors.lastname: Maze
authors.forename: Daqing
authors.initials: D
authors.lastname: Ma
mesh_terms: D018685:Anesthetics, Inhalation / Q000008:administration & dosage*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000254:growth & development*; D015331:Cohort Studies; D000860:Hypoxia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D019194:Ischemic Preconditioning / Q000379:methods; D009609:Nitrous Oxide / Q000008:administration & dosage / Q000633:toxicity*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D014978:Xenon / Q000008:administration & dosage*
chemical_list: D018685:Anesthetics, Inhalation; D014978:Xenon; D009609:Nitrous Oxide