Xenon pretreatment attenuates anesthetic-induced apoptosis in the developing brain in comparison with nitrous oxide and hypoxia.
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.
Shu
Yi
Y
Division of Surgery, Department of Surgery, Imperial College London, London, United Kingdom.
Patel
Shivali M
SM
Pac-Soo
Chen
C
Fidalgo
António Rei
AR
Wan
Yanjie
Y
Maze
Mervyn
M
Ma
Daqing
D
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*
D018685:Anesthetics, Inhalation; D014978:Xenon; D009609:Nitrous Oxide