Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain.
BACKGROUND
Anesthetics, including isoflurane and nitrous oxide, an antagonist of the N-methyl-D-aspartate subtype of the glutamate receptor, have been demonstrated to induce apoptotic neurodegeneration when administered during neurodevelopment. Xenon, also an N-methyl-D-aspartate antagonist, not only lacks the characteristic toxicity produced by other N-methyl-D-aspartate antagonists, but also attenuates the neurotoxicity produced by this class of agent. Therefore, the current study sought to investigate xenon's putative protective properties against anesthetic-induced neuronal apoptosis.


METHODS
Separate cohorts (n = 5 or 6 per group) of 7-day-old rats were randomly assigned and exposed to eight gas mixtures: air, 75% nitrous oxide, 75% xenon, 0.75% isoflurane, 0.75% isoflurane plus 35% or 75% nitrous oxide, 0.75% isoflurane plus 30% or 60% xenon for 6 h. Rats were killed, and cortical and hippocampal apoptosis was assessed using caspase-3 immunostaining. In separate cohorts, cortices were isolated for immunoblotting of caspase 3, caspase 8, caspase 9, and cytochrome c. Organotypic hippocampal slices of postnatal mice pups were derived and cultured for 24 h before similar gas exposures, as above, and subsequently processed for caspase-3 immunostaining.


RESULTS
In vivo administration of isoflurane enhances neuronal apoptosis. When combined with isoflurane, nitrous oxide significantly increases whereas xenon significantly reduces apoptosis to a value no different from that of controls. In vitro studies corroborate the ability of xenon to attenuate isoflurane-induced apoptosis. Isoflurane enhanced expression of indicators of the intrinsic and common apoptotic pathways; this enhancement was increased by nitrous oxide but attenuated by xenon.


CONCLUSIONS
The current study demonstrates that xenon prevents isoflurane-induced neonatal neuronal apoptosis.
Ma
Daqing
D
Department of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, United Kingdom. d.ma@imperial.ac.uk
Williamson
Peter
P
Januszewski
Adam
A
Nogaro
Marie-Caroline
MC
Hossain
Mahmuda
M
Ong
Lay Ping
LP
Shu
Yi
Y
Franks
Nicholas P
NP
Maze
Mervyn
M
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D053148:Caspase 3 / Q000032:analysis; D006624:Hippocampus / Q000187:drug effects; D015151:Immunoblotting; D007530:Isoflurane / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects*; D009609:Nitrous Oxide / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014978:Xenon / Q000494:pharmacology*
D018685:Anesthetics, Inhalation; D014978:Xenon; D007530:Isoflurane; D053148:Caspase 3; D009609:Nitrous Oxide