title: Inhalation anesthetic-induced neuronal damage in the developing rhesus monkey.
abstract: The combination of nitrous oxide gas (N(2)O) and isoflurane (ISO) vapor is commonly used in pediatric surgical procedures for human infants and children to produce unconsciousness and analgesia. Because of obvious limitations it is difficult to thoroughly explore the effects of pediatric anesthetic agents on neurons in human infants or children. Due to the complexity of the primate brain, the monkey is often the animal model of choice for developmental neurotoxicology experiments, and it is in the rhesus monkey that the phenomenon of interest (anesthetic-induced neuronal cell death in the brain) has been previously reported. Recent reports indicate that exposure of the developing brain to general anesthetics that block N-methyl-D-aspartate (NMDA)-type glutamate receptors or potentiate gamma-aminobutyric acid (GABA) receptors can trigger widespread apoptotic cell death in rodents. The present study was performed to determine whether prolonged exposure of developing nonhuman primates to a clinically relevant combination of nitrous oxide and isoflurane produces neuronal damage. Postnatal day (PND) 5-6 rhesus monkeys were exposed to N(2)O (70%) or ISO (1.0%) alone, or N(2)O plus ISO for 8 h. Inhalation of the combination of 70% N(2)O+1% ISO produces a surgical plane of anesthesia. Six hours after completion of anesthetic administration the monkeys were examined for neurotoxic effects. No significant neurotoxic effects were observed for the monkeys exposed to N(2)O or ISO alone. However, neuronal damage was apparent when N(2)O was combined with ISO as indicated by increased numbers of caspase-3-, Silver staining- and Fluoro-Jade C-positive cells in the frontal cortex, temporal gyrus and hippocampus. Electron micrographs indicated typical swelling of the cytoplasm and nuclear condensation in the frontal cortex. These data suggest that prolonged exposure to inhaled anesthetics (a combination of N(2)O and ISO) in the developing rhesus monkey results in neuronal damage, and that the cell death observed is apoptotic and necrotic in nature.
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research/U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Xiaoju
authors.initials: X
authors.lastname: Zou
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Tucker A
authors.initials: TA
authors.lastname: Patterson
authors.forename: Ralph
authors.initials: R
authors.lastname: Callicott
authors.forename: Shuliang
authors.initials: S
authors.lastname: Liu
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Hanig
authors.forename: Merle G
authors.initials: MG
authors.lastname: Paule
authors.forename: William
authors.initials: W
authors.lastname: Slikker
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
mesh_terms: D018685:Anesthetics, Inhalation / Q000009:adverse effects*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D007530:Isoflurane / Q000008:administration & dosage / Q000009:adverse effects*; D008253:Macaca mulatta; D008297:Male; D057054:Molecular Imaging / Q000379:methods; D009336:Necrosis / Q000139:chemically induced; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology; D009609:Nitrous Oxide / Q000008:administration & dosage / Q000009:adverse effects*; D013702:Temporal Lobe / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure
chemical_list: D018685:Anesthetics, Inhalation; D007530:Isoflurane; D009609:Nitrous Oxide