Inhalation anesthetic-induced neuronal damage in the developing rhesus monkey

The combination of nitrous oxide gas (N2O) 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 N2O (70%) or ISO (1.0%) alone, or N2O plus ISO for 8 h. Inhalation of the combination of 70% N2O + 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 N2O or ISO alone. However, neuronal damage was apparent when N2O 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 N2O and ISO) in the developing rhesus monkey results in neuronal damage, and that the cell death observed is apoptotic and necrotic in nature.

► We examined the effects of N2O & isoflurane (ISO) on developing nonhuman primates.
► No significant neurotoxic effects were seen in brain exposed to N2O or ISO alone.
► N2O & ISO caused significant increase of neuronal cell death after 8 h exposure.
► The cell death was observed in the frontal cortex, temporal gyrus and hippocampus.
► The cell death is apoptotic and necrotic in nature.