Division of Neurotoxicology, National Center for Toxicological Research/U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
Neurotoxicol Teratol. 2011 Sep-Oct;33(5):592-7. doi: 10.1016/j.ntt.2011.06.003. Epub 2011 Jun 25.
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.
一氧化二氮（N(2)O）气体和异氟烷（ISO）蒸气的联合使用在小儿外科手术中较为常见，用于使人类婴儿和儿童失去意识和止痛。由于存在明显的局限性，因此难以彻底探究小儿麻醉剂对人类婴儿或儿童神经元的影响。由于灵长类动物大脑的复杂性，猴子通常是发育神经毒理学实验的首选动物模型，并且在恒河猴中已经报道了引起关注的现象（麻醉诱导的大脑神经元细胞死亡）。最近的报告表明，暴露于可阻断 N-甲基-D-天冬氨酸（NMDA）型谷氨酸受体或增强γ-氨基丁酸（GABA）受体的全身麻醉剂的发育中的大脑，会在啮齿动物中引发广泛的凋亡性细胞死亡。本研究旨在确定发育中的非人类灵长类动物长时间暴露于具有临床相关性的一氧化二氮和异氟烷混合物是否会产生神经元损伤。对出生后 5-6 天的恒河猴暴露于 N(2)O（70%）或 ISO（1.0%）单独或 N(2)O+ISO 8 小时。吸入 70%N(2)O+1%ISO 混合物可产生手术麻醉平面。麻醉给药完成后 6 小时，检查猴子是否有神经毒性作用。单独暴露于 N(2)O 或 ISO 的猴子未观察到明显的神经毒性作用。但是，当 N(2)O 与 ISO 结合使用时，在前额皮质、颞叶和海马中， caspase-3-、银染色和 Fluoro-Jade C 阳性细胞的数量增加，表明出现了明显的神经元损伤。电子显微镜照片显示，在额皮质中细胞质和核浓缩典型肿胀。这些数据表明，在发育中的恒河猴中长时间暴露于吸入麻醉剂（N(2)O 和 ISO 的混合物）会导致神经元损伤，并且观察到的细胞死亡是凋亡性和坏死性的。
