Zou X, Sadovova N, Patterson T A, Divine R L, Hotchkiss C E, Ali S F, Hanig J P, Paule M G, Slikker W, Wang C
Division of Neurotoxicology, National Center for Toxicological Research, HFT-132, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA.
Neuroscience. 2008 Feb 19;151(4):1053-65. doi: 10.1016/j.neuroscience.2007.12.013. Epub 2007 Dec 15.
The anesthetic gas nitrous oxide (N2O) and the volatile anesthetic isoflurane (ISO) are commonly used in surgical procedures for human infants and in veterinary and laboratory animal practice to produce loss of consciousness and analgesia. Recent reports indicate that exposure of the developing brain to general anesthetics that block N-methyl-D-aspartate (NMDA) glutamate receptors or potentiate GABA(A) receptors can trigger widespread apoptotic neurodegeneration. In the present study, the question arises whether a relatively low dose of ISO alone or its combination with N2O entails significant risk of inducing enhanced apoptosis. In addition, the role of L-carnitine to attenuate these effects was also examined. Postnatal day 7 (PND-7) rat pups were exposed to N2O (75%) or a low dose of ISO (0.55%) alone, or N2O plus ISO for 2, 4, 6 or 8 h with or without L-carnitine. The neurotoxic effects were evaluated 6 h after completion of anesthetic administration. No significant neurotoxic effects were observed for the animals exposed to N2O or ISO alone. However, enhanced apoptotic cell death was apparent when N2O was combined with ISO at exposure durations of 6 h or more. Co-administration of L-carnitine (300 or 500 mg/kg, i.p.) effectively protected neurons from the anesthetic-induced damage. These data indicate that 6 h or more of inhaled anesthetic exposure consisting of a combination of N2O and ISO results in enhanced neuronal apoptosis, and L-carnitine effectively blocks the neuronal apoptosis caused by inhalation anesthetics in the developing rat brain.
麻醉气体氧化亚氮（N₂O）和挥发性麻醉剂异氟烷（ISO）常用于人类婴儿的外科手术以及兽医和实验室动物实践中，以产生意识丧失和镇痛效果。最近的报告表明，发育中的大脑暴露于阻断N-甲基-D-天冬氨酸（NMDA）谷氨酸受体或增强γ-氨基丁酸A（GABA(A)）受体的全身麻醉剂中，可引发广泛的凋亡性神经变性。在本研究中，出现了一个问题，即单独使用相对低剂量的ISO或其与N₂O的组合是否会带来诱导凋亡增强的重大风险。此外，还研究了左旋肉碱减轻这些影响的作用。将出生后第7天（PND-7）的幼鼠单独暴露于N₂O（75%）或低剂量的ISO（0.55%），或N₂O加ISO 2、4、6或8小时，同时给予或不给予左旋肉碱。在麻醉给药完成后6小时评估神经毒性作用。单独暴露于N₂O或ISO的动物未观察到明显的神经毒性作用。然而，当N₂O与ISO联合暴露6小时或更长时间时，凋亡性细胞死亡明显增加。联合给予左旋肉碱（300或500mg/kg，腹腔注射）可有效保护神经元免受麻醉诱导的损伤。这些数据表明，由N₂O和ISO组合而成的吸入性麻醉剂暴露6小时或更长时间会导致神经元凋亡增加，而左旋肉碱可有效阻断发育中大鼠大脑中吸入性麻醉剂引起的神经元凋亡。
