Zhang Xiaoyu, Shen Fengyan, Xu Daojie, Zhao Xuan
International Peace Maternity & Child Health Hospital, Shanghai Jiaotong University School of Medicine, 910 Hengshan Road, Shanghai 200030, China.
Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
Int J Dev Neurosci. 2016 Nov;54:62-69. doi: 10.1016/j.ijdevneu.2016.01.008. Epub 2016 Mar 26.
Sevoflurane is widely used in pediatric anesthesia and studies have shown that it is capable of inducing neurodegeneration and subsequent cognitive disorders in the developing brain. However, the evidence that anesthetics are toxic to the human brain is insufficient. N-Methyl-d-aspartate (NMDA) receptors, critical for learning and memory, display expression changes with age and can be modulated by inhalation anesthetics. Generally, NMDA receptor (NR) type 1 is expressed at birth, peaks around the third postnatal week, and then declines slightly to adult levels. NR2Bs slowly decrease and NR2As gradually increase during postnatal development. These developmental switches of NMDA receptor subunits composition mark the transition from immature to adult neural processing and allow for the final maturation of associative learning abilities. In this study, we aimed to evaluate the effect of repeated sevoflurane anesthesia on NMDA receptor subunits composition in the developing rat brain and related behavioral disorders. Six-day-old male Sprague Dawley rats were randomly allocated into either a control group (group con) or a sevoflurane group (group sevo). Group sevo inhaled 2.1% sevoflurane carried by 70% oxygen for 2h each day from postnatal day (PND) 6 to PND 8. The same procedure, without applying the sevoflurane, was executed in group con. The membrane protein expression of NR1, NR2A and NR2B in the prefrontal cortex (PFC) and hippocampus was assessed at the end of the three days of anesthesia and at PND 21. An open field test was carried out to assess spontaneous locomotion on PNDs 21, 28 and 35. Y maze performance was used to assess attention and working memory on PND 28. Sevoflurane induced upregulation of NR1 and NR2B in the PFC at the end of anesthesia. On PND 21, NR1 and NR2B receptors were significantly increased whereas NR2A receptors were significantly decreased in the PFC in group sevo. Sevoflurane-treated rats showed hyper-locomotion and impairment of working memory in the behavior tests. These results indicate that repeated sevoflurane anesthesia at early stage of life can induce a long lasting effect of interfering with NMDA receptor subunits composition in rat PFC. These changes may contribute to the effects of sevoflurane on neuronal development and subsequent neurobehavioral disorders.
七氟醚广泛应用于小儿麻醉，且研究表明它能够在发育中的大脑中诱发神经退行性变及随后的认知障碍。然而，麻醉剂对人脑有毒性的证据并不充分。对学习和记忆至关重要的N-甲基-D-天冬氨酸（NMDA）受体，其表达会随年龄变化，且可被吸入麻醉剂调节。一般来说，NMDA受体1型（NR1）在出生时表达，在出生后第三周左右达到峰值，然后略微下降至成人水平。在出生后发育过程中，NR2B缓慢减少，NR2A逐渐增加。NMDA受体亚基组成的这些发育转变标志着从未成熟到成人神经处理的过渡，并使联想学习能力最终成熟。在本研究中，我们旨在评估反复七氟醚麻醉对发育中大鼠大脑中NMDA受体亚基组成及相关行为障碍的影响。将6日龄雄性Sprague Dawley大鼠随机分为对照组（con组）或七氟醚组（sevo组）。sevo组从出生后第6天（PND6）至PND8每天吸入由70%氧气携带的2.1%七氟醚2小时。con组执行相同程序，但不使用七氟醚。在麻醉三天结束时及PND21评估前额叶皮质（PFC）和海马中NR1、NR2A和NR2B的膜蛋白表达。在PND21、28和35进行旷场试验以评估自发运动。在PND28使用Y迷宫表现评估注意力和工作记忆。麻醉结束时，七氟醚诱导PFC中NR1和NR2B上调。在PND21，sevo组PFC中NR1和NR2B受体显著增加，而NR2A受体显著减少。在行为测试中，经七氟醚处理的大鼠表现出运动亢进和工作记忆受损。这些结果表明，生命早期反复七氟醚麻醉可诱导对大鼠PFC中NMDA受体亚基组成的长期干扰作用。这些变化可能导致七氟醚对神经元发育及随后神经行为障碍的影响。
