Zhu Gang, Tao Lei, Wang Ronglin, Xue Ying, Wang Xingqin, Yang Shaosong, Sun Xude, Gao Guodong, Mao Zixu, Yang Qian
Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
Department of Anesthesiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
J Neurochem. 2017 Jul;142(2):272-285. doi: 10.1111/jnc.14057. Epub 2017 Jun 1.
Sevoflurane, a typical inhaled anesthetic, is widely used in patients of all ages during surgery. The negative effects, such as inducing cell death and damaging spatial memory, of sevoflurane on neurodevelopment have raised increasing concerns in recent years. However, the molecular mechanism remains unclear. This study focused on the crucial role of endoplasmic reticulum (ER) stress in sevoflurane-induced hippocampal injury. Three-week-old rats were exposed to sevoflurane or control air for 5 h with or without ER stress inhibitor (4-phenylbutyric acid, 4-PBA) injection. The hippocampus was harvested to measure the ER stress sensors by western immunoblotting. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling staining was used to detect cell apoptosis and electrophysiology was used to measure the intrinsic excitability of neurons in hippocampus. We measured learning and memory ability by Morris water maze tests 5 weeks after sevoflurane exposure. Interestingly, persistent sevoflurane exposure significantly increased the levels of ER stress sensors in hippocampus. But it resulted in different effects in CA1 and dentate gyrus. Greatly increased caspase-12-mediated apoptotic cells, which were proved to be the neural stem cells, were detected in the dentate gyrus. Meanwhile, CA1 pyramidal neurons exhibited significantly reduced intrinsic excitability. Furthermore, the administration of ER stress inhibitor attenuated the above mentioned detrimental effects evidently and prevented the following relevant learning and memory deficits. In conclusion, sevoflurane-mediated ER stress performs distinct effects on the different subfields of the immature hippocampus and inhibiting ER stress during sevoflurane anesthesia will be a potential method to prevent the following learning and memory deficits in adulthood.
七氟醚是一种典型的吸入性麻醉剂，广泛应用于各年龄段患者的手术过程中。近年来，七氟醚对神经发育的负面影响，如诱导细胞死亡和损害空间记忆，引起了越来越多的关注。然而，其分子机制仍不清楚。本研究聚焦于内质网（ER）应激在七氟醚诱导的海马损伤中的关键作用。将三周龄大鼠暴露于七氟醚或对照空气中5小时，同时注射或不注射ER应激抑制剂（4-苯基丁酸，4-PBA）。采集海马组织，通过蛋白质免疫印迹法检测ER应激传感器。采用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记染色法检测细胞凋亡，并用膜片钳电生理技术检测海马神经元的内在兴奋性。在七氟醚暴露5周后，通过莫里斯水迷宫试验测量学习和记忆能力。有趣的是，持续暴露于七氟醚会显著增加海马中ER应激传感器的水平。但在海马CA1区和齿状回产生了不同的影响。在齿状回中检测到大量由caspase-12介导的凋亡细胞，这些细胞被证实为神经干细胞。同时，CA1区锥体神经元的内在兴奋性显著降低。此外，给予ER应激抑制剂可明显减轻上述有害影响，并预防随后出现的相关学习和记忆缺陷。总之，七氟醚介导的ER应激对未成熟海马的不同亚区产生不同影响，在七氟醚麻醉期间抑制ER应激将是预防成年后出现学习和记忆缺陷的一种潜在方法。
