Department of Anesthesiology, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Endocrine Department of Liyuan Hospital; Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Eur J Neurosci. 2023 Jan;57(2):217-232. doi: 10.1111/ejn.15874. Epub 2022 Dec 8.
Sevoflurane is a widely used general anaesthetic in paediatric patients. Although repeated sevoflurane exposure is known to cause neurodevelopmental disorders in children, the mechanism of this neurotoxicity remains largely unknown. Herein, we investigated the role of glutamate transporter 1 (GLT1) in sevoflurane-induced decreased neurogenesis. Neonatal rat pups (postnatal Day 7, PN7) were exposed to 3% sevoflurane for 2 h for three consecutive days. Neuron loss and decreased neurogenesis have been observed in the neonatal rat brain, along with decreased number of astrocytes. Apoptotic astrocytes were observed after repeated sevoflurane exposure in vitro, resulting in decreased levels of brain-derived neurotrophic factor (BDNF). Calcium overload was observed in astrocytes after repeated sevoflurane exposure, in addition to upregulation of GLT1. Inhibition of GLT1 activity ameliorates repeated sevoflurane exposure-induced cognitive deficits in adult rats. Mechanically, the upregulation of GLT1 was caused by the activation of mRNA translation. RNA-sequencing analysis further confirmed that translation-related genes were activated by repeated sevoflurane exposure. These results indicate that cognitive deficits caused by repeated sevoflurane exposure during PN7-9 are triggered decreased neurogenesis. The proposed underlying mechanism involves upregulation of apoptosis in astrocytes induced by GLT1; therefore, we propose GLT1 as a potential pharmacological target for brain injury in paediatric practice.
七氟醚是小儿患者中广泛使用的全身麻醉剂。虽然反复暴露于七氟醚会导致儿童神经发育障碍，但这种神经毒性的机制在很大程度上仍不清楚。在此，我们研究了谷氨酸转运体 1 (GLT1) 在七氟醚诱导的神经发生减少中的作用。新生大鼠 (出生后第 7 天，PN7) 连续 3 天每天暴露于 3%七氟醚 2 小时。在新生大鼠大脑中观察到神经元丢失和神经发生减少，同时星形胶质细胞数量减少。反复暴露于七氟醚后，体外观察到凋亡星形胶质细胞，导致脑源性神经营养因子 (BDNF) 水平降低。反复暴露于七氟醚后，星形胶质细胞中观察到钙超载，同时 GLT1 上调。抑制 GLT1 活性可改善成年大鼠反复暴露于七氟醚引起的认知缺陷。从机制上讲，GLT1 的上调是由 mRNA 翻译的激活引起的。RNA 测序分析进一步证实，反复暴露于七氟醚会激活与翻译相关的基因。这些结果表明，PN7-9 期间反复暴露于七氟醚引起的认知缺陷是由神经发生减少引起的。潜在的机制涉及 GLT1 诱导的星形胶质细胞凋亡增加；因此，我们提出 GLT1 是儿科实践中脑损伤的潜在药物靶点。
