Abstract：
Studies have shown that sevoflurane, a halogenated inhalational anesthetic, interferes with neurogenesis in the developing rodent brain. However, the mechanisms by which sevoflurane affects neural stem cells (NSCs) differentiation require further elucidation. Pregnant rats (gestational day 14) were anesthetized with 3.5% sevoflurane for 2 h, with or without ML385 pretreatment. ML385 is a specific nuclear factor erythroid 2-related factor 2 (NRF2) inhibitor. NRF2 expression and the downstream Sonic Hedgehog (SHH)/glioma-associated oncogene homolog 1 (GLI1) signaling cascade were determined by western blotting in the fetal brain at 24 h and 72 h after maternal sevoflurane exposure. Immunofluorescence and western blotting were performed to evaluate NSC neuronal and astrocytic differentiation in fetal brain tissues at 24 h and 72 h post-anesthesia as well as in the hippocampus on postnatal day (P) 28. Nissl staining was performed to measure the neuronal density on P28. Morris Water Maze tests were used to evaluate learning and memory function on P28-33. Neuronal and astrocytic differentiation of NSCs was markedly promoted in the fetal brain at 24 h and 72 h after maternal sevoflurane exposure, accompanied by upregulated NRF2. However, neuronal reduction and astrocyte proliferation were observed in the rat hippocampus at P28. Pretreatment with ML385 reversed sevoflurane-induced premature differentiation of NSCs, accompanied by suppression of SHH/GLI1 signaling. Furthermore, ML385 rescued sevoflurane-induced decreased neuronal density and impaired learning and memory function in the offspring. Prenatal sevoflurane exposure promotes neuronal and astrocytic differentiation of NSCs in the fetal rat brain, leading to long-term neuron reduction but astrocyte proliferation in the postnatal rat hippocampus. Prenatal sevoflurane exposure modulates NSC differentiation through NRF2/SHH/GLI1.
摘要：
研究表明七氟醚,卤化吸入麻醉剂,干扰正在发育的啮齿动物大脑中的神经发生。然而,七氟醚影响神经干细胞(NSC)分化的机制需要进一步阐明.妊娠大鼠（妊娠第14天）用3.5％七氟醚麻醉2小时，有或没有ML385预处理。ML385是一种特定的核因子类红细胞2相关因子2（NRF2）抑制剂。NRF2表达和下游SonicHedgehog（SHH）/神经胶质瘤相关癌基因同源物1（GLI1）信号级联在母亲七氟醚暴露后24小时和72小时通过蛋白质印迹在胎儿大脑中确定。进行免疫荧光和蛋白质印迹以评估麻醉后24小时和72小时胎儿脑组织以及出生后第28天海马中NSC神经元和星形细胞的分化。进行Nissl染色以测量P28上的神经元密度。使用Morris水迷宫测试来评估P28-33的学习和记忆功能。母体七氟醚暴露后24小时和72小时，在胎儿脑中神经干细胞的神经元和星形细胞分化显着促进，伴有上调的NRF2。然而,在P28时，在大鼠海马中观察到神经元减少和星形胶质细胞增殖。用ML385预处理可逆转sevofi诱导的神经干细胞过早分化，伴随着SHH/GLI1信号的抑制。此外，ML385在后代中拯救七氟醚诱导的神经元密度降低和学习和记忆功能受损。产前七氟醚暴露促进胎鼠脑神经干细胞的神经元和星形细胞分化,导致长期神经元减少，但在出生后大鼠海马中星形胶质细胞增殖。产前七氟醚暴露通过NRF2/SHH/GLI1调节NSC分化。
