Maternal sevoflurane exposure affects neural stem cell differentiation in offspring rats through NRF2 signaling

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.