目的 建立孕晚期大鼠暴露于七氟烷对子代大鼠产生神经毒性的动物模型，探讨姜黄素能否减轻七氟烷对子代大鼠的神经毒性。方法 将32只孕19 d母鼠随机分为对照组、模型组和姜黄素低、高剂量（20、40 mg/kg）组。除对照组外，其余各组母鼠吸入2.5%七氟烷6 h。子代出生后21 d，子代连续3周ip药物。观察各组子代的神经发育情况，评价子代海马CA1区神经元凋亡和脑源性神经营养因子（brain-derived neurotrophic factor，BDNF）、酪氨酸激酶受体B（tyrosine kinase receptor B，TrkB）蛋白表达情况，以及子代神经发育和学习记忆能力。结果 与对照组、模型组和姜黄素低剂量组比较，姜黄素高剂量组子代神经元细胞凋亡率显著升高（P＜0.001）。与对照组比较，模型组BDNF和TrkB蛋白表达水平均显著降低（P＜0.001），子代海马CA1区神经元树突棘密度显著降低（P＜0.001），子代逃避潜伏期显著延长（P＜0.001），子代穿越平台所在象限时间显著缩短（P＜0.001），穿越平台所在区域次数显著减少（P＜0.01）；与模型组比较，姜黄素低剂量组BDNF和TrkB蛋白表达水平显著升高（P＜0.001），姜黄素高剂量组BDNF蛋白表达水平显著升高（P＜0.001），姜黄素低剂量组神经元树突棘密度显著升高（P＜0.001），姜黄素各剂量组子代逃避潜伏期显著缩短（P＜0.05、0.001），姜黄素低剂量组子代穿越平台所在象限时间显著延长（P＜0.001）；与姜黄素低剂量组比较，姜黄素高剂量组BDNF和TrkB蛋白表达水平显著降低（P＜0.001），神经元树突棘密度显著降低（P＜0.05），子代穿越平台所在象限时间显著缩短（P＜0.05），穿越平台所在区域次数显著减少（P＜0.05）。结论 20 mg/kg姜黄素可通过增加海马CA1区BNDF、TrkB表达，促进海马神经元发育，减轻七氟烷对发育中大脑的神经毒性并改善子代的学习记忆能力。然而，40 mg/kg姜黄素可加速子代海马CA1区神经元凋亡，推测可能存在药物过量。

Objective To establish an animal model of neurotoxicity in offspring rats exposed to sevoflurane during late pregnancy, and to explore whether curcumin can alleviate the neurotoxicity of sevoflurane in offspring rats. Methods A total of 32 pregnant female mice at 19 d of gestation were randomly divided into control group, model group, curcumin low- and high-dose (20, 40 mg/kg) groups. Except for the control group, all other groups of female mice were inhaled 2.5% sevoflurane for 6 h. At 21 d after birth, the offspring were ip drugs for three consecutive weeks. The neural development of each group of offspring was observed, the neuronal apoptosis and expressions of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB) proteins in hippocampal CA1 region of offspring, as well as their neural development and learning and memory abilities were evaluated. Results Compared with control group, model group and curcumin low-dose group, the apoptosis rate of offspring neurons in curcumin high-dose group was significantly increased (P < 0.001). Compared with control group, the expression levels of BDNF and TrkB proteins in model group were significantly reduced (P < 0.001), the dendritic spine density of hippocampal CA1 neurons in offspring was significantly reduced (P < 0.001), the escape latency of offspring was significantly prolonged (P < 0.001), the time for offspring to cross the quadrant where the platform is located was significantly shortened (P < 0.001), and the number of times they cross the region where the platform is located was significantly reduced (P < 0.01). Compared with model group, the expression levels of BDNF and TrkB proteins were significantly increased in curcumin low-dose group (P < 0.001), the BDNF protein expression level was significantly increased in curcumin high-dose group (P < 0.001), the dendritic spine density of neurons was significantly increased in curcumin low-dose group (P < 0.001), the escape latency of offspring in each dose group of curcumin was significantly shortened (P < 0.05, 0.001), and the time for offspring to cross the platform quadrant was significantly prolonged in curcumin low-dose group (P < 0.001). Compared with curcumin low-dose group, rats in curcumin high-dose group showed a significant decrease in the expression levels of BDNF and TrkB proteins (P < 0.001), a significant decrease in the density of dendritic spines in neurons (P < 0.05), a significant reduction in the time for offspring to cross the quadrant where the platform is located (P < 0.05), and a significant reduction in the number of times they cross the region where the platform is located (P < 0.05). Conclusion 20 mg/kg curcumin can promote the development of hippocampal neurons, alleviate the neurotoxicity of sevoflurane in the developing brain, and improve the learning and memory abilities of offspring by increasing the expressions of BNDF and TrkB in hippocampal CA1 region. However, 40 mg/kg curcumin can accelerate neuronal apoptosis in hippocampal CA1 region of offspring, suggesting the possibility of drug overdose.

R285.5

天津市卫生健康委员会中医、中西医结合科研项目（2023091）;天津市卫生健康委员会面上项目（TJWJ2022MS042）