在孕期中期多次暴露于西沃弗兰会诱导发育中的大脑的神经毒性,由15LO2-介导的铁灭症引起
Qian Jiang1, Cong Wang1, Qiushi Gao1
1Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China.
CNS neuroscience & therapeutics
|June 8, 2023
概括
在怀孕中期的孕产妇使用sevoflurane麻醉可能会损害后代的神经发育. 这项研究揭示了由ATM通路激活驱动的15-lipoxygenase-2介导的铁亡,是导致这种发育神经毒性的关键机制.
科学领域:
- 神经科学是一个神经科学.
- 毒理学 毒理学 毒理学
- 发展生物学 发展生物学
背景情况:
- 在怀孕中期,母亲暴露于诸如sevoflurane之类的麻醉剂,引发了对后代长期神经认知障碍的担忧.
- 铁亡是一种受调节的细胞死亡形式,越来越多地与各种神经疾病有关.
研究的目的:
- 为了研究铁病在妊娠第二个三个月期间的赛沃兰诱导的发育神经毒性中的作用.
- 阐明潜在的分子机制,包括ATM信号通路和15-氧酶2 (15LO2) 的参与.
主要方法:
- 孕妇大鼠被暴露在sevoflurane中,并使用特定的铁死抑制剂 (Ferrostatin-1,PD146176,Ku55933).
- 评估了线粒体形态,铁灭标志物 (MDA,铁,GPX4),海马神经元发育,15LO2-PEBP1相互作用和ATM通路激活.
- 使用莫里斯水迷宫和尼斯尔染色评估了长期的神经认知影响.
主要成果:
- 暴露于西沃兰诱导了铁亡,增加了MDA和铁水平,并降低了GPX4活性,导致后代的学习和记忆缺陷.
- 这些效应通过铁灭抑制剂得到改善.
- 塞沃兰增强了15LO2-PEBP1相互作用,并激活了ATM/P53/SAT1通路,可能是通过p-ATM核转移.
结论:
- 通过15-利波基因酶2介导的铁致死会导致中期三分期内暴露于西沃弗兰的神经毒性.
- ATM通路的过度激活和增强的15LO2-PEBP1相互作用是关键机制.
- 针对这些途径提供了一个潜在的治疗策略,以减轻sevoflurane诱导的神经毒性.
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