Liu Pengfei, Yuan Jing, Feng Yetong, Chen Xin, Wang Guangsuo, Zhao Lei
Ambulatory Surgical Center, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), 518020, Shenzhen, China.
The First Affiliated Hospital, Jinan University, 510632, Guangzhou, China.
Cell Death Discov. 2021 Apr 7;7(1):72. doi: 10.1038/s41420-021-00454-8.
Ferroptosis is a novel type of programmed cell death, which is different from apoptosis and autophagic cell death. Recently, ferroptosis has been indicated to contribute to the in vitro neurotoxicity induced by isoflurane, which is one of the most common anesthetics in clinic. However, the in vivo position of ferroptosis in isoflurane-induced neurotoxicity as well as learning and memory impairment remains unclear. In this study, we mainly explored the relationship between ferroptosis and isoflurane-induced learning and memory, as well as the therapeutic methods in mouse model. Our results indicated that isoflurane induced the ferroptosis in a dose-dependent and time-dependent manner in hippocampus, the organ related with learning and memory ability. In addition, the activity of cytochrome c oxidase/Complex IV in mitochondrial electron transport chain (ETC) was increased by isoflurane, which might further contributed to cysteine deprivation-induced ferroptosis caused by isoflurane exposure. More importantly, isoflurane-induced ferroptosis could be rescued by both ferroptosis inhibitor (ferrostatin-1) and mitochondria activator (dimethyl fumarate), which also showed effective therapeutic action against isoflurane-induced learning and memory impairment. Taken together, our data indicate the close association among ferroptosis, mitochondria and isoflurane, and provide a novel insight into the therapy mode against isoflurane-induced learning and memory impairment.
铁死亡是一种新型的程序性细胞死亡，不同于凋亡和自噬性细胞死亡。最近，有研究表明铁死亡参与了异氟烷诱导的体外神经毒性，异氟烷是临床最常用的麻醉剂之一。然而，铁死亡在异氟烷诱导的神经毒性以及学习和记忆障碍中的体内作用尚不清楚。在本研究中，我们主要探讨了铁死亡与异氟烷诱导的学习和记忆之间的关系，以及在小鼠模型中的治疗方法。我们的结果表明，异氟烷在与学习和记忆能力相关的海马体中以剂量和时间依赖性方式诱导铁死亡。此外，异氟烷增加了线粒体电子传递链（ETC）中细胞色素c氧化酶/复合物IV的活性，这可能进一步导致异氟烷暴露引起的半胱氨酸剥夺诱导的铁死亡。更重要的是，铁死亡抑制剂（铁抑素-1）和线粒体激活剂（富马酸二甲酯）均可挽救异氟烷诱导的铁死亡，它们对异氟烷诱导的学习和记忆障碍也显示出有效的治疗作用。综上所述，我们的数据表明铁死亡、线粒体和异氟烷之间密切相关，并为异氟烷诱导的学习和记忆障碍的治疗模式提供了新的见解。
