Department of Anesthesiology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing City, China.
Neurochem Res. 2024 Jul;49(7):1703-1719. doi: 10.1007/s11064-024-04128-6. Epub 2024 Mar 21.
Propofol is a clinically common intravenous general anesthetic and is widely used for anesthesia induction, maintenance and intensive care unit (ICU) sedation in children. Hypoxemia is a common perioperative complication. In clinical work, we found that children with hypoxemia who received propofol anesthesia experienced significant postoperative cognitive changes. To explore the causes of this phenomenon, we conducted the study. In this study, our in vivo experiments found that immature rats exposed to hypoxia combined with propofol (HCWP) could develop cognitive impairment. We performed the RNA-seq analysis of its hippocampal tissues and found that autophagy and ferroptosis may play a role in our model. Next, we verified the participation of the two modes of death by detecting the expression of autophagy-related indexes Sequestosome 1 (SQSTM1) and Beclin1, and ferroptosis-related indicators Fe, reactive oxygen species (ROS) and glutathione peroxidase 4 (GPX4). Meanwhile, we found that ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, could improve cognitive impairment in immature rats caused by HCWP. In addition, we found that nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy, which acted as a key junction between autophagy and ferroptosis, was also involved. Finally, our in vitro experiments concluded that autophagy activation was an upstream factor in HCWP-induced hippocampus ferroptosis through the intervention of autophagy inhibitor 3-methyladenine (3-MA). Our study was expected to provide an attractive therapeutic target for cognitive impairment that occurred after HCWP exposures.
异丙酚是一种临床常用的静脉全身麻醉药，广泛应用于儿童麻醉诱导、维持和重症监护病房（ICU）镇静。低氧血症是一种常见的围手术期并发症。在临床工作中，我们发现接受异丙酚麻醉的低氧血症患儿术后认知功能发生明显变化。为了探讨这种现象的原因，我们进行了这项研究。在这项研究中，我们的体内实验发现，暴露于缺氧和异丙酚（HCWP）的未成熟大鼠可发展为认知障碍。我们对其海马组织进行了 RNA-seq 分析，发现自噬和铁死亡可能在我们的模型中发挥作用。接下来，我们通过检测自噬相关指标自噬体相关蛋白 1（SQSTM1）和 Beclin1 的表达，以及铁死亡相关指标铁、活性氧（ROS）和谷胱甘肽过氧化物酶 4（GPX4），验证了这两种死亡方式的参与。同时，我们发现铁死亡抑制剂 Fer-1 可改善 HCWP 引起的未成熟大鼠认知障碍。此外，我们发现核受体共激活因子 4（NCOA4）介导的铁蛋白自噬作为自噬和铁死亡之间的关键连接点也参与其中。最后，我们的体外实验得出结论，自噬激活是 HCWP 诱导海马铁死亡的上游因素，通过自噬抑制剂 3-甲基腺嘌呤（3-MA）的干预。我们的研究有望为 HCWP 暴露后发生的认知障碍提供有吸引力的治疗靶点。
