Chen Jing, Xiao Fei, Chen Lifei, Zhou Zhan, Wei Yi, Zhong Yu, Li Li, Xie Yubo
Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Front Pharmacol. 2023 Feb 2;14:1121280. doi: 10.3389/fphar.2023.1121280. eCollection 2023.
An increasing number of studies have reported that neurotoxicity of propofol may cause long-term learning and cognitive dysfunction. Hypoxic preconditioning has been shown to have neuroprotective effects, reducing the neurotoxicity of propofol. Ferroptosis is a new form of death that is different from apoptosis, necrosis, autophagy and pyroptosis. However, it is unclear whether hypoxic preconditioning reduces propofol neurotoxicity associated with ferroptosis. Thus, we aimed to evaluate the effect of propofol on primary hippocampal neurons to investigate the neuroprotective mechanism of hypoxic preconditioning and the role of ferroptosis in the reduction of propofol neurotoxicity by hypoxic preconditioning. Primary hippocampal neurons were cultured for 8 days and pretreated with or without propofol, hypoxic preconditioning, agonists or inhibitors of ferroptosis. Cell counting kit-8, Calcein AM, Reactive oxygen species (ROS), Superoxide dismutase (SOD), Ferrous iron (Fe), Malondialdehyde (MDA) and Mitochondrial membrane potential assay kit with JC-1 (JC-1) assays were used to measure cell viability, Reactive oxygen species level, Superoxide dismutase content, Fe level, MDA content, and mitochondrial membrane potential. Cell apoptosis was evaluated using flow cytometry analyses, and ferroptosis-related proteins were determined by Western blot analysis. Propofol had neurotoxic effects that led to decreased hippocampal neuronal viability, reduced mitochondrial membrane potential, decreased SOD content, increased ROS level, increased Fe level, increased MDA content, increased neuronal apoptosis, altered expression of ferroptosis-related proteins and activation of ferroptosis. However, hypoxic preconditioning reversed these effects, inhibited ferroptosis caused by propofol and reduced the neurotoxicity of propofol. The neurotoxicity of propofol in developing rats may be related to ferroptosis. Propofol may induce neurotoxicity by activating ferroptosis, while hypoxic preconditioning may reduce the neurotoxicity of propofol by inhibiting ferroptosis.
越来越多的研究报道，丙泊酚的神经毒性可能导致长期学习和认知功能障碍。缺氧预处理已被证明具有神经保护作用，可降低丙泊酚的神经毒性。铁死亡是一种不同于凋亡、坏死、自噬和焦亡的新型细胞死亡形式。然而，尚不清楚缺氧预处理是否能降低与铁死亡相关的丙泊酚神经毒性。因此，我们旨在评估丙泊酚对原代海马神经元的影响，以研究缺氧预处理的神经保护机制以及铁死亡在缺氧预处理减轻丙泊酚神经毒性中的作用。原代海马神经元培养8天，分别用或不用丙泊酚、缺氧预处理、铁死亡激动剂或抑制剂进行预处理。使用细胞计数试剂盒-8、钙黄绿素AM、活性氧（ROS）、超氧化物歧化酶（SOD）、亚铁（Fe）、丙二醛（MDA）以及用JC-1的线粒体膜电位检测试剂盒（JC-1）检测来测量细胞活力、活性氧水平、超氧化物歧化酶含量、铁水平、丙二醛含量和线粒体膜电位。使用流式细胞术分析评估细胞凋亡，并通过蛋白质免疫印迹分析确定铁死亡相关蛋白。丙泊酚具有神经毒性作用，导致海马神经元活力下降、线粒体膜电位降低、超氧化物歧化酶含量减少、活性氧水平升高、铁水平升高、丙二醛含量增加、神经元凋亡增加、铁死亡相关蛋白表达改变以及铁死亡激活。然而，缺氧预处理逆转了这些作用，抑制了丙泊酚引起的铁死亡，并降低了丙泊酚的神经毒性。丙泊酚在发育中的大鼠中的神经毒性可能与铁死亡有关。丙泊酚可能通过激活铁死亡诱导神经毒性，而缺氧预处理可能通过抑制铁死亡降低丙泊酚的神经毒性。
