Department of Anesthesiology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, No. 2800 Gongwei Road, Shanghai, 201399, People's Republic of China.
Neurochem Res. 2024 Aug;49(8):2131-2147. doi: 10.1007/s11064-024-04163-3. Epub 2024 Jun 1.
Sepsis-associated encephalopathy (SAE) develops in 30-70% of hospitalized patients with sepsis. In intensive care units (ICUs), propofol is often administered to ensure an appropriate level of sedation in mechanically ventilated patients. Ferroptosis is a newly identified mode of cellular death characterized by the peroxidation of membrane lipids and excessive iron. This study was conducted to explore the interplay between propofol, sepsis, and ferroptosis.
An acute systemic inflammatory model was constructed via the intraperitoneal administration of lipopolysaccharide (LPS). Nissl and Fluoro-Jade C (FJC) staining were employed to display neuronal damage and degeneration. Western blotting and immunofluorescence (IF) staining of Bax and Bcl-2 were used to confirm the neural apoptosis. QPCR of cytokines and DHE staining were used to indicate neuroinflammation. To validate ferroptosis, we assessed the content of malondialdehyde (MDA), GSH, and tissue iron, accompanied by transcription level of CHAC1, PTGS2 and GPX4. Additionally, we examined the content of acyl-CoA synthetase long-chain family member 4 (ACSL4), xCT (SLC7A11, solute carrier family 7 member 11), and glutathione peroxidase 4 (GPX4). The IF staining of Iba1-labeled microglia and GFAP-marked astrocytes were used to measure the gliosis. Erastin was pre-pretreated to confirm the anti-ferroptotic capability of propofol. ML385 was preconditioned to explore the role of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in propofol-repressed ferroptosis.
Propofol dose-dependently inhibited the decrease of Nissl-positive neurons and the increase of FJC-stained neurons in septic hippocampus and cortex. Neural cytokines, oxidative stress, apoptosis and gliosis were reduced by propofol. Propofol repressed the level of MDA, iron, CHAC1, PTGS2, ACLS4 and restored the content of GSH, GPX4, xCT, Nrf2 and HO-1, thus inhibiting sepsis-induced ferroptosis. All protections from propofol could be reversed by eratsin and ML385 pretreatment.
Propofol protected against sepsis-induced brain damage, neuroinflammation, neuronal apoptosis and gliosis through the activation of the Nrf2/HO-1 axis to combat ferroptosis.
脓毒症相关性脑病（SAE）发生于 30%-70%的住院脓毒症患者中。在重症监护病房（ICU）中，常给予异丙酚以确保机械通气患者的镇静水平适当。铁死亡是一种新发现的细胞死亡方式，其特征为膜脂质过氧化和铁蓄积过多。本研究旨在探讨异丙酚、脓毒症和铁死亡之间的相互作用。
通过腹腔内给予脂多糖（LPS）构建急性全身炎症模型。采用尼氏染色和氟代-琼酯（FJC）染色显示神经元损伤和变性。采用 Western blot 和免疫荧光（IF）染色检测 Bax 和 Bcl-2 以确认神经细胞凋亡。采用细胞因子 QPCR 和 DHE 染色显示神经炎症。通过评估丙二醛（MDA）、GSH 和组织铁的含量，以及酰基辅酶 A 合成酶长链家族成员 4（ACSL4）、xCT（SLC7A11，溶质载体家族 7 成员 11）和谷胱甘肽过氧化物酶 4（GPX4）的转录水平，来验证铁死亡。IF 染色显示 Iba1 标记的小胶质细胞和 GFAP 标记的星形胶质细胞，以测量神经胶质增生。预先用 Erastin 预处理以确认异丙酚的抗铁死亡能力。用 ML385 预处理以探讨核因子红细胞 2 相关因子 2（Nrf2）和血红素加氧酶-1（HO-1）在异丙酚抑制铁死亡中的作用。
异丙酚呈剂量依赖性地抑制脓毒症海马和皮质中 Nissl 阳性神经元减少和 FJC 染色神经元增加。异丙酚降低神经细胞因子、氧化应激、凋亡和神经胶质增生。异丙酚抑制 MDA、铁、CHAC1、PTGS2、ACSL4 的水平，恢复 GSH、GPX4、xCT、Nrf2 和 HO-1 的含量，从而抑制脓毒症诱导的铁死亡。用 Erastin 和 ML385 预处理可逆转异丙酚的所有保护作用。
异丙酚通过激活 Nrf2/HO-1 轴对抗铁死亡，从而防止脓毒症引起的脑损伤、神经炎症、神经元凋亡和神经胶质增生。
