Zheng Zi-Lei, Wang Xu-Peng, Hu Yu-Fei, Li Wen-Guang, Zhou Qi, Xu Fang, Wang Qiu-Jun
Department of Anesthesiology, The Third Hospital of Hebei Medical University, Shijiazhuang, China.
Department of Anesthesiology, The No.4 Hospital of Zhangjiakou, Zhangjiakou, China.
Brain Behav. 2024 Dec;14(12):e70187. doi: 10.1002/brb3.70187.
This study aims to explore the neuroprotective effect of propofol in improving traumatic brain injury (TBI) by inhibiting ferroptosis through the modulation of the endothelial nitric oxide (NO) synthase (eNOS)/NO signaling pathway.
The GSE173975 dataset was used to analyze the differentially expressed genes between TBI and sham surgery control groups in the short and long term. A TBI model was established in 2-month-old male SPF C57BL/6 mice by impact exposure of the exposed dura mater. After the establishment of the TBI model, propofol (30 mg/kg) or saline was administered via intraperitoneal injection for intervention. Nissl staining and Perls staining were employed to assess neuronal function and iron deposition, respectively. Western blot technology was employed to detect the expression of proteins related to ferroptosis. Immunofluorescence staining of astrocytes and microglia was utilized to assess the neuroinflammatory response induced by TBI. The Morris water maze (MWM) and novel object recognition (NOR) tests were employed to assess cognitive dysfunction induced by TBI.
Bioinformatics analysis revealed aberrant gene expression associated with iron transport, neuronal death, and inflammatory response in the initial stages of TBI. Long-term abnormalities were predominantly linked to genes involved in inflammatory response. Perls staining and protein expression analysis confirmed the occurrence of iron deposition and ferroptosis following TBI. Propofol treatment significantly reduced iron deposition and ferroptosis induced by TBI. Nissl staining demonstrated enhanced neuronal function, while TUNEL staining indicated reduced neuronal apoptosis. Immunofluorescence analysis demonstrated that propofol significantly reduced the proliferation of astrocytes and activation of microglia induced by TBI in the long term. The results of MWM and NOR tests indicated that propofol significantly improved the long-term cognitive dysfunction induced by TBI. Propofol exerts neuroprotective effects by increasing the expression of eNOS protein and the content of NO. The neuroprotective effects of propofol can be reversed by the eNOS inhibitor L-NAME.
Propofol significantly improves the prognosis of TBI by inhibiting ferroptosis through the modulation of the eNOS/NO signaling pathway. The study results provide a scientific basis for the clinical use of propofol as a neuroprotective agent and offer a new direction for the development of new treatment strategies for TBI.
本研究旨在探讨丙泊酚通过调节内皮型一氧化氮合酶（eNOS）/一氧化氮（NO）信号通路抑制铁死亡，从而改善创伤性脑损伤（TBI）的神经保护作用。
使用GSE173975数据集分析TBI组与假手术对照组在短期和长期的差异表达基因。通过暴露硬脑膜撞击法在2月龄雄性SPF C57BL/6小鼠中建立TBI模型。TBI模型建立后，通过腹腔注射给予丙泊酚（30mg/kg）或生理盐水进行干预。分别采用尼氏染色和普鲁士蓝染色评估神经元功能和铁沉积。采用蛋白质印迹技术检测与铁死亡相关的蛋白质表达。利用星形胶质细胞和小胶质细胞的免疫荧光染色评估TBI诱导的神经炎症反应。采用莫里斯水迷宫（MWM）和新物体识别（NOR）试验评估TBI诱导的认知功能障碍。
生物信息学分析揭示了TBI初始阶段与铁转运、神经元死亡和炎症反应相关的异常基因表达。长期异常主要与参与炎症反应的基因有关。普鲁士蓝染色和蛋白质表达分析证实了TBI后铁沉积和铁死亡的发生。丙泊酚治疗显著减少了TBI诱导的铁沉积和铁死亡。尼氏染色显示神经元功能增强，而TUNEL染色表明神经元凋亡减少。免疫荧光分析表明，丙泊酚长期显著减少了TBI诱导的星形胶质细胞增殖和小胶质细胞激活。MWM和NOR试验结果表明，丙泊酚显著改善了TBI诱导的长期认知功能障碍。丙泊酚通过增加eNOS蛋白表达和NO含量发挥神经保护作用。丙泊酚的神经保护作用可被eNOS抑制剂L-NAME逆转。
丙泊酚通过调节eNOS/NO信号通路抑制铁死亡，显著改善TBI的预后。研究结果为丙泊酚作为神经保护剂的临床应用提供了科学依据，并为TBI新治疗策略的开发提供了新方向。
