Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University, Beijing, China.
China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China.
CNS Neurosci Ther. 2024 Sep;30(9):e70026. doi: 10.1111/cns.70026.
Incidence of acute mountain sickness (AMS) ranges from 40%-90%, with high-altitude cerebral edema (HACE) representing a life-threatening end stage of severe AMS. However, practical and convenient preventive strategies for HACE are lacking. Remote ischemic preconditioning (RIPC) has demonstrated preventive effects on ischemia- or hypoxia-induced cardiovascular and cerebrovascular diseases. This study aimed to investigate the potential molecular mechanism of HACE and the application of RIPC in preventing HACE onset.
A hypobaric hypoxia chamber was used to simulate a high-altitude environment of 7000 meters. Metabolomics and metabolic flux analysis were employed to assay metabolite levels. Transcriptomics and quantitative real-time PCR (q-PCR) were used to investigate gene expression levels. Immunofluorescence staining was performed on neurons to label cellular proteins. The fluorescent probes Mito-Dendra2, iATPSnFR1.0, and CMTMRos were used to observe mitochondria, ATP, and membrane potential in cultured neurons, respectively. TUNEL staining was performed to detect and quantify apoptotic cell death. Hematoxylin and eosin (H&E) staining was utilized to analyze pathological changes, such as tissue swelling in cerebral cortex samples. The Rotarod test was performed to assess motor coordination and balance in rats. Oxygen-glucose deprivation (OGD) of cultured cells was employed as an in vitro model to simulate the hypoxia and hypoglycemia induced by RIPC in animal experiments.
We revealed a causative perturbation of glucose metabolism in the brain preceding cerebral edema. Ischemic preconditioning treatment significantly reprograms glucose metabolism, ameliorating cell apoptosis and hypoxia-induced energy deprivation. Notably, ischemic preconditioning improves mitochondrial membrane potential and ATP production through enhanced glucose-coupled mitochondrial metabolism. In vivo studies confirm that RIPC alleviates cerebral edema, reduces cell apoptosis induced by high-altitude hypoxia, and improves motor dysfunction resulting from cerebral edema.
Our study elucidates the metabolic basis of HACE pathogenesis. This study provides a new strategy for preventing HACE that RIPC reduces brain edema through reprogramming metabolism, highlighting the potential of targeting metabolic reprogramming for neuroprotective interventions in neurological diseases caused by ischemia or hypoxia.
急性高山病（AMS）的发病率为 40%-90%，其中高山脑水肿（HACE）是严重 AMS 的致命终末期表现。然而，目前缺乏针对 HACE 的实用和方便的预防策略。远程缺血预处理（RIPC）已证明对缺血或缺氧引起的心血管和脑血管疾病具有预防作用。本研究旨在探讨 HACE 的潜在分子机制及 RIPC 预防 HACE 发病的应用。
使用低压缺氧舱模拟 7000 米高空环境。采用代谢组学和代谢通量分析检测代谢物水平。转录组学和实时定量 PCR（q-PCR）用于研究基因表达水平。免疫荧光染色标记神经元中的细胞蛋白。使用荧光探针 Mito-Dendra2、iATPSnFR1.0 和 CMTMRos 分别观察培养神经元中的线粒体、ATP 和膜电位。TUNEL 染色检测和定量细胞凋亡。苏木精和伊红（H&E）染色分析大脑皮质样本中的组织肿胀等病理变化。转棒试验评估大鼠的运动协调和平衡。培养细胞的氧葡萄糖剥夺（OGD）用于模拟动物实验中 RIPC 引起的缺氧和低血糖。
我们揭示了大脑中葡萄糖代谢的因果失调先于脑水肿。缺血预处理治疗可显著重编程葡萄糖代谢，改善细胞凋亡和缺氧诱导的能量耗竭。值得注意的是，缺血预处理通过增强葡萄糖偶联的线粒体代谢改善线粒体膜电位和 ATP 生成。体内研究证实，RIPC 可减轻脑水肿、减少高空缺氧引起的细胞凋亡，并改善脑水肿引起的运动功能障碍。
本研究阐明了 HACE 发病机制的代谢基础。本研究为预防 HACE 提供了一种新策略，即 RIPC 通过重编程代谢减轻脑水肿，突出了针对代谢重编程的神经保护干预在缺血或缺氧引起的神经疾病中的潜在应用。
