Zhao Xingxing, Chen Peipei, Yu Lun, Gao Chuchu, Wang Sannan, Yang Zuming, Feng Zongtai
Department of Neonatology, The Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), No. 26, Daofront Street, Suzhou 215002, China.
Biomedicines. 2025 Jun 11;13(6):1431. doi: 10.3390/biomedicines13061431.
Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal death and neurodevelopmental disorders, and its pathological mechanisms are closely related to disturbed energy metabolism and lipid remodeling. Exploring the spatial heterogeneity of metabolomics is essential to analyze the pathological process of HIE. In this study, we established a neonatal mouse hypoxic-ischemic brain damage (HIBD) model by the modified Rice method, and analyzed various metabolic pathways such as the tricarboxylic acid (TCA) cycle, purine metabolism, and lipid metabolism in the ischemic edema area, with contralateral and control brain tissues using matrix-assisted laser desorption mass spectrometry imaging (MALDI-MSI) with a spatial resolution of 50 μm. In the HIBD model, key metabolites of the tricarboxylic acid (TCA) cycle (citrate, succinate, L-glutamate, glucose, aspartate, and glutamine) were significantly enriched in the edematous area compared with the control (fold change: 1.52-2.82), which suggests a blockage of mitochondrial function; ATP/ADP/AMP levels were reduced by 53-73% in the edematous area, and xanthine was abnormally accumulated in the hippocampus of the affected side, suggesting energy depletion and altered purine metabolism; lipid remodeling showed regional specificity: some unsaturated fatty acids, such as docosahexaenoic acid, were abnormally accumulated in the hippocampus. In contrast, pentadecanoic acid levels were reduced across the entire brain in the HIBD model, with a more pronounced decrease in the ipsilateral hippocampus, suggesting impaired membrane stability. The neonatal mouse HIBD model exhibits reprogramming of energy metabolism, characterized by a blockage in the tricarboxylic acid (TCA) cycle and ATP depletion, along with an abnormal spatial distribution of lipids. By targeting xanthine metabolic pathways, restoring mitochondrial function, and intervening in region-specific lipid remodeling, brain energy homeostasis may be improved and neurological damage attenuated. Further studies should validate the clinical feasibility of xanthine and lipid imbalance as diagnostic markers of HIBD and explore the critical time window for metabolic intervention to optimize therapeutic strategies.
新生儿缺氧缺血性脑病（HIE）是新生儿死亡和神经发育障碍的主要原因，其病理机制与能量代谢紊乱和脂质重塑密切相关。探索代谢组学的空间异质性对于分析HIE的病理过程至关重要。在本研究中，我们采用改良的赖斯法建立了新生小鼠缺氧缺血性脑损伤（HIBD）模型，并使用空间分辨率为50μm的基质辅助激光解吸质谱成像（MALDI-MSI）分析了缺血水肿区域以及对侧和对照脑组织中的各种代谢途径，如三羧酸（TCA）循环、嘌呤代谢和脂质代谢。在HIBD模型中，与对照相比，三羧酸（TCA）循环的关键代谢物（柠檬酸、琥珀酸、L-谷氨酸、葡萄糖、天冬氨酸和谷氨酰胺）在水肿区域显著富集（倍数变化：1.52 - 2.82），这表明线粒体功能受阻；水肿区域的ATP/ADP/AMP水平降低了53 - 73%，并且黄嘌呤在患侧海马中异常蓄积，提示能量耗竭和嘌呤代谢改变；脂质重塑表现出区域特异性：一些不饱和脂肪酸，如二十二碳六烯酸，在海马中异常蓄积。相比之下，HIBD模型中全脑的十五烷酸水平降低，在同侧海马中下降更为明显，提示膜稳定性受损。新生小鼠HIBD模型表现出能量代谢重编程，其特征为三羧酸（TCA）循环受阻和ATP耗竭，以及脂质的异常空间分布。通过靶向黄嘌呤代谢途径、恢复线粒体功能以及干预区域特异性脂质重塑，可能改善脑能量稳态并减轻神经损伤。进一步的研究应验证黄嘌呤和脂质失衡作为HIBD诊断标志物的临床可行性，并探索代谢干预的关键时间窗以优化治疗策略。
