Lammert Dawn B, Fernandez Regina F, Liu Xiuyun, Chen Jingyao, Koehler Raymond C, Scafidi Susanna, Scafidi Joseph
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
The Michael V. Johnston Center for Developmental Neuroscience, Kennedy Krieger Institute, Baltimore, Maryland, United States of America.
PLoS One. 2025 Apr 24;20(4):e0320869. doi: 10.1371/journal.pone.0320869. eCollection 2025.
Neonatal hypoxic-ischemic encephalopathy (HIE) remains a leading cause of long-term neurologic morbidity. Fifty percent of HIE cases are mild and do not have clearly defined therapeutic interventions. Emergent evidence now demonstrates that up to 25% of children with mild HIE suffer motor and developmental delay by 18 months and 35% have cognitive impairments by age 5 years. Interestingly, the hippocampus, which is responsible for learning and memory, does not show overt injury but does demonstrate volume changes on imaging that correlate with cognitive and behavioral outcomes. Although there is extensive data regarding pathophysiological changes following moderate and severe HIE, there is a paucity of understanding regarding the extent, duration, and compensatory adaptations in the mild neonatal HIE brain. We performed hippocampal proteomic analysis using a swine model of mild neonatal hypoxia-asphyxia. Hippocampi were collected at 24 or 72 hours after injury, and proteomics was performed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Pathway analysis demonstrated that several metabolic pathways are temporally regulated after mild HIE. Specifically, amino acid, carbohydrate, and one-carbon metabolism increased at 24 hours while fat metabolism and oxidative phosphorylation decreased at 24 hours. Downregulation of oxidative phosphorylation was more pronounced at 72 hours. Our data demonstrate that metabolic reprogramming occurs after mild HIE, and these changes persist up to 72 hours after injury. These results provide new evidence that mild HIE disrupts brain metabolism, emphasizing the need for a better understanding of the underlying pathophysiology of mild HIE and development of targeted therapeutic interventions for this population.
新生儿缺氧缺血性脑病（HIE）仍然是导致长期神经功能障碍的主要原因。50%的HIE病例为轻度，尚无明确的治疗干预措施。最新证据表明，高达25%的轻度HIE患儿在18个月时出现运动和发育迟缓，35%在5岁时出现认知障碍。有趣的是，负责学习和记忆的海马体并未显示出明显损伤，但在影像学上确实显示出体积变化，且这些变化与认知和行为结果相关。尽管有大量关于中度和重度HIE后病理生理变化的数据，但对于轻度新生儿HIE脑内变化的程度、持续时间和代偿性适应的了解却很少。我们使用轻度新生儿缺氧缺血的猪模型进行了海马蛋白质组学分析。在损伤后24小时或72小时收集海马体，并通过液相色谱串联质谱（LC-MS/MS）进行蛋白质组学分析。通路分析表明，轻度HIE后几种代谢通路受到时间调控。具体而言，氨基酸、碳水化合物和一碳代谢在24小时时增加，而脂肪代谢和氧化磷酸化在24小时时减少。氧化磷酸化的下调在72小时时更为明显。我们的数据表明，轻度HIE后发生了代谢重编程，且这些变化在损伤后长达72小时持续存在。这些结果提供了新的证据，表明轻度HIE会扰乱脑代谢，强调需要更好地了解轻度HIE的潜在病理生理学，并为该人群开发针对性的治疗干预措施。
