Ehlting Anne, Zweyer Margit, Maes Elke, Schleehuber Yvonne, Doshi Hardik, Sabir Hemmen, Bernis Maria Eugenia
Department of Neonatology and Pediatric Intensive Care, Children's Hospital, University of Bonn, 53127 Bonn, Germany.
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany.
Life (Basel). 2022 Jul 30;12(8):1164. doi: 10.3390/life12081164.
Hypoxic-ischemic encephalopathy (HIE) is a common type of brain injury caused by a lack of oxygen and blood flow to the brain during the perinatal period. The incidence of HIE is approximately 2−3 cases per 1000 live births in high-income settings; while in low- and middle-income countries, the incidence is 3−10-fold higher. Therapeutic hypothermia (TH) is the current standard treatment for neonates affected by moderate−severe HIE. However, more than 50% of all infants with suspected HIE have mild encephalopathy, and these infants are not treated with TH because of their lower risk of adverse outcomes. Despite this, several analyses of pooled data provide increasing evidence that infants who initially have mild encephalopathy may present signs of more significant brain injury later in life. The purpose of this study was to expand our knowledge about the effect of mild−moderate hypoxia-ischemia (HI) at the cellular, structural, and functional levels. An established rat model of mild−moderate HI was used, where postnatal day (P) 7 rats were exposed to unilateral permanent occlusion of the left carotid artery and 90 min of 8% hypoxia, followed by TH or normothermia (NT) treatment. The extent of injury was assessed using histology (P14 and P42) and MRI (P11 and P32), as well as with short-term and long-term behavioral tests. Neurogenesis was assessed by BrdU staining. We showed that mild−moderate HI leads to a progressive loss of brain tissue, pathological changes in MRI scans, as well as an impairment of long-term motor function. At P14, the median area loss assessed by histology for HI animals was 20% (p < 0.05), corresponding to mild−moderate brain injury, increasing to 55% (p < 0.05) at P42. The data assessed by MRI corroborated our results. HI led to a decrease in neurogenesis, especially in the hippocampus and the lateral ventricle at early time points, with a delayed partial recovery. TH was not neuroprotective at early time points following mild−moderate HI, but prevented the increase in brain damage over time. Additionally, rats treated with TH showed better long-term motor function. Altogether, our results bring more light to the understanding of pathophysiology following mild-moderate HI. We showed that, in the context of mild-moderate HI, TH failed to be significantly neuroprotective. However, animals treated with TH showed a significant improvement in motor, but not cognitive long-term function. These results are in line with what is observed in some cases where neonates with mild HIE are at risk of neurodevelopmental deficits in infancy or childhood. Whether TH should be used as a preventive treatment to reduce adverse outcomes in mild-HIE remains of active interest, and more research has to be carried out in order to address this question.
缺氧缺血性脑病（HIE）是围产期因大脑缺氧和血流供应不足所致的一种常见脑损伤类型。在高收入地区，HIE的发病率约为每1000例活产中有2 - 3例；而在低收入和中等收入国家，发病率要高出3至10倍。治疗性低温（TH）是目前治疗中重度HIE新生儿的标准疗法。然而，所有疑似HIE的婴儿中，超过50%患有轻度脑病，由于这些婴儿出现不良后果的风险较低，因此未接受TH治疗。尽管如此，多项汇总数据分析越来越多地表明，最初患有轻度脑病的婴儿在日后生活中可能会出现更严重脑损伤的迹象。本研究的目的是在细胞、结构和功能水平上拓展我们对轻度至中度缺氧缺血（HI）影响的认识。我们使用了一种成熟的轻度至中度HI大鼠模型，即出生后第7天（P7）的大鼠接受左侧颈动脉单侧永久性闭塞，并在8%的低氧环境中暴露90分钟，随后进行TH或正常体温（NT）治疗。使用组织学方法（P14和P42）、MRI（P11和P32）以及短期和长期行为测试来评估损伤程度。通过BrdU染色评估神经发生情况。我们发现，轻度至中度HI会导致脑组织逐渐丧失、MRI扫描出现病理变化以及长期运动功能受损。在P14时，通过组织学评估的HI动物脑区损失中位数为20%（p < 0.05），对应轻度至中度脑损伤，到P42时增加至55%（p < 0.05）。MRI评估的数据证实了我们的结果。HI导致神经发生减少，尤其是在早期海马体和侧脑室，且部分恢复延迟。在轻度至中度HI后的早期阶段，TH并无神经保护作用，但可防止脑损伤随时间增加。此外，接受TH治疗的大鼠长期运动功能更好。总之，我们的结果为理解轻度至中度HI后的病理生理学提供了更多线索。我们发现，在轻度至中度HI的情况下，TH未能发挥显著的神经保护作用。然而，接受TH治疗的动物在运动方面有显著改善，但认知方面的长期功能没有改善。这些结果与一些轻度HIE新生儿在婴儿期或儿童期有神经发育缺陷风险的病例观察结果一致。TH是否应作为预防治疗手段以减少轻度HIE的不良后果仍备受关注，需要开展更多研究来解决这一问题。
