The Fetal Physiology and Neuroscience Group, Department of Physiology, The University of Auckland, Auckland, New Zealand.
Brain. 2023 Apr 19;146(4):1453-1466. doi: 10.1093/brain/awac331.
Cystic white matter injury is highly associated with severe neurodevelopmental disability and cerebral palsy in preterm infants, yet its pathogenesis remains poorly understood and there is no established treatment. In the present study, we tested the hypothesis that slowly evolving cystic white matter injury after hypoxia-ischaemia is mediated by programmed necrosis initiated by tumour necrosis factor. Tumour necrosis factor blockade was begun 3 days after hypoxia-ischaemia to target the tertiary phase of injury, when most secondary cell death is thought to be complete. Chronically instrumented preterm foetal sheep (0.7 gestation) received 25 min of hypoxia-ischaemia induced by complete umbilical cord occlusion or sham-umbilical cord occlusion (controls, n = 10), followed by intracerebroventricular infusion of the soluble TNF inhibitor, Etanercept, at 3, 8 and 13 days after umbilical cord occlusion (n = 9) or vehicle (n = 9). Foetal brains were processed for histology at 21 days after umbilical cord occlusion. Umbilical cord occlusion with vehicle was associated with a spectrum of macroscopic white matter degeneration, including white matter atrophy, ventriculomegaly and overt temporal lobe cystic white matter injury. Oligodendrocyte maturational arrest and impaired labelling of myelin proteins, characteristic of diffuse white matter injury, was observed in the parietal lobe and surrounding the cystic lesions in the temporal lobe. Etanercept markedly attenuated cystic white matter injury on the side of the intracerebroventricular infusion, with partial contralateral protection. Further, Etanercept improved oligodendrocyte maturation and labelling of myelin proteins in the temporal and parietal lobes. The present study shows that cystic white matter injury reflects late-onset tertiary cell death mediated by delayed neuroinflammation through the tumour necrosis factor pathway. Delayed tumour necrosis factor blockade markedly attenuated cystic white matter injury and restored oligodendrocyte maturation and deficits in myelin protein expression. These data suggest that delayed tumour necrosis factor blockade may represent a viable therapeutic strategy to reduce the risk of cystic and diffuse white matter injury and potentially cerebral palsy after preterm birth, with a surprisingly wide therapeutic window.
囊性脑白质损伤与早产儿严重神经发育障碍和脑瘫高度相关，但发病机制尚不清楚，也没有确立的治疗方法。本研究旨在验证如下假说：缺氧缺血后缓慢进展的囊性脑白质损伤是由肿瘤坏死因子（TNF）引发的程序性细胞坏死介导的。TNF 阻断治疗在缺氧缺血后 3 天开始，以靶向损伤的三级阶段，此时大多数继发性细胞死亡被认为已经完成。慢性植入的早产胎羊（0.7 孕周）接受完全脐带结扎引起的 25 分钟缺氧缺血，或假手术（对照组，n=10），然后在脐带结扎后 3、8 和 13 天接受脑室注射可溶性 TNF 抑制剂依那西普（n=9）或载体（n=9）。在脐带结扎后 21 天对胎羊大脑进行组织学处理。载体处理的脐带结扎与一系列明显的白质变性有关，包括白质萎缩、脑室扩大和明显的颞叶囊性脑白质损伤。在顶叶和颞叶囊性病变周围观察到少突胶质细胞成熟停滞和髓鞘蛋白标记受损，这是弥漫性脑白质损伤的特征。依那西普明显减轻了脑室注射侧的囊性脑白质损伤，对侧也有部分保护作用。此外，依那西普改善了颞叶和顶叶的少突胶质细胞成熟和髓鞘蛋白标记。本研究表明，囊性脑白质损伤反映了迟发性三级细胞死亡，其通过 TNF 途径介导的延迟神经炎症。延迟 TNF 阻断明显减轻了囊性脑白质损伤，并恢复了少突胶质细胞成熟和髓鞘蛋白表达缺陷。这些数据表明，延迟 TNF 阻断可能是一种可行的治疗策略，可降低早产儿出生后囊性和弥漫性脑白质损伤及脑瘫的风险，其治疗窗口相当宽。
