PROTECT, Inserm U1141, Université Paris Diderot, Paris, France.
Division of Neonatology and Pediatric Intensive Care, Children's University Hospital of Geneva, Geneva, Switzerland.
Glia. 2019 Feb;67(2):345-359. doi: 10.1002/glia.23546. Epub 2018 Dec 2.
Prematurity and fetal growth restriction (FGR) are frequent conditions associated with adverse neurocognitive outcomes. We have previously identified early deregulation of genes controlling neuroinflammation as a putative mechanism linking FGR and abnormal trajectory of the developing brain. While the oxytocin system was also found to be impaired following adverse perinatal events, its role in the modulation of neuroinflammation in the developing brain is still unknown. We used a double-hit rat model of perinatal brain injury induced by gestational low protein diet (LPD) and potentiated by postnatal injections of subliminal doses of interleukin-1β (IL1β) and a zebrafish model of neuroinflammation. Effects of the treatment with carbetocin, a selective, long lasting, and brain diffusible oxytocin receptor agonist, have been assessed using a combination of histological, molecular, and functional tools in vivo and in vitro. In the double-hit model, white matter inflammation, deficient myelination, and behavioral deficits have been observed and the oxytocin system was impaired. Early postnatal supplementation with carbetocin alleviated microglial activation at both transcriptional and cellular levels and provided long-term neuroprotection. The central anti-inflammatory effects of carbetocin have been shown in vivo in rat pups and in a zebrafish model of early-life neuroinflammation and reproduced in vitro on stimulated sorted primary microglial cell cultures from rats subjected to LPD. Carbetocin treatment was associated with beneficial effects on myelination, long-term intrinsic brain connectivity and behavior. Targeting oxytocin signaling in the developing brain may be an effective approach to prevent neuroinflammation - induced brain damage of perinatal origin.
早产和胎儿生长受限（FGR）是与不良神经认知结果相关的常见情况。我们之前已经确定，控制神经炎症的基因早期失调是将 FGR 与发育中大脑的异常轨迹联系起来的一种潜在机制。虽然在不良围产期事件后也发现催产素系统受损，但它在调节发育中大脑的神经炎症中的作用尚不清楚。我们使用了一种双重打击大鼠模型，该模型由妊娠期低蛋白饮食（LPD）引起围产期脑损伤，并通过产后注射亚阈剂量的白细胞介素 1β（IL1β）增强，以及一种神经炎症的斑马鱼模型。使用催产素受体激动剂卡贝缩宫素（carbetocin）进行治疗，并用组织学、分子和功能工具组合进行了体内和体外评估。在双重打击模型中，观察到白质炎症、髓鞘形成不足和行为缺陷，并且催产素系统受损。早期产后补充卡贝缩宫素可减轻小胶质细胞的激活，具有长期的神经保护作用。卡贝缩宫素的中枢抗炎作用已在大鼠幼仔和早期生活神经炎症的斑马鱼模型中得到证实，并在体外对接受 LPD 的大鼠刺激的分选原代小胶质细胞培养物中得到复制。卡贝缩宫素治疗与髓鞘形成、长期内在脑连接和行为的有益效果相关。针对发育中大脑中的催产素信号可能是预防围产期起源的神经炎症性脑损伤的有效方法。
