Reduced uterine perfusion pressure (RUPP) is a well-established model which mimics many clinical features of preeclampsia (PE). Edaravone is a free radical scavenger with neuroprotective, antioxidant and anti-inflammatory effects against different models of cerebral ischemia. Therefore, we aimed to elucidate the different potential mechanisms through which PE affects fetal brain development using our previously established RUPP-placental ischemia mouse model. In addition, we investigated the neuroprotective effect of edaravone against the RUPP-induced fetal brain development alterations. On gestation day (GD) 13, pregnant mice were divided into four groups; sham (SV), edaravone (SE), RUPP (RV), and RUPP+edaravone (RE). SV and SE groups underwent sham surgeries, however, RV and RE groups were subjected to RUPP surgery via bilateral uterine ligation. Edaravone (3mg/kg) was injected via tail i.v. injection from GD 14-18. The fetal brains from different groups were collected on GD 18 and subjected to further investigations. The results showed that RUPP altered the structure of fetal brain cortex, induced neurodegeneration, increased the expression of the investigated pro-inflammatory markers; TNF-α, IL-6, IL-1β, and MMP-9. RUPP resulted in microglial and astrocyte activation in the fetal brains, in addition to upregulation of Hif-1α and iNOS. Edaravone conferred a neuroprotective effect via alleviating the inflammatory response, restoring the neuronal structure and decreasing oxidative stress in the developing fetal brain. In conclusion, RUPP-placental ischemia mouse model could be a useful tool to further understand the underlying mechanisms of PE-induced child neuronal alterations. Edaravone could be a potential adjuvant therapy during PE to protect the developing fetal brain.

Graphical Abstract

The current study investigated the effects of a placenta-induced ischemia mouse model using reduced uterine perfusion pressure (RUPP) surgery on the fetal brain development and the potential neuroprotective effects of the drug edaravone. The study found that the RUPP model caused neurodegeneration and a pro-inflammatory response in the developing fetal brain, as well as hypoxia and oxidative stress. However, maternal injection of edaravone showed a strong ability to protect against these detrimental effects and target multiple pathways associated with neuronal damage. The current study suggests that the RUPP model could be useful for further study of the impact of preeclampsia on fetal brain development and that edaravone may have potential as a therapy for protecting against this damage.

中文翻译：

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依达拉奉对胎盘缺血小鼠模型的胎儿大脑具有神经保护、抗炎和抗氧化作用

子宫灌注压降低（RUPP）是一种完善的模型，可模仿先兆子痫（PE）的许多临床特征。Edaravone 是一种自由基清除剂，对不同的脑缺血模型具有神经保护、抗氧化和抗炎作用。因此，我们的目的是利用我们之前建立的 RUPP 胎盘缺血小鼠模型来阐明 PE 影响胎儿大脑发育的不同潜在机制。此外，我们还研究了依达拉奉对 RUPP 诱导的胎儿大脑发育改变的神经保护作用。在妊娠第13天（GD），将怀孕小鼠分为四组；假手术 (SV)、依达拉奉 (SE)、RUPP (RV) 和 RUPP+依达拉奉 (RE)。SV和SE组进行假手术，而RV和RE组通过双侧子宫结扎进行RUPP手术。从GD 14-18起通过尾静脉注射注射依达拉奉(3mg/kg)。在GD 18收集不同组的胎儿大脑并进行进一步研究。结果表明，RUPP 改变了胎儿大脑皮层的结构，诱导神经退行性变，增加了所研究的促炎标记物的表达；TNF-α、IL-6、IL-1β 和 MMP-9。除了 Hif-1α 和 iNOS 上调外，RUPP 还导致胎儿大脑中的小胶质细胞和星形胶质细胞激活。依达拉奉通过减轻炎症反应、恢复神经元结构和减少发育中胎儿大脑的氧化应激来发挥神经保护作用。总之，RUPP-胎盘缺血小鼠模型可能是进一步了解 PE 诱导的儿童神经元改变的潜在机制的有用工具。依达拉奉可能是 PE 期间的一种潜在辅助疗法，可保护发育中的胎儿大脑。

图形概要

目前的研究调查了使用降低子宫灌注压（RUPP）手术的胎盘诱导缺血小鼠模型对胎儿大脑发育的影响以及药物依达拉奉的潜在神经保护作用。研究发现，RUPP 模型会导致发育中的胎儿大脑神经变性和促炎症反应，以及缺氧和氧化应激。然而，母体注射依达拉奉表现出强大的能力，可以防止这些有害影响，并针对与神经元损伤相关的多种途径。目前的研究表明，RUPP 模型可用于进一步研究先兆子痫对胎儿大脑发育的影响，并且依达拉奉可能具有作为预防这种损害的治疗方法的潜力。