Background

RE1 Silencing Transcription factor (REST) corepressor 1 (RCOR1) has been reported to orchestrate neurogenesis, while its role in cerebral palsy (CP) remains elusive. Besides, RCOR1 can interact with Endothelin-1 (EDN1), and EDN1 expression is related to brain damage. Therefore, this study aimed to explore the effects of RCOR1/EDN1 on brain damage during the progression of CP.

Methods

CP rats were established via hypoxia–ischemia insult, and injected with lentivirus-RCOR1, followed by examination of brain pathological conditions. The RCOR1 and EDN1 interaction was recognized using hTFtarget. Healthy rat cortical neuron cells received interference of RCOR1/EDN1 expression, and underwent oxygen-glucose deprivation/reoxygenation (OGD/R) treatment, after which phenotypic and molecular assays were conducted through the biochemical method, qRT-PCR and/or western blot.

Results

RCOR1 was low-expressed but EDN1 was high-expressed in CP model rats and OGD/R-treated neurons. RCOR1 overexpression ameliorated rat neurobehaviors, alleviated brain pathological conditions, reduced TUNEL-positive cells, decreased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), increased superoxide dismutase (SOD) level and repressed EDN1 expression in the brains of CP model rats. In neurons, RCOR1 overexpression counteracted OGD/R-induced viability decrease, reduction of the levels of RCOR1, SOD, Bcl-2, caspase-3, p-Akt/Akt and p-GSK-3β/GSK-3β, and elevation of the levels of EDN1, ROS, Bax, and cleaved caspase-3, while EDN1 overexpression did contrarily on these events. Moreover, there was a negative interplay between RCOR1 overexpression and EDN1 overexpression in OGD/R-induced neurons.

Conclusion

RCOR1 ameliorates neurobehaviors and suppresses neuronal apoptosis and oxidative stress in CP through EDN1 targeting-mediated upregulation of Akt/GSK-3β.

中文翻译：

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RCOR1 通过内皮素 1 靶向诱导 Akt/GSK-3β 通路上调改善脑瘫大鼠的神经行为和神经元损伤

背景

据报道， RE1 沉默转录因子(REST) 辅阻遏物 1 (RCOR1) 可以协调神经发生，但其在脑瘫 (CP) 中的作用仍然难以捉摸。此外，RCOR1可以与内皮素1（EDN1）相互作用，EDN1的表达与脑损伤有关。因此，本研究旨在探讨RCOR1/EDN1对CP进展过程中脑损伤的影响。

方法

通过缺氧缺血损伤建立CP大鼠，注射慢病毒-RCOR1，然后检查脑部病理情况。使用 hTFtarget 识别 RCOR1 和 EDN1 相互作用。健康大鼠皮质神经元细胞受到RCOR1/EDN1表达的干扰，并接受氧糖剥夺/复氧（OGD/R）处理，然后通过生化方法、qRT-PCR和/或蛋白质印迹进行表型和分子测定。

结果

在 CP 模型大鼠和 OGD/R 处理的神经元中，RCOR1 低表达，但 EDN1 高表达。RCOR1过表达改善大鼠神经行为，缓解脑部病理状况，减少CP模型脑中TUNEL阳性细胞，降低活性氧（ROS）和丙二醛（MDA）水平，增加超氧化物歧化酶（SOD）水平并抑制EDN1表达老鼠。在神经元中，RCOR1 过表达抵消了 OGD/R 诱导的活力下降、RCOR1、SOD、Bcl-2、caspase-3、p-Akt/Akt 和 p-GSK-3β/GSK-3β 水平的降低以及EDN1、ROS、Bax 和 cleaved caspase-3 的水平，而 EDN1 过表达则对这些事件产生相反的影响。此外，在 OGD/R 诱导的神经元中，RCOR1 过表达和 EDN1 过表达之间存在负相互作用。

结论

RCOR1通过 EDN1 靶向介导的 Akt/GSK-3β 上调来改善神经行为并抑制 CP 中的神经元凋亡和氧化应激。