Pleiotrophin ameliorates white matter injury of neonatal rats by activating the mTOR/YY1/Id4 signaling pathway
Pleiotrophin ameliorates white matter injury of neonatal rats by activating the mTOR/YY1/Id4 signaling pathway
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DOI：
10.1096/fj.202201766rrr
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发表时间：
2023-08-01
期刊：
影响因子：
4.8
通讯作者：
Mu，Dezhi
中科院分区：
文献类型：
--
作者：
Qiu，Xia;Zhou，Ruixi;Mu，Dezhi
脑白质损伤(WMI)是一种严重的中枢神经系统疾病。多突胶质细胞营养素(PTN)在体外可促进少突胶质细胞的分化和髓鞘形成。然而，PTN在WMI中的作用仍不清楚。因此，本研究旨在探讨PTN对WMI新生大鼠的神经保护作用及其可能机制。用PTN和哺乳动物靶标雷帕霉素(MTOR)抑制剂依维莫司治疗出生后3d SD大鼠的WMI模型，分离、结扎大鼠右侧颈总动脉，暴露于低氧环境(6%O2+ 94%N_2)中2 h，观察PTN对大鼠空间学习记忆能力的影响。通过检测mTOR信号通路中的两个蛋白--盈阳1(YY1)和DNA结合抑制因子4(Id4)，探讨PTN在大鼠WMI模型和氧糖剥夺(OGD)模型中的作用机制。我们发现，WMI后OL的分化和髓鞘形成受到了损害。PTN通过激活mTOR/YY1和抑制Id4而挽救了这种损伤。依维莫司抑制mTOR/YY1，激活Id4，从而阻断PTN在WMI中的神经保护作用。PTN对新生WMI大鼠具有神经保护作用，其机制可能与mTOR/YY1/Id4信号通路有关。
Brain white matter injury (WMI) is a serious disease of the central nervous system. Pleiotrophin (PTN) promotes the differentiation and myelination of oligodendrocytes (OLs) in vitro. However, the role of PTN in WMI remains unknown. Therefore, this study aimed to investigate the neuroprotective role and potential mechanisms of PTN function in neonatal rats with WMI. The PTN and mammalian target of rapamycin (mTOR) inhibitor everolimus was used to treat a WMI model in postnatal day 3 Sprague–Dawley rats, in which the right common carotid arteries of these rats were isolated, ligated, and exposed to a hypoxic environment (6% O2+ 94% N2) for 2 h. OL differentiation and myelination, as well as the spatial learning and memory abilities of the rats were evaluated to examine the effects of PTN. Two proteins of the mTOR signaling pathway, YingYang1 (YY1) and inhibitor of DNA binding 4 (Id4), were detected and were used to explore the potential mechanisms of PTN in rat WMI experiment and oxygen glucose deprivation (OGD) model. We found that the differentiation and myelination of OLs were impaired after WMI. PTN administration rescued this injury by activating mTOR/YY1 and inhibiting Id4. Everolimus administration inhibited mTOR/YY1 and activated Id4, which blocked the neuroprotective role of PTN in WMI. PTN plays a neuroprotective role in neonatal rats with WMI, which could be involved in the mTOR/YY1/Id4 signaling pathway.