GSK-3β inhibitor TWS119 alleviates hypoxic-ischemic brain damage via a crosstalk with Wnt and Notch signaling pathways in neonatal rats
GSK-3β inhibitor TWS119 alleviates hypoxic-ischemic brain damage via a crosstalk with Wnt and Notch signaling pathways in neonatal rats
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DOI：
10.1016/j.brainres.2021.147588
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发表时间：
2021-07-31
期刊：
影响因子：
2.9
通讯作者：
Cui, Hong
中科院分区：
文献类型：
--
作者：
Gao, Limin;Yang, Lijun;Cui, Hong
早产儿脑损伤是早产儿存活者发病和残疾的主要原因。不幸的是，仍然缺乏有效的治疗方法。最近的证据表明GSK-3 β抑制剂TWS 119通过激活Wnt/β-catenin信号通路在成人脑损伤中具有神经保护作用。然而，其对新生儿脑损伤的作用尚未探讨。本研究旨在评价TWS 119在新生大鼠缺氧缺血性脑损伤后7 d的作用，并探讨其在缺氧缺血性脑损伤后24 h调节Wnt和Notch信号通路的机制。3日龄大鼠随机分为假手术组、HI组和TWS 119组。新生大鼠结扎左颈总动脉，然后缺氧2 h（8.0%O-2）。在缺氧缺血（HI）前20分钟腹腔内注射单剂量的TWS 119（30 mg/kg）。HI后7 d，TWS 119可改善组织结构，减少细胞凋亡，上调bcl-2表达，上调PSD-95和Synapsin-1表达。HI后24 h，通过上调β-catenin蛋白表达和wnt 3a/wnt 5a/wnt 7a mRNA表达，激活Wnt/β-catenin信号通路。同时，通过下调Notch 1和HES-1蛋白的表达，抑制Notch信号通路。本研究提示，TWS 119在新生大鼠缺氧缺血性脑损伤后7 d起神经保护作用，其作用机制可能与缺氧缺血性脑损伤后24 h Wnt/beta-catenin和Notch信号通路的相互作用有关。
Preterm infant brain injury is a leading cause of morbidity and disability in survivors of preterm infants. Unfortunately, the effective treatment remains absent. Recent evidence suggests that GSK-3 beta inhibitor TWS119 has a neuroprotective role in adult brain injury by activation of Wnt/beta-catenin signaling pathway. However, the role on neonatal brain injury is not yet explored. The study aims to evaluate the effect of TWS119 at 7 d after hypoxicischemic brain damage and investigate the mechanism that it regulates Wnt and Notch signaling pathways at 24 h after hypoxic-ischemic brain damage in neonatal rats. Three-day-old rats were randomly divided into 3 groups: sham group, HI group and TWS119 group. The neonatal rats were subjected to left carotid artery ligation followed by 2 h of hypoxia (8.0% O-2). A single dose of TWS119 (30 mg/kg) was intraperitoneally injected 20 min prior to hypoxia-ischemia (HI). At 7 d after HI, TWS119 improved the tissue structure, reduced cell apoptosis, upregulated bcl-2 expression, up-regulated the expression of PSD-95 and Synapsin-1. At 24 h after HI, it activated Wnt/beta-catenin signaling pathway by up-regulation of beta-catenin protein expression and wnt3a/wnt5a/wnt7a mRNA expression. Simultaneously, it suppressed Notch signaling pathway by down-regulation of Notch1 and HES-1 proteins expression. Our study suggested that TWS119 performed a neuroprotective function at 7 d after hypoxic-ischemic brain damage via a crosstalk with Wnt/beta-catenin and Notch signaling pathways at 24 h after hypoxic-ischemic brain damage in neonatal rats.