中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (2): 394-400.doi: 10.4103/1673-5374.290913

• 原著:颅神经损伤修复保护与再生 • 上一篇    

促进缺血视网膜神经元DNA修复的糖原合酶激酶3β抑制剂SB216763

  

  • 出版日期:2021-02-15 发布日期:2020-12-04
  • 基金资助:

    国家自然科学基金项目(8167084881900850

Glycogen synthase kinase-3β inhibitor SB216763 promotes DNA repair in ischemic retinal neurons

Jing Zhang#, Zhi-Peng Lai#, Pei Chen, Yang Ying, Jing Zhuang*, Ke-Ming Yu*   

  1. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong Province, China
  • Online:2021-02-15 Published:2020-12-04
  • Contact: Jing Zhuang, PhD, zhuangj@mail.sysu.edu.cn; Ke-Ming Yu, PhD, yukeming@mail.sysu.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 81670848 (to JZhuang) and 81900850 (to YY).

摘要:

抑制糖原合酶激酶3β可减弱神经细胞DNA损伤,从而改善病理条件下神经元的存活,但其机制尚不明确。实验对体外培养缺血视网膜神经元和体内缺血再灌注视网膜损伤大鼠模型行糖原合酶激酶3β抑制剂SB216763干预。(1)结果显示,SB216763可减少视网膜神经细胞中H2AX阳性病灶的形成,并改善缺血性视网膜神经元的活性。SB216763还可上调连接酶IV转录因子磷酸化CREB1的表达,并显著增加DNA连接酶IV在缺血性视网膜神经元中的转录活性,在缺血再灌注损伤后的大鼠视网膜中也证实上述的结果;(2)实验还发现与直接抑制糖原合酶激酶3β的LiCl不同,SB21676 3是通过抑制糖原合酶激酶3β的磷酸化而发挥作用的,是其上调了缺血性视网膜神经元中连接酶 IV表达,促进了缺血视网膜神经元中DNA的修复。实验于2018年2月18日获得中山眼科中心动物伦理委员会批准,批准号SYXK(Yue)2019-075A。

https://orcid.org/0000-0001-5335-3318 (Jing Zhuang)

关键词: 视神经, 体外, 损伤, 修复, 蛋白, 因子, 通路, 糖原合酶激酶3β, DNA连接酶IV, 神经保护

Abstract: Glycogen synthase kinase-3β (GSK-3β) has been shown to attenuate DNA damage in nerve cells, thereby enhancing neuronal survival under pathological conditions; however, the underlying mechanism remains unclear. An in vitro serum-starvation retinal neuron model and in vivo ischemia/reperfusion retina injury rat model were established and treated with SB216763, a GSK-3β inhibitor. SB21673 decreased the formation of γ-H2A histone family member X foci and enhanced the viability of ischemic retinal neurons. In addition, SB216763 upregulated expression of phosphorylated-CREB1, a ligase IV transcription factor, and significantly increased the transcriptional activity of ligase IV in ischemic retinal neurons. These results were confirmed in rat retinas following ischemia/reperfusion injury. Furthermore, we found that unlike lithium chlorine (a well-known direct inhibitor of GSK-3β), SB216763 inhibited GSK-3β activity by suppressing its phosphorylation. Taken together, our results suggest that GSK-3β inhibition enhances repair of DNA double-strand breaks by upregulating ligase IV expression in ischemic retinal neurons. This study was approved by the Institutional Animal Care and Use Committee of Zhongshan Ophthalmic Center on February 18, 2018.

Key words: factor, GSK-3β, in vitro, injury, ligase IV, neuroprotection, optic nerve, pathways, protein, repair