中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (7): 1607-1612.doi: 10.4103/1673-5374.357913

• 原著:视神经损伤修复保护与再生 • 上一篇    下一篇

丙戊酸减少大鼠视神经挤压伤后视网膜神经节细胞的凋亡

  

  • 出版日期:2023-07-15 发布日期:2023-01-12
  • 基金资助:
    国家自然科学基金项目(30772368,81371034);陕西省自然科学基金重点项目(2017JZ025)

Valproate reduces retinal ganglion cell apoptosis in rats after optic nerve crush

Feng Pan, Dan Hu*, Li-Juan Sun, Qian Bai, Yu-Sheng Wang, Xu Hou*   

  1. Eye Institute of Chinese PLA and Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, China
  • Online:2023-07-15 Published:2023-01-12
  • Contact: Dan Hu, MD, PhD, hoodan2020@163.com; Xu Hou, MD, PhD, hxfmmu@163.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 30772368 (to DH), 81371034 (to XH); and the Key Project of Natural Science Foundation of Shaanxi Province, No. 2017JZ025 (to DH). 

摘要:

视神经和视网膜神经节细胞在损伤后的自我修复能力有限。丙戊酸(VPA)是一种组蛋白去乙酰化酶抑制剂和多靶点药物,已被证明对视网膜神经元具有神经保护作用。此次实验建立视神经挤压伤大鼠模型后,立即在其玻璃体腔注射丙戊酸。以透射电镜评估视网膜神经节内质网超微结构时程变化;采用免疫组化和蛋白印迹检测发现丙戊酸可上调视神经挤压伤大鼠视网膜神经节中内质网应激标志分子葡萄糖调节蛋白78表达,并降低转录因子C/EBP同源蛋白、磷酸化真核细胞起始因子2α和caspase-12表达。提示丙戊酸可通过减弱内质网应激期间的真核细胞起始因子2α-C/EBP同源蛋白信号传导和caspase-12的活化,来减少视神经挤压伤后视网膜神经节细胞的凋亡,将为进一步明确丙戊酸的神经保护调控机制提出一个新的途径。

https://orcid.org/0000-0002-2781-7219 (Xu Hou)

关键词: 视神经挤压伤, 视网膜神经节细胞, 细胞凋亡, 非折叠蛋白反应, 丙戊酸, 内质网, 葡萄糖调节蛋白78, 转录因子C/EBP同源蛋白, 真核细胞起始因子2α, caspase-12

Abstract: The retinal ganglion cells of the optic nerve have a limited capacity for self-repair after injury. Valproate is a histone deacetylase inhibitor and multitarget drug, which has been demonstrated to protect retinal neurons. In this study, we established rat models of optic nerve-crush injury and injected valproate into the vitreous cavity immediately after modeling. We evaluated changes in the ultrastructure morphology of the endoplasmic reticulum of retinal ganglion cells over time via transmission electron microscope. Immunohistochemistry and western blot assay revealed that valproate upregulated the expression of the endoplasmic reticulum stress marker glucose-regulated protein 78 and downregulated the expression of transcription factor C/EBP homologous protein, phosphorylated eukaryotic translation initiation factor 2α, and caspase-12 in the endoplasmic reticulum of retinal ganglion cells. These findings suggest that valproate reduces apoptosis of retinal ganglion cells in the rat after optic nerve-crush injury by attenuating phosphorylated eukaryotic translation initiation factor 2α-C/EBP homologous protein signaling and caspase-12 activation during endoplasmic reticulum stress. These findings represent a newly discovered mechanism that regulates how valproate protects neurons.

Key words: apoptosis, C/EBP homologous protein, caspase-12, endoplasmic reticulum, glucose-regulated protein 78, optic nerve crush, phosphorylated eukaryotic translation initiation factor 2α, retinal ganglion cells, unfolded protein response, valproate