Protective effect of recombinant neuregulin-1 on enhancing retinal ganglion cells survival in rat models with acute optic nerve injury

GENG Yan; CUI Xiao-meng; WANG Shuang

doi:10.11659/jjssx.10E022138

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Protective effect of recombinant neuregulin-1 on enhancing retinal ganglion cells survival in rat models with acute optic nerve injury

Basic Research | 更新时间：2023-09-26

- Protective effect of recombinant neuregulin-1 on enhancing retinal ganglion cells survival in rat models with acute optic nerve injury
- JOURNAL OF REGIONAL ANATOMY AND OPERATIVE SURGERY Vol. 32, Issue 9, Pages: 783-789(2023)
- 作者机构：
  
  1.北京积水潭医院眼科，北京 100035
  2.北京积水潭医院回龙观院区眼科，北京 100035
- 作者简介：
- 基金信息：
- DOI：10.11659/jjssx.10E022138
  CLC： R774
- Published：25 September 2023，
  
  Received：26 October 2022，
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耿岩,崔晓萌,王爽.人重组神经调节蛋白1增强急性视神经损伤大鼠模型视网膜神经节细胞存活的保护作用[J].局解手术学杂志,2023,32(09):783-789.

GENG Yan,CUI Xiao-meng,WANG Shuang.Protective effect of recombinant neuregulin-1 on enhancing retinal ganglion cells survival in rat models with acute optic nerve injury[J].JOURNAL OF REGIONAL ANATOMY AND OPERATIVE SURGERY,2023,32(09):783-789.
耿岩,崔晓萌,王爽.人重组神经调节蛋白1增强急性视神经损伤大鼠模型视网膜神经节细胞存活的保护作用[J].局解手术学杂志,2023,32(09):783-789. DOI： 10.11659/jjssx.10E022138.

GENG Yan,CUI Xiao-meng,WANG Shuang.Protective effect of recombinant neuregulin-1 on enhancing retinal ganglion cells survival in rat models with acute optic nerve injury[J].JOURNAL OF REGIONAL ANATOMY AND OPERATIVE SURGERY,2023,32(09):783-789. DOI： 10.11659/jjssx.10E022138.

摘要

目的

探究人重组神经调节蛋白1（NRG-1）对急性视神经损伤大鼠模型视网膜神经节细胞（RGCs）存活的保护作用及可能的机制。

方法

通过动脉夹夹持法建立视神经损伤大鼠模型，大鼠随机分为假手术组、模型组、NRG-1（0.5 μg、1.0 μg、3.0 μg）组。NRG-1组大鼠术后30 min于玻璃体内分别注射0.5 μg、1.0 μg、3.0 μg人重组NRG-1，其余大鼠以同样的方式注射等量生理盐水。通过闪光视觉诱发电位（F-VEP）检测术后2 h、1 d、2 d、7 d、14 d、28 d大鼠视神经P100波潜伏期和波幅的变化；术后28 d，通过霍乱毒素亚单位（CTB）示踪视网膜受压状态；另外采用TUNEL法检测视网膜和视神经组织中RGCs凋亡情况，酶联免疫吸附试验检测视神经组织中一氧化氮（NO）、一氧化氮合酶（NOS）、丙二醛（MDA）、超氧化物歧化酶（SOD）、肿瘤坏死因子α（TNF-α）和白细胞介素1β（IL-1β），免疫组化法检测NRG-1蛋白表达，Western blot法检测Nrf2、HO-1、Bach1蛋白表达。

结果

术后28 d，与假手术组相比，模型组P100波潜伏期延长，波幅降低，视网膜和视神经组织中RGCs凋亡数量增加，视神经组织中TNF-α、IL-1β、NO、MDA水平升高，且总蛋白HO-1、核蛋白Nrf2和Bach1蛋白表达下调，差异均有统计学意义（

0.05）；而与模型组相比，NRG-1 1.0 µg组和3.0 µg组P100波潜伏期缩短，波幅升高，视网膜和视神经组织中RGCs凋亡数量减少，视神经组织中TNF-α、IL-1β、NO、MDA水平降低，总蛋白HO-1、核蛋白Nrf2和Bach1蛋白表达上调，差异均有统计学意义（

0.05）；而NRG-1 3.0 µg组大鼠P100波潜伏期和波幅，RGCs和神经胶质细胞凋亡数量，视神经组织中TNF-α、IL-1β、NO、MDA水平与假手术组相比，差异无统计学意义（

0.05）。

结论

NRG-1蛋白在大鼠急性视神经损伤后期表达明显降低，而给予外源性人重组NRG-1能够通过抑制视网膜RGCs凋亡以及激活Nrf2/HO-1/Bach1通路发挥抗炎、抗氧化作用，从而实现对视神经损伤的修复和保护作用。

Abstract

Objective

To explore the protective effect of recombinant neuregulin-1 （NRG-1） on enhancing retinal ganglion cells （RGCs） survival in rat with acute optic nerve injury and its mechanism.

Methods

A rat model of optic nerve injury was established by clipping the optic nerve with artery clip， and rats were randomly divided into the sham-operation group，model group， and NRG-1（0.5 μg，1.0 μg，3.0 μg） groups.Rats in each NRG-1 group were injected 0.5 μg，1.0 μg，3.0 μg recombinant NRG-1 into vitreous 30 minutes after modeling.The rats in the rest groups were injected with the same amount of normal saline in the same way.The changes of P100 wave latency and amplitude of optic nerve in rats 2 hours，1 day，2 days，7 days，14 days，28 days after surgery were detected by flash visual evoked potential （F-VEP）. The retinal compression 28 days after surgery was detected by the cholera toxin subunit B （CTB），and the apoptosis of RGCs in retina and optic nerve tissues was detected by TUNEL assay.The contents of nitric oxide （NO），nitric oxide synthase （NOS），malondialdehyde （MDA），superoxide dismutase （SOD），tumor necrosis factor α （TNF-α） and interleukin-1β（IL-1β） in optic nerve tissue of rats were determined by enzyme-linked immunosorbent assay.The NRG-1 protein expression was determined by immunohistochemistry，the expression of Nrf2，HO-1 and Bach1 proteins were detected by Western blot.

Results

Compared with the sham-operation group，the model group had longer latencies of P100 wave 28 days after surgery，lower amplitude of P100 wave， more apoptosis numbers of RGCs cells in retinal and optic nerve tissues， higher levels of TNF-α，IL-1β，NO and MDA in optic nerve tissue and lower expression of total protein HO-1，nucleoprotein Nrf2 and Bach1，with significant differences （

0.05）.Compared with the model group，NRG-1 1.0 µg group and 3.0 µg group had shorter latencies of P100 wave，higher amplitude of P100 wave，less apoptosis numbers of RGCs in retinal and optic nerve tissues， lower levels of TNF-α，IL-1β，NO and MDA in optic nerve tissue and higher expression of total protein HO-1，nucleoprotein Nrf2 and Bach1，with significant differences （

0.05）.There was no statistically significant differences in the latency or amplitude of P100 wave，the apoptosis of RGCs or neuroglia and the levels of TNF-α，IL-1β，NO and MDA in the optic nerve tissue of rats between the NRG-1 3.0 µg group and sham-operated group （

0.05）.

Conclusion

NRG-1 protein expression is significantly reduced in the late stage of acute optic nerve injury in rats，but exogenous recombinant NRG-1 can exert anti-inflammatory and anti-oxidative effects by inhibiting RGCs apoptosis and activating Nrf2/HO-1/Bach1 pathway， thereby achieving the repair and protection of optic nerve injury.

关键词

神经调节蛋白1视神经损伤核因子E2相关因子2氧化应激炎症反应

Keywords

neuregulin-1optic nerve injurynuclear factor E2 related factor 2oxidative stressinflammatory response

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