Effects of Ziziphi Spinosae Semen and Albiziae Flos on Behavior and Endoplasmic Reticulum Stress PERK/ATF4/CHOP Pathway in Depression Model Rats

Zhi-yi CAO; Ling LI; Li-li FAN; Ming-jie WANG; Chao-feng GUO; Xue-li SHI

doi:10.13422/j.cnki.syfjx.20210205

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Effects of Ziziphi Spinosae Semen and Albiziae Flos on Behavior and Endoplasmic Reticulum Stress PERK/ATF4/CHOP Pathway in Depression Model Rats

Pharmacology | 更新时间：2021-03-29

- Effects of Ziziphi Spinosae Semen and Albiziae Flos on Behavior and Endoplasmic Reticulum Stress PERK/ATF4/CHOP Pathway in Depression Model Rats
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 27, Issue 7, Pages: 66-72(2021)
- 作者机构：
  
  1.广西中医药大学，南宁 530200
  2.广西中医药大学第一附属医院，南宁 530023
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20210205
  CLC： R2-0;R22;R285.5
- Received：17 November 2020，
  
  Published Online：22 January 2021，
  
  Published：05 April 2021
- 稿件说明：
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曹智怡,李玲,范丽丽等.酸枣仁-合欢花对抑郁模型大鼠行为学及内质网应激PERK/ATF4/CHOP通路的影响[J].中国实验方剂学杂志,2021,27(07):66-72.

CAO Zhi-yi,LI Ling,FAN Li-li,et al.Effects of Ziziphi Spinosae Semen and Albiziae Flos on Behavior and Endoplasmic Reticulum Stress PERK/ATF4/CHOP Pathway in Depression Model Rats[J].Chinese Journal of Experimental Traditional Medical Formulae,2021,27(07):66-72.
曹智怡,李玲,范丽丽等.酸枣仁-合欢花对抑郁模型大鼠行为学及内质网应激PERK/ATF4/CHOP通路的影响[J].中国实验方剂学杂志,2021,27(07):66-72. DOI： 10.13422/j.cnki.syfjx.20210205.

CAO Zhi-yi,LI Ling,FAN Li-li,et al.Effects of Ziziphi Spinosae Semen and Albiziae Flos on Behavior and Endoplasmic Reticulum Stress PERK/ATF4/CHOP Pathway in Depression Model Rats[J].Chinese Journal of Experimental Traditional Medical Formulae,2021,27(07):66-72. DOI： 10.13422/j.cnki.syfjx.20210205.

摘要

目的

研究酸枣仁-合欢花对抑郁模型大鼠行为学及内质网应激蛋白激酶R样内质网激酶（PERK）/活化的转录因子4（ATF4）/CCAAT/增强子结合蛋白同源蛋白（CHOP）通路的影响，并探讨其抗抑郁作用的机制。

方法

将雄性SD大鼠按随机数字表法分为正常组，模型组，盐酸文拉法辛组（0.008 g·kg

-1

），酸枣仁-合欢花高、中、低剂量组（16，8，4 g·kg

-1

），每组15只。除正常组外，其余5组采用慢性不可预见性温和应激（CUMS）结合孤养的方式建立抑郁模型，造模的同时给予正常组和模型组大鼠等体积的蒸馏水灌胃，各给药组大鼠予相应剂量的药物灌胃，连续21 d。于实验的第1天和第21天进行旷场实验和糖水消耗实验观察各组大鼠行为学变化；采用透射电镜观察大鼠海马神经元超微结构变化；采用原位末端标记（TUNEL）法检测大鼠海马区神经元凋亡情况；采用蛋白免疫印迹法（Western blot）技术检测大鼠海马组织PERK，CHOP，B淋巴细胞瘤-2相关X蛋白（Bax），半胱氨酸天冬氨酸蛋白酶-3（Caspase-3）蛋白表达情况。

结果

与正常组比较，模型组大鼠旷场实验得分、糖水消耗率显著下降（

0.01）；与模型组大鼠比较，酸枣仁-合欢花各剂量组及盐酸文拉法辛组大鼠旷场实验得分、糖水消耗率均显著升高（

0.01）；透射电镜显示，与正常组比较，模型组大鼠海马区神经元损伤明显，与模型组比较，酸枣仁-合欢花各剂量组及盐酸文拉法辛组大鼠海马区神经元损伤减轻；TUNEL显示，与正常组比较，模型组大鼠海马区神经元凋亡数量增加（

0.01），与模型组比较，酸枣仁-合欢花各剂量组及盐酸文拉法辛组大鼠海马区神经元凋亡数量减少（

0.01）。Western blot结果显示，与正常组大鼠比较，模型组大鼠海马PERK，CHOP，Bax，Caspase-3蛋白表达水平显著升高（

0.01）；与模型组大鼠比较，盐酸文拉法辛组和酸枣仁-合欢花各剂量组大鼠海马PERK，CHOP，Bax，Caspase-3蛋白表达水平均降低（

0.05，

0.01）。

结论

酸枣仁-合欢花可能通过调节内质网应激PERK/ATF4/CHOP通路而发挥抗抑郁作用。

Abstract

Objective

To investigate the effect of Ziziphi Spinosae Semen （ZSS） and Albiziae Flos （AF） on behavior and endoplasmic reticulum stress endoplasmic reticulum stress protein kinase R-like endoplasmic reticulum kinase （PERK）/activated transcription factor 4 （ATF4）/CCAAT enhancer binding protein （CHOP） pathway in depression model rats， and to explore its antidepressant mechanism.

Method

The male SD rats were divided into normal group， model group， ZSS-AF high dose， middle dose and low dose groups （16， 8， 4 g·kg

-1

） and Venlafaxine group （0.008 g·kg

-1

），

=15 in each group. Except the normal group， the depression model was established in the rats of other 5 groups by the method of chronic unpredictable mild stress （CUMS） combined with isolated feeding. The normal group and model group were given with distilled water by gavage when modeling， while other groups received corresponding drug by intragastric administration for 21 days. Behavior changes of rats in each group were observed by the open field test and sugar water consumption test on 1

and 21

day of the experiment. The protein expressions of PERK， CHOP， B-cell lymphoma-2 associated X protein （Bax） and cysteine-containing aspartate-specific proteases-3（Caspase-3） were detected by Western blot（WB）， the ultrastructural changes of the hippocampus were observed by transmission electron microscope， the apoptosis of hippocampal neurons was observed by terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL） method.

Result

Compared with the normal group， the scores of open field test and sugar water consumption rate in model group rats decreased （

0.01）. Compared with the model group， the scores of open field test and water consumption rate increased （

0.01） in ZSS-AF groups and Venlafaxine group. Transmission electron microscope showed that the changes of neuronal damage in hippocampal were revealed in the model group， whereas those neuronal damages were relieved in ZSS-AF groups and Venlafaxine group. TUNEL method showed that the number of apoptotic neurons in hippocampal increased in the model group （

0.01）， but decreased in ZSS-AF groups and Venlafaxine group （

0.01）. WB results showed that as compared with the normal group， protein expressions of PERK， CHOP， Bax and Caspase-3 were up-regulated significantly in the model group （

0.01）， whereas those were down-regulated in ZSS-AF groups and Venlafaxine group （

0.05，

0.01）.

Conclusion

The antidepressant effect of ZSS-AF herbal pair may be correlated with the regulation of endoplasmic reticulum stress PERK/ATF4/-CHOP pathway.

关键词

Keywords

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