Effect of Yinxing Mihuan Oral Solutionon P2RX7/NLRP3 Signaling Pathway in Depression Model Rats Induced by Isolation Combined with Chronic Unpredictable Mild Stress

Shan CAO; Xiao-di FAN; Bu-chang ZHAO; Li XU; Yi-min WANG; Wen-ting SONG; Yong WANG; Ming-jiang YAO; Guo-qiang GU; Chang-qing HE; Guang-rui WANG; Jian-xun LIU

doi:10.13422/j.cnki.syfjx.20211103

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Effect of Yinxing Mihuan Oral Solutionon P2RX7/NLRP3 Signaling Pathway in Depression Model Rats Induced by Isolation Combined with Chronic Unpredictable Mild Stress

Pharmacology | 更新时间：2021-06-25

- Effect of Yinxing Mihuan Oral Solutionon P2RX7/NLRP3 Signaling Pathway in Depression Model Rats Induced by Isolation Combined with Chronic Unpredictable Mild Stress
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 27, Issue 12, Pages: 33-39(2021)
- 作者机构：
  
  1.中国中医科学院西苑医院基础医学研究所，中药药理北京市重点实验室，北京 100091
  2.云南中医药大学，昆明 650500
  3.步长制药，西安 710082
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20211103
  CLC： R2-0;R22;R285.5;R289;R33
- Received：22 January 2021，
  
  Published Online：08 April 2021，
  
  Published：20 June 2021
- 稿件说明：
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曹姗,范晓迪,赵步长等.银杏蜜环口服溶液对孤养结合慢性不可预知温和应激大鼠抑郁模型P2RX7/NLRP3信号通路的影响[J].中国实验方剂学杂志,2021,27(12):33-39.

CAO Shan,FAN Xiao-di,ZHAO Bu-chang,et al.Effect of Yinxing Mihuan Oral Solutionon P2RX7/NLRP3 Signaling Pathway in Depression Model Rats Induced by Isolation Combined with Chronic Unpredictable Mild Stress[J].Chinese Journal of Experimental Traditional Medical Formulae,2021,27(12):33-39.
曹姗,范晓迪,赵步长等.银杏蜜环口服溶液对孤养结合慢性不可预知温和应激大鼠抑郁模型P2RX7/NLRP3信号通路的影响[J].中国实验方剂学杂志,2021,27(12):33-39. DOI： 10.13422/j.cnki.syfjx.20211103.

CAO Shan,FAN Xiao-di,ZHAO Bu-chang,et al.Effect of Yinxing Mihuan Oral Solutionon P2RX7/NLRP3 Signaling Pathway in Depression Model Rats Induced by Isolation Combined with Chronic Unpredictable Mild Stress[J].Chinese Journal of Experimental Traditional Medical Formulae,2021,27(12):33-39. DOI： 10.13422/j.cnki.syfjx.20211103.

摘要

目的

通过观察银杏蜜环口服溶液对抑郁模型大鼠的影响，探讨银杏蜜环口服溶液抗抑郁的机制。

方法

50只SD大鼠，除正常组外，采用孤养结合慢性不可预见性应激（CUMS）大鼠抑郁模型，模型成功的大鼠分为模型组，氟西汀组（10 mg·kg

-1

），银杏蜜环口服溶液高、低剂量组（618，309 mg·kg

-1

），每组10只；连续造模21 d，刺激第7天给药，以10 mL·kg

-1

体积连续给药14 d，正常组与模型组灌胃蒸馏水；进行糖水偏好实验、旷场实验、悬尾不动实验；苏木素-伊红（HE）染色法观察抑郁大鼠海马组织病理形态变化；运用多因子检测技术（Luminex）及蛋白免疫印迹法（Western blot）技术检测各组大鼠海马组织白细胞介素-1

（IL-1

），白细胞介素-6（IL-6），肿瘤坏死因子-

（TNF-

）的含量及NOD样受体3（NLRP3）及其相关激活信号通路蛋白的表达水平。

结果

连续给药14 d后，与正常组比较，模型组大鼠糖水消耗率明显降低、直立次数明显减少、悬尾不动累积时间明显延长（

0.05，

0.01）；与模型组比较，氟西汀及银杏蜜环口服溶液高剂量组大鼠表现为直立、穿格次数增加，糖水消耗率增加，悬尾不动累积时间明显缩短（

0.05，

0.01）。HE结果显示，银杏蜜环口服溶液高剂量组大鼠海马区神经元细胞排列有序，轻度疏松，小胶质细胞浸润不明显；与正常组比较，模型组海马组织中IL-1

β，

IL-6和TNF-

的含量明显增加（

0.05，

0.01）；与模型组比较，银杏蜜环口服溶液高剂量组大鼠脑组织IL-1

，IL-6和TNF-

的含量明显降低（

0.05，

0.01）。分子生物学实验表明，与正常组比较，模型组嘌呤能受体P2X7（P2RX7），NLRP3，凋亡相关斑点样蛋白（ASC），半胱氨酸天冬氨酸蛋白水解酶-1（Caspase-1），IL-1

蛋白表达明显增加（

0.05，

0.01）；与模型组比较，氟西汀及银杏蜜环口服溶液高剂量组可明显抑制P2RX7，NLRP3，ASC，Caspase-1，IL-1

蛋白表达（

0.05，

0.01）。

结论

银杏蜜环口服溶液可以改善孤养结合CUMS诱导的大鼠抑郁样行为，其作用机制与调控P2RX7/NLRP3信号通路相关。

Abstract

Objective

To explore the antidepressant mechanism of Yinxing Mihuan oral solution （YMO） by investigating its effect on depression model rats.

Method

The depression rats were induced by isolation combined with chronic unpredictable mild stress （CUMS） and then randomly divided into model group， fluoxetine group （10 mg·kg

-1

） and high-dose （618 mg·kg

-1

） and low-dose （309 mg·kg

-1

） YMO groups. A blank control group was also set up and ten rats were included in each group. Modeling lasted for 21 consecutive days， and rats were administered the 8th day after stimulation at a dose of 10 mL·kg

-1

for 14 days， except those in the blank control and model groups which were given distilled water. Afterward， the sucrose preference test， open field test， tail suspension test were carried out. The pathological changes of hippocampus in depression rats were observed after hematoxylin-eosin （HE） staining. The content of interleukin-1

（IL-1

）， interleukin-6 （IL-6） and tumor necrosis factor-

（TNF-

） in the hippocampus of rats in each group and the expression of NOD-like receptor 3 （NLRP3） and other proteins in its related activation signaling pathways were detected with multi-factor detection （Luminex） and Western blot.

Result

After 14 days of continuous administration， compared with the blank control group， the model group witnessed significantly reduced sugar water consumption rate and the times of rearing and significantly prolonged cumulative time of immobility during tail suspension （

0.05，

0.01）. Compared with the model group， the fluoxetine group and the high-dose YMO group saw increases in the times of rearing， times of crossing and sugar water consumption rate and a significant decrease in the cumulative time of immobility during tail suspension （

0.05，

0.01）. The results of HE staining showed that the neurons in the hippocampus of rats in the high-dose YMO group were arranged in order and slightly loosened， without obvious microglia infiltration observed. The levels of IL-1

， IL-6 and TNF-

in the hippocampus of the model group increased significantly as compared with the blank control group （

0.05，

0.01）， and their content in the high-dose YMO group was significantly lowered in the comparison with the model group （

0.05，

0.01）. Molecular biology experiments demonstrated that compared with the results of blank group， the expression of purinergic receptor P2X7 （P2RX7）， NLRP3， apoptosis-associated speck-like protein （ASC）， Caspase-1 and IL-1

remarkably increased in the model group （

0.05，

0.01）. Additionally， the expression of P2RX7， NLRP3， ASC， Caspase-1 and IL-1

was significantly inhibited in the fluoxetine group and the high-dose YMO group compared with the model group （

0.05，

0.01）.

Conclusion

YMO can improve the depression-like behaviors of rats induced by isolation combined with CUMS， and its mechanism of action is related to the regulation of the P2RX7/NLRP3 signaling pathway.

关键词

Keywords

references

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