Effects of <italic style="font-style: italic">Zuogui Jiangtang Jieyu Formula </italic>（左归降糖解郁方） on Dendritic Spines of Hippocampal Dentate Gyrus and Wnt5a/RhoA Signaling Pathway in Diabetic with Depression Model Rats

YANG Hui; LI Wei; LEI Shihui; JIANG Fan; LIU Jian; WANG Jinxi; YANG Yi; WANG Yuhong

doi:10.13288/j.11-2166/r.2024.05.013

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Effects of Zuogui Jiangtang Jieyu Formula （左归降糖解郁方） on Dendritic Spines of Hippocampal Dentate Gyrus and Wnt5a/RhoA Signaling Pathway in Diabetic with Depression Model Rats

更新时间：2024-02-26

- Effects of Zuogui Jiangtang Jieyu Formula （左归降糖解郁方） on Dendritic Spines of Hippocampal Dentate Gyrus and Wnt5a/RhoA Signaling Pathway in Diabetic with Depression Model Rats
- Journal of Traditional Chinese Medicine Vol. 65, Issue 5, Pages: 520-528(2024)
- 作者机构：
  
  1.湖南中医药大学第一附属医院，湖南省长沙市雨花区韶山中路95号，410007
  2.湖南中医药大学科技创新中心
- 作者简介：
- 基金信息：
- DOI：10.13288/j.11-2166/r.2024.05.013
  CLC：
- Received：12 July 2023，
  
  Revised：2023-12-18，
  
  Published：02 March 2024
- 稿件说明：
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杨蕙,李薇,雷诗卉等.左归降糖解郁方对糖尿病并发抑郁症模型大鼠海马齿状回神经元树突及Wnt5a/RhoA信号通路的影响[J].中医杂志,2024,65(05):520-528.

YANG Hui,LI Wei,LEI Shihui,et al.Effects of Zuogui Jiangtang Jieyu Formula （左归降糖解郁方） on Dendritic Spines of Hippocampal Dentate Gyrus and Wnt5a/RhoA Signaling Pathway in Diabetic with Depression Model Rats[J].Journal of Traditional Chinese Medicine,2024,65(05):520-528.
杨蕙,李薇,雷诗卉等.左归降糖解郁方对糖尿病并发抑郁症模型大鼠海马齿状回神经元树突及Wnt5a/RhoA信号通路的影响[J].中医杂志,2024,65(05):520-528. DOI： 10.13288/j.11-2166/r.2024.05.013.

YANG Hui,LI Wei,LEI Shihui,et al.Effects of Zuogui Jiangtang Jieyu Formula （左归降糖解郁方） on Dendritic Spines of Hippocampal Dentate Gyrus and Wnt5a/RhoA Signaling Pathway in Diabetic with Depression Model Rats[J].Journal of Traditional Chinese Medicine,2024,65(05):520-528. DOI： 10.13288/j.11-2166/r.2024.05.013.

摘要

目的

探讨左归降糖解郁方治疗糖尿病并发抑郁症的可能作用机制。

方法

60只大鼠随机分为正常组、模型组、无翅型MMTV整合位点家族成员5a（Wnt5a）激动剂组、左归降糖解郁方组、左归降糖解郁方+Wnt5a抑制剂组，每组12只。除正常组外，其余各组大鼠采用高脂饲料饲养、链脲佐菌素注射和慢性温和不可预知应激联用法建立糖尿病并发抑郁症大鼠模型。造模成功后Wnt5a激动剂组大鼠给予双侧海马立体定位注射Wnt5a激动剂Foxy-5各5 μl，连续7天；左归降糖解郁方组给予左归降糖解郁方20.52 g/（kg·d）灌胃；左归降糖解郁方+Wnt5a抑制剂组进行灌胃给药和双侧海马立体定位注射Wnt5a抑制剂Box5，给药剂量和注射方法同上。正常组和模型组给予10 ml/（kg·d）生理盐水灌胃。各组灌胃均连续4周。干预结束后采用强迫游泳实验（不动时间）和旷场实验（活动次数）评价大鼠的抑郁样行为；检测大鼠的血糖和胰岛素含量，并计算胰岛素抵抗指数；采用高尔基染色观察大鼠海马齿状回神经元的树突形态；采用5-溴脱氧尿嘧啶核苷（Brdu）注射及免疫荧光检测齿状回神经元增殖水平；采用RT-qPCR和Western blot法检测齿状回Wnt5a、Ras同源物基因组成员A（RhoA）和Rho同源物相关卷曲螺旋蛋白激酶1（ROCK1）mRNA和蛋白表达。

结果

与正常组比较，模型组大鼠血糖、胰岛素及胰岛素抵抗指数均显著升高，不动时间显著延长，活动次数显著减少，海马齿状回中Brdu积分光密度值和Wnt5a、RhoA、ROCK1蛋白及mRNA表达均显著降低（

＜0.05或

＜0.01）；大鼠海马齿状回神经元可见树突分支明显减少或断裂，长度缩短。与模型组比较，左归降糖解郁方组和左归降糖解郁方+Wnt5a抑制剂组大鼠血糖、胰岛素及胰岛素抵抗指数显著降低（

＜0.05或

＜0.01）；Wnt5a激动剂组和左归降糖解郁方组大鼠不动时间显著缩短、活动次数显著增加、Brdu积分光密度值显著升高，Wnt5a、RhoA、ROCK1蛋白及mRNA表达均升高（

＜0.05或

＜0.01），海马齿状回神经元的树突分支数量显著增加、长度延长，树突的复杂性增加。与Wnt5a激动剂组比较，左归降糖解郁方组大鼠血糖、胰岛素及胰岛素抵抗指数显著降低，不动时间显著延长，活动次数显著减少，Brdu积分光密度值显著降低；除左归降糖解郁方组Wnt5a mRNA外，左归降糖解郁方组和左归降糖解郁方+Wnt5a抑制剂组Wnt5a、RhoA、ROCK1蛋白及mRNA表达均降低（

＜0.05或

＜0.01）。与左归降糖解郁方组比较，左归降糖解郁方+Wnt5a抑制剂组Wnt5a、RhoA、ROCK1蛋白及mRNA表达均降低（

＜0.05或

＜0.01）。

结论

左归降糖解郁方可改善糖尿病并发抑郁症模型大鼠的高血糖和抑郁样行为，其抗抑郁作用可能与激活海马Wnt5a/RhoA信号，促进齿状回神经元树突生长有关。

Abstract

Objective

To explore the potential mechanism of

Zuogui Jiangtang Jieyu Formula

（左归降糖解郁方， ZJJF） for diabetic rats with depression.

Methods

Sixty rats were randomly divided into normal group， model group， wingless MMTV integration site family member 5a （Wnt5a） agonist group， ZJJF group， and ZJJF plus Wnt5a inhibitor group， with 12 rats in each group. Except for the normal group， the rats were fed with high-fat chow， streptozotocin injection， and chronic mild unpredictable stress combination， to establish model of diabetes mellitus complicated with depression. After successful modelling， rats in the Wnt5a agonist group were given bilateral hippocampal stereotactic injections of Wnt5a agonist Foxy-5 with 5 μl each for 7 consecutive days； rats in ZJJF group were given 20.52 g/（kg·d） of ZJJF by gavage； rats in ZJJF plus Wnt5a inhibitor group were given the drug by gavage， and bilateral hippocampal stereotactic injections of Wnt5a inhibitors Box5， with the same dosage and injection method as above. The normal group and model group were given 10 ml/（kg·d） of normal saline by gavage. All groups were gavaged for 4 consecutive weeks. At the end of the intervention， the depression-like behaviour of rats was evaluated using the forced swimming experiment （immobility time） and the absent field experiment （number of activities）； the blood glucose and insulin levels of rats were measured and the insulin resistance index was calculated； the dendritic morphology of dentate gyrus neurons in the hippocampus was observed using Golgi staining； the level of dentate gyrus neuron proliferation was measured using 5-bromodeoxyuracil nucleoside （Brdu） injection and immunofluorescence； RT-qPCR and Western blot were used to detect the mRNA and protein expression of Wnt5a， Ras homologue genomic member A （RhoA） and Rho homologue-associated coiled-coil protein kinase 1 （ROCK1） in the dentate gyrus.

Results

Compared with the normal group， rats in the model group had significantly higher blood glucose， insulin and insulin resistance indices， longer immobility time， fewer activities， lower Brdu integral optical density values and Wnt5a， RhoA， ROCK1 protein and mRNA expression in the dentate gyrus of the hippocampus （

＜0.05 or

＜ 0.01）； the dendritic branches of rat hippocampal dentate gyrus neurons could be seen to be significantly reduced or broken， and their length shortened. Compared with the model group， the blood glucose， insulin and insulin resistance indices of rats in ZJJF group and the ZJJF plus Wnt5a inhibitor group significantly reduced （

＜0.05 or

＜0.01）； the immobility time of rats in the Wnt5a agonist group and ZJJF group was significantly shortened， the number of activities increased， the Brdu integral optical density values elevated， and the Wnt5a， RhoA， ROCK1 protein and mRNA expression elevated （

＜0.05 or

＜0.01）， and the number of dendritic branches of hippocampal dentate gyrus neurons significantly increased， the length lengthened， and the complexity of dendrites increased. Compared with the Wnt5a agonist group， rats in the ZJJF group showed significant decrease in blood glucose， insulin and insulin resistance indices， prolongation of immobilisation time， reduction in the number of activities， and reduction in the Brdu integral optical density value； except for the Wnt5a mRNA in ZJJF group， Wnt5a， RhoA， ROCK1 protein and mRNA expression reduced in both ZJJF group and ZJJF

plus Wnt5a inhibitor group （

＜0.05 or

＜0.01）. Compared with ZJJF

group， Wnt5a， RhoA， ROCK1 protein and mRNA expression were reduced in ZJJF plus Wnt5a inhibitor group （

＜0.05 or

＜0.01）.

Conclusion

ZJJF can improve hyperglycemia and depressive-like behaviours in rat models of diabetes with depression， and its antidepressant effects may be related to the activation of hippocampal Wnt5a/RhoA signaling and promotion of dentate gyrus neuron dendritic growth.

关键词

Keywords

references

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Effects of Zuogui Jiangtang Jieyu Formula （左归降糖解郁方） on Dendritic Spines of Hippocampal Dentate Gyrus and Wnt5a/RhoA Signaling Pathway in Diabetic with Depression Model Rats

DOI：10.13288/j.11-2166/r.2024.05.013

摘要

Abstract

关键词

Keywords

references