Liuwei Dihuangtang Alleviates Myelin Injury in vHIP and Depression-like Behavior of Diabetes Mellitus Combined with Comorbid Depression Rats via AMPK/Akt/GSK3<italic style="font-style: italic">β</italic>/Nrf2 Pathway

Fang HUANG; Zi-hu TAN; Nan SHAN; Wen-jing YAN

doi:10.13422/j.cnki.syfjx.20212402

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Liuwei Dihuangtang Alleviates Myelin Injury in vHIP and Depression-like Behavior of Diabetes Mellitus Combined with Comorbid Depression Rats via AMPK/Akt/GSK3β/Nrf2 Pathway

更新时间：2021-12-14

- Liuwei Dihuangtang Alleviates Myelin Injury in vHIP and Depression-like Behavior of Diabetes Mellitus Combined with Comorbid Depression Rats via AMPK/Akt/GSK3β/Nrf2 Pathway
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 28, Issue 2, Pages: 38-46(2022)
- 作者机构：
  
  1.湖北中医药大学，武汉 430065
  2.华中科技大学同济医学院附属武汉中心医院，武汉 430014
  3.湖北省中医院，武汉 430061
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20212402
  CLC： R2-0;R22;R285.5;R289;R33
- Published：20 January 2022，
  
  Published Online：25 October 2021，
  
  Received：05 August 2021，
- 稿件说明：
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黄芳,谭子虎,单楠等.六味地黄汤通过调节AMPK/Akt/GSK3β/Nrf2通路减轻糖尿病抑郁大鼠vHIP髓鞘损伤及抑郁样行为[J].中国实验方剂学杂志,2022,28(02):38-46.

HUANG Fang,TAN Zi-hu,SHAN Nan,et al.Liuwei Dihuangtang Alleviates Myelin Injury in vHIP and Depression-like Behavior of Diabetes Mellitus Combined with Comorbid Depression Rats via AMPK/Akt/GSK3β/Nrf2 Pathway[J].Chinese Journal of Experimental Traditional Medical Formulae,2022,28(02):38-46.
黄芳,谭子虎,单楠等.六味地黄汤通过调节AMPK/Akt/GSK3β/Nrf2通路减轻糖尿病抑郁大鼠vHIP髓鞘损伤及抑郁样行为[J].中国实验方剂学杂志,2022,28(02):38-46. DOI： 10.13422/j.cnki.syfjx.20212402.

HUANG Fang,TAN Zi-hu,SHAN Nan,et al.Liuwei Dihuangtang Alleviates Myelin Injury in vHIP and Depression-like Behavior of Diabetes Mellitus Combined with Comorbid Depression Rats via AMPK/Akt/GSK3β/Nrf2 Pathway[J].Chinese Journal of Experimental Traditional Medical Formulae,2022,28(02):38-46. DOI： 10.13422/j.cnki.syfjx.20212402.

摘要

目的

观察六味地黄汤对糖尿病抑郁（DD）大鼠抑郁样行为的影响，并探讨其作用机制。

方法

50只SPF级雄性SD大鼠采用高脂饮食喂养加尾静脉注射小剂量链脲佐菌素（STZ）的方法制备糖尿病模型，随后糖尿病大鼠予28 d慢性不可预测的轻度应激（CUMS）的方法建立DD模型。随机分为5组，模型组，氟西汀组（10 mg·kg

-1

·d

-1

），六味地黄汤低、中、高剂量组（3.375，6.75，13.5 g·kg

-1

·d

-1

），每组10只。另取正常组10只，生理盐水灌胃。连续灌胃4周后，悬尾实验和旷场实验用于评估大鼠的抑郁表型，酶联免疫吸附测定法（ELISA）检测腹侧海马（vHIP）中丙二醛（MDA），活性氧（ROS），8-羟基脱氧鸟苷（8-OHdG），超氧化物歧化酶（SOD），谷胱甘肽（GSH）；采用免疫荧光检测vHIP区域髓鞘碱性蛋白（MBP）表达，蛋白免疫印迹法检测MBP，髓鞘脂蛋白（PLP），髓鞘少突胶质细胞糖蛋白（MOG）表达水平及通路蛋白磷酸化腺苷酸活化蛋白激酶/腺苷酸活化蛋白激酶（p-AMPK/AMPK），磷酸化蛋白激酶B/蛋白激酶B（p-Akt/Akt），磷酸化糖原合成酶激酶3

/糖原合成酶激酶3

（p-GSK3

/GSK3

），核因子E

Abstract

Objective

To observe the effect of Liuwei Dihuangtang on depression-like behavior of diabetes mellitus combined with comorbid depression （DD） rats， so as to explore its action mechanism.

Method

Fifty male SD rats of SPF grade were fed with high fat diet and injected with low-dose streptozotocin （STZ） via tail vein for inducing diabetes. Afterwards， the diabetic rats were exposed to chronic unpredictable mild stress （CUMS） for 28 d. The successfully modeled DD rats were randomly divided into five groups： model group， fluoxetine （10 mg·kg

-1

·d

-1

） group， and low-， medium-， and high-dose （3.375， 6.75， 13.5 g·kg

-1

·d

-1

） Liuwei Dihuangtang groups， with 10 in each group. Another 10 rats were classified into the normal control group and treated with intragastric administration of normal saline for four weeks. The tail suspension test and open field test were conducted to evaluate the depressive-like phenotype of rats. The contents of malondialdehyde （MDA）， reactive oxygen species （ROS）， 8-hydroxy-2 deoxyguanosine （8-OHdG）， superoxide dismutase （SOD）， and glutathione （GSH） in ventral hippocampus （vHIP） were measured by enzyme-linked immunosorbent assay （ELISA）， and the myelin basic protein （MBP） expression in vHIP by immunofluorescence assay. The expression levels of MBP， myelin protein lipoprotein （PLP）， myelin oligodendrocyte glycoprotein （MOG）， phosphorylated adenosine 5'-monophosphate-activated protein kinase （p-AMPK）/AMPK， phosphorylated protein kinase B （p-Akt）/Akt， phosphorylated glycogen synthase kinase 3

（p-GSK3

）/GSK3

， and nuclear factor erythroid-2 related factor 2（Nrf2） were determined by Western blotting.

Result

Compared with the normal control group， the model group exhibited significantly prolonged immobility in the tail suspension test （

0.01） and shortened residence at the central area in the open field test （

0.01）. The immobility time in the medium- and high-dose Liuwei Dihuangtang groups declined to different degrees as compared with that of the model group （

0.01）， while the residence time at the central area was significantly increased （

0.05，

0.01）. Compared with the normal control group， the model group displayed down-regulated MBP， PLP， and MOG protein expression in vHIP （

0.01）. Compared with the model group， Liuwei Dihuangtang at the low dose up-regulated the expression of MBP （

0.05）， but did not obviously affect the expression of MOG and PLP. Fluoxetine and Liuwei Dihuangtang at the medium and high doses up-regulated the expression of MBP， PLP， and MOG （

0.05，

0.01）. Comparison with the normal control group revealed that the MBP fluorescence intensity in vHIP of the model group was significantly weakened （

0.01）. After the intervention， the MBP fluorescence intensities in the medium- and high-dose Liuwei Dihuangtang groups and fluoxetine group were enhanced in contrast to that of the model group （

0.05，

0.01）. SOD and GSH in the model group were lower than those in the normal control group （

0.01）， whereas the MDA， ROS， and 8-OHdG expression levels were higher （

0.01）. Compared with the model group， Liuwei Dihuangtang at the medium and high doses and fluoxetine all down-regulated the expression levels of MDA， ROS， and 8-OHdG （

0.05，

0.01）， while up-regulated SOD and GSH expression （

0.05，

0.01）. The expression levels of p-AMPK， p-Akt， and Nrf2 in the model group were down-regulated as compared with those in the control group， and the expression of p-GSK3

was up-regulated （

0.01）. As demonstrated by comparison with the model group， the protein expression of p-AMPK in the low-dose Liuwei Dihuangtang group was elevated （

0.05）， while p-Akt and Nrf2 were slightly increased， exhibiting no statistical significant difference. However， the protein expression levels of p-AMPK， p-Akt， and Nrf2 in the medium- and high-dose Liuwei Dihuangtang groups and fluoxetine group were up-regulated， while those of p-GSK3

were down-regulated （

0.05

，P

0.01）.

Conclusion

Liuwei Dihuangtang improves the depressive-like behavior of DD rats， which may be related to its activation of the AMPK/Akt/GSK3

/NRF2 pathway， regulation of the oxidative stress in vHIP， and enhancement of myelin repair.

关键词

糖尿病抑郁髓鞘氧化应激六味地黄汤

Keywords

diabetesdepressionmyelin sheathoxidative stressLiuwei Dihuangtang

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Liuwei Dihuangtang Alleviates Myelin Injury in vHIP and Depression-like Behavior of Diabetes Mellitus Combined with Comorbid Depression Rats via AMPK/Akt/GSK3β/Nrf2 Pathway

DOI：10.13422/j.cnki.syfjx.20212402

摘要

Abstract

关键词

Keywords

references