Xiaoyaosan Promotes Myelin Regeneration and Alleviates Depressive Symptoms in Vascular Dementia Mice with Depression via Promoting Microglia Polarization

Nan SHAN; Zi-hu TAN; Bing YANG; Zheng-ling MA; Xi-xi YIN

doi:10.13422/j.cnki.syfjx.20211803

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Xiaoyaosan Promotes Myelin Regeneration and Alleviates Depressive Symptoms in Vascular Dementia Mice with Depression via Promoting Microglia Polarization

更新时间：2021-09-07

- Xiaoyaosan Promotes Myelin Regeneration and Alleviates Depressive Symptoms in Vascular Dementia Mice with Depression via Promoting Microglia Polarization
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 27, Issue 19, Pages: 19-27(2021)
- 作者机构：
  
  1.湖北中医药大学，武汉 430065
  2.湖北省中医院，武汉 430061
  3.湖北省第三人民医院，武汉 430033
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20211803
  CLC： R2-0;R22;R285.5;R289;R33
- Received：27 April 2021，
  
  Published Online：29 July 2021，
  
  Published：05 October 2021
- 稿件说明：
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单楠,谭子虎,杨冰等.逍遥散促进小胶质细胞极化改善血管性痴呆伴抑郁小鼠髓鞘再生及抑郁表型[J].中国实验方剂学杂志,2021,27(19):19-27.

SHAN Nan,TAN Zi-hu,YANG Bing,et al.Xiaoyaosan Promotes Myelin Regeneration and Alleviates Depressive Symptoms in Vascular Dementia Mice with Depression via Promoting Microglia Polarization[J].Chinese Journal of Experimental Traditional Medical Formulae,2021,27(19):19-27.
单楠,谭子虎,杨冰等.逍遥散促进小胶质细胞极化改善血管性痴呆伴抑郁小鼠髓鞘再生及抑郁表型[J].中国实验方剂学杂志,2021,27(19):19-27. DOI： 10.13422/j.cnki.syfjx.20211803.

SHAN Nan,TAN Zi-hu,YANG Bing,et al.Xiaoyaosan Promotes Myelin Regeneration and Alleviates Depressive Symptoms in Vascular Dementia Mice with Depression via Promoting Microglia Polarization[J].Chinese Journal of Experimental Traditional Medical Formulae,2021,27(19):19-27. DOI： 10.13422/j.cnki.syfjx.20211803.

摘要

目的

探讨逍遥散对血管性痴呆（VaD）小鼠抑郁行为表型的作用及可能机制。

方法

3月龄雄性C57/BL6小鼠60只，分为正常组、模型组、氟西汀组及逍遥散低、中、高剂量组。除正常组外，其余5组小鼠采用双侧颈总动脉狭窄术，术后2周开始给予慢性束缚应激，每天6 h，构建VaD伴抑郁小鼠模型；逍遥散低、中、高组予逍遥散水煎剂（5，10，20 g·kg

-1

）灌胃，氟西汀组给予氟西汀（10 mg·kg

-1

）灌胃，正常组、模型组给予等体积生理盐水灌胃，共计4周，给药期间给予束缚应激维持；糖水偏好试验、悬尾试验检测小鼠抑郁行为表型，免疫荧光法检测小鼠腹侧海马（vHIP）髓鞘碱性蛋白（MBP）荧光表达水平；透射电镜观察小鼠vHIP髓鞘超微结构；蛋白免疫印迹法（Western blot）检测MBP，少突胶质细胞糖蛋白（MOG），髓鞘相关醣蛋白（MAG），髓样细胞触发性受体-2（TREM2），诱导型一氧化氮合酶（iNOS），精氨酸酶1（Arg1），白细胞介素-1

（IL-1

），肿瘤坏死因子-

（TNF-

），白细胞介素-4（IL-4），白细胞介素-10（IL-10）蛋白表达水平。

结果

行为学检测结果显示：与正常组比较，模型组小鼠不动时间增加、糖水偏好百分比下降（

0.01）；与模型组比较，给予逍遥散干预后小鼠不动时间缩短（

0.05），糖水偏好百分比增加（

0.01）；Western blot结果显示：与正常组比较，模型组小鼠vHIP中髓鞘相关蛋白（MBP，MOG，MAG）表达下降（

0.01）；与模型组比较，低剂量组小鼠vHIP中MBP，MOG，MAG蛋白表达增加（P

0.05，

0.01），iNOS蛋白表达降低（

0.01），中、高剂量组MBP，MOG，MAG，TREM2，Arg1，IL-4，IL-10蛋白表达均增加（

0.05，

0.01），iNOS，IL-1

，TNF-

蛋白表达水平降低（

0.01）；免疫荧光结果显示：与正常组比较，模型组小鼠MBP平均荧光强度降低（

0.01），低、中、高剂量组MBP平均荧光强度不同程度增加（

0.01）；透射电镜结果显示：模型组髓鞘结构松解，致密层分离，排列紊乱，给予逍遥散干预改善小鼠髓鞘结构完整性及板层结构松散度。

结论

逍遥散改善VaD小鼠的抑郁表型，其机制可能是通过上调TREM2诱导小胶质细胞M2型极化，增加其抗炎及吞噬能力，促进受损髓鞘再生。

Abstract

Objective

To investigate the effect of Xiaoyaosan on depressive behavioral phenotype in mice with vascular dementia （VaD） mice and its possible mechanism.

Method

Sixty three-month-old male C57/BL6 mice were divided into the normal control group， model group， positive control group， as well as low-， medium-， and high-dose Xiaoyaosan groups. Mice in all groups except for the normal control group underwent bilateral carotid artery stenosis. Two weeks later， they were subjected to chronic restraint stress， 6 h per day， for inducing VaD complicated with depression. Mice in the low-， medium-， and high-dose Xiaoyaosan groups were treatment with intragastric administration of Xiaoyaosan decoction （5， 10， 20 g·kg

-1

）， the ones in the positive control group with fluoxetine （10 mg·kg

-1

）， and those in the normal control group and model group with an equal volume of normal saline for four weeks， during which the restraint stress was maintained. The depressive behavioral phenotype of mice was observed in sugar water preference test and tail suspension test. The fluorescence expression of myelin basic protein （MBP） in ventral hippocampus （vHIP） was detected by fluorescence immunoassay. The ultrastructure of myelin sheath in vHIP was observed by transmission electron microscopy. The protein expression levels of MBP， myelin oligodendrocyte glycoprotein （MOG）， myelin-associated glycoprotein （MAG）， triggering receptor expressed on myeloid cells-2 （TREM2）， inducible nitric oxide synthase （iNOS）， arginase 1 （Arg1）， interleukin-I

（IL-1

）， tumor necrosis factor-

（TNF-

）， interleukin-4 （IL-4）， and interleukin-10 （IL-10） were assayed by Western blot.

Result

As revealed by behavioral test， compared with the normal control group， the model group exhibited prolonged immobility time and decreased percentage of sugar water preference （

0.01）. Compared with the model group， Xiaoyaosan significantly shortened the immobility time of mice （

0.05） and increased the percentage of sugar water preference （

0.01）. Western blot results showed that the protein expression levels of MBP， MOG， and MAG in vHIP of the model group were remarkably decreased as compared with those of the normal control group （

0.01）. The protein expression levels of MBP， MOG， and MAG in vHIP of the low-dose Xiaoyaosan group were increased in contrast to those in the model group （

0.05，

0.01）， while the protein expression of iNOS was decreased （

0.01）. The protein expression levels of MBP， MOG， MAG， TREM2， Arg1， IL-4， and IL-10 in the medium- and high-dose Xiaoyaosan groups were up-regulated （

0.05，

0.01）， whereas those of iNOS， IL-1

， and TNF-

were down-regulated （

0.01）. The immunofluorescence findings demonstrated that the mean fluorescence intensity of MBP in the model group declined in comparison with that in the normal control group （

0.01）， while the mean fluorescence intensities of MBP in the low-， medium-， and high-dose Xiaoyaosan groups were enhanced to different degrees （

0.01）. It was observed under the transmission electron microscope that the myelin structure of the model group was loosened and the dense layer was separated and irregularly arranged. Xiaoyaosan improved the structural integrity of myelin sheath and the looseness of lamellar structure.

Conclusion

Xiaoyaosan ameliorates the depressive behavioral phenotype of VaD mice， which may be related to the up-regulation of TREM2， the induction of M2 polarization of microglia cells， the enhancement of their anti-inflammatory and phagocytic abilities， and the promotion of damaged myelin sheath regeneration.

关键词

Keywords

references

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