Meranzin Hydrate Improves Depression-Like Behaviors and Hypomotility via Ghrelin and Neurocircuitry

LIU Ya-lin; XU Jian-jun; HAN Lin-ran; LIU Xiang-fei; LIN Mu-hai; WANG Yun; XIAO Zhe; HUANG Yun-ke; REN Ping; HUANG Xi

doi:10.1007/s11655-022-3308-2

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Meranzin Hydrate Improves Depression-Like Behaviors and Hypomotility via Ghrelin and Neurocircuitry

Original Article | Updated：2023-05-25

- Meranzin Hydrate Improves Depression-Like Behaviors and Hypomotility via Ghrelin and Neurocircuitry
- Chinese Journal of Integrative Medicine Vol. 29, Issue 6, Pages: 490-499(2023)
- Affiliations：
  
  1.Institute of Traditional Chinese Medicine-Related Comorbid Depression, Nanjing University of Chinese Medicine, Nanjing(210023), China
  2.School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou (450046), China
  3.Department of Outpatient, Xuzhou Central Hospital, Xuzhou, Shangdong Province (221000), China
  4.Department of Obstetrics and Gynecology, Women's Hospital School of Medicine, Zhejiang University, Hangzhou (310006), China
  5.Department of Geriatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing (210023), China
- Author bio：
  
  Prof. HUANG Xi, E-mail: tcmhuangx59@163.com
- Funds：
- DOI：10.1007/s11655-022-3308-2
  CLC：
- Published：2023-06，
  
  Published Online：26 July 2022，
  
  Accepted：21 March 2021
Scan for full text
LIU Ya-lin, XU Jian-jun, HAN Lin-ran, et al. Meranzin Hydrate Improves Depression-Like Behaviors and Hypomotility via Ghrelin and Neurocircuitry. [J]. Chinese Journal of Integrative Medicine 29(6):490-499(2023)
DOI：

LIU Ya-lin, XU Jian-jun, HAN Lin-ran, et al. Meranzin Hydrate Improves Depression-Like Behaviors and Hypomotility via Ghrelin and Neurocircuitry. [J]. Chinese Journal of Integrative Medicine 29(6):490-499(2023) DOI： 10.1007/s11655-022-3308-2.

摘要

目的

研究柴胡疏肝散(CSP)及其吸收有效活性成分水合橙皮内酯(MH)的抗抑郁和促胃肠动力作用及其潜在的共享机制.

方法

通过随机数字表法将120只SD大鼠随机分为空白组、模型组、氟西汀组(20 mg/kg)、莫沙必利组(10 mg/kg)、CSP组(30 g/kg)、MH组(9.18 mg/kg)、拮抗剂[D-Lys3]-GHRP-6组(0.5 mg/kg)和(MH+[D-Lys3]-GHRP-6)组

每组8只. 将32只小鼠随机分为野生型组、MH(18 mg/kg)组、生长激素促泌素受体基因敲除组(GHSR-KO)、GHSR+MH组

每组8只. 采用强迫游泳实验(FST)、旷场实验(OFT)、悬尾实验(TST)、胃排空实验(GE)和肠推进实验(IT)在单次给药30分钟后评价SD大鼠和小鼠的抗抑郁和促胃肠动力(A&P)作用. 通过蛋白免疫印迹法(Western blot) 检测大鼠海马中脑源性神经营养因子(BDNF)和磷酸化雷帕霉素靶蛋白(p-mTOR)的表达情况. 采用7.0血氧水平依赖功能磁共振成像技术(fMRI-BOLD)

观察药物干预前后脑区变化.

结果

在急性强迫游泳应急大鼠中

MH灌胃治疗发挥了与母方CSP类似的抗抑郁(FST

OFT)和促胃肠动力(GE

IT)作用(

0.05); 拮抗剂[D-Lys3]-GHRP-6可抑制MH对FST和GE的调节作用(

0.05). 同样

MH灌胃治疗也缓解了野生型小鼠的抑郁样行为(FST、TST)

对GHSR-KO小鼠中MH无效. 此外

MH干预可显著增加急性应激大鼠海马BDNF及p-mTOR蛋白表达(

0.01)

其效果可被[D-Lys3]-GHRP-6抑制(

0.01). 急性应激大鼠脑区血氧水平变化主要与海马-丘脑-基底节(HTB)神经回路相关

[D-Lys3]-GHRP-6也同步抑制HTB脑区血氧水平表达

促胃肠动力药物莫沙必利仅对丘脑和基底节有作用

对海马无作用效果.

结论

MH可通过共享调节胃饥饿素和脑区BOLD信号表达

发挥类似于母方CSP的抗抑郁和促动力作用. 与急性应激、干预和共享调节三者密切相关的HTB神经回路突出了抗抑郁的统一理论.

Abstract

Objective:

To investigate whether meranzin hydrate (MH) can alleviate depression-like behavior and hypomotility similar to Chaihu Shugan Powder (CSP)

and further explore the potential common mechanisms.

Methods:

Totally 120 Spraque-Dawley rats were randomly divided into 5–8 groups including sham

vehicle

fluoxetine (20 mg/kg)

mosapride (10 mg/kg)

CSP (30 g/kg)

MH (9.18 mg/kg)

[D-Lys3]-GHRP-6 (Dlys

0.5 mg/kg)

and MH+Dlys groups by a random number table

8 rats in each group. And 32 mice were randomly divided into wild-type

MH (18 mg/kg)

growth hormone secretagogue receptor-knockout (GHSR-KO)

and GHSR+MH groups

8 mice in each group. The forced swimming test (FST)

open field test (OFT)

tail suspension test (TST)

gastric emptying (GE) test

and intestinal transit (IT) test were used to assess antidepressant and prokinetic (AP) effects after drug single administration for 30 min with absorbable identification in rats and mice

respectively. The protein expression levels of brain-derived neurotrophic factor (BDNF) and phosphorylated mammalian target of rapamycin (p-mTOR) in the hippocampus of rats were evaluated by Western blot. The differences in functional brain changes were determined via 7.0 T functional magnetic resonance imaging-blood oxygen level-dependent (fMRI-BOLD).

Results:

MH treatment improved depression-like behavior (FST

OFT) and hypomotility (GE

IT) in the acute forced swimming (FS) rats (all

0.05)

and the effects are similar to the parent formula CSP. The ghrelin antagonist [D-Lys3]-GHRP-6 inhibited the effect of MH on FST and GE (

0.05). Similarly

MH treatment also alleviated depression-like behavior (FST

TST) in the wild-type mice

however

no effects were found in the GHSR KO mice. Additionally

administration of MH significantly stimulated BDNF and p-mTOR protein expressions in the hippocampus (both

0.01)

which were also prevented by [D-Lys3]-GHRP-6 (

0.01). Besides

3 main BOLD foci following acute FS rats implicated activity in hippocampus–thalamus–basal ganglia (HTB) circuits. The [D-Lys3]-GHRP-6 synchronously inhibited BOLD HTB foci. As expected

prokinetic mosapride only had effects on the thalamus and basal ganglia

but not on the hippocampus. Within the HTB

the hippocampus is implicated in depression and FD.

Conclusions:

MH accounts for part of AP effects of parent formula CSP in acute FS rats

mainly via ghrelin-related shared regulation coupled to BOLD signals in brain areas. This novel functionally connection of HTB following acute stress

treatment

and regulation highlights anti-depression unified theory.

关键词

Keywords

Chinese medicineGan (Liver) governing free flow of qicomorbiditydepressionhypomotilityghrelinblood oxygen level-dependent

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Xiyuan Clinical Medical College, Beijing University of Chinese Medicine

Department of Encephalopathy, Xiyuan Hospital, China Academy of Chinese Medical Sciences

First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine

Institute of Clinical Pharmacology, Xiyuan Hospital, China Academy of Chinese Medical Sciences

Department of Encephalopathy, Botou Traditional Chinese Medicine Hospital of Hebei Province

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