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

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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 P<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 (P<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 P<0.01), which were also prevented by [D-Lys3]-GHRP-6 (P<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.

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Authors and Affiliations

  1. Institute of Traditional Chinese Medicine-Related Comorbid Depression, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Ya-lin Liu, Jian-jun Xu, Xiang-fei Liu, Mu-hai Lin, Yun Wang, Zhe Xiao & Xi Huang

  2. School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, China

    Ya-lin Liu

  3. Department of Outpatient, Xuzhou Central Hospital, Xuzhou, Shangdong Province, 221000, China

    Lin-ran Han

  4. Department of Obstetrics and Gynecology, Women’s Hospital School of Medicine, Zhejiang University, Hangzhou, 310006, China

    Yun-ke Huang

  5. Department of Geriatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Ping Ren

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  1. Ya-lin Liu
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  2. Jian-jun Xu
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  3. Lin-ran Han
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  4. Xiang-fei Liu
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  7. Zhe Xiao
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  8. Yun-ke Huang
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  9. Ping Ren
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  10. Xi Huang
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Contributions

Huang X and Ren P designed the experiments, acquired funding, and supervised the project; Liu YL, Xu JJ, Han LR, and Liu XF performed the experiments; Xu JJ, Lin MH, Wang Y, Xiao Z, and Huang YK analyzed the data; Huang X and Xu JJ wrote and revised the manuscript.

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Correspondence to Xi Huang.

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Conflict of Interest

The authors declare that they have no conflict of interests to disclose.

Supported by National Natural Science Foundation of China (No. 81573797, 81973589, and 81072967), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine)

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Liu, Yl., Xu, Jj., Han, Lr. et al. Meranzin Hydrate Improves Depression-Like Behaviors and Hypomotility via Ghrelin and Neurocircuitry. Chin. J. Integr. Med. 29, 490–499 (2023). https://doi.org/10.1007/s11655-022-3308-2

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