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Geniposide ameliorates chronic unpredictable mild stress induced depression-like behavior through inhibition of ceramide-PP2A signaling via the PI3K/Akt/GSK3β axis

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Abstract

Background

Depression is a severe mental disorder. Unfortunately, more than half of patients with major depression disorder cannot achieve remission after initial treatment with an antidepressant. Geniposide, a bioactive iridoid glycoside isolated from Gardenia jasminoides Ellis, can ameliorate depressive-like behaviors in mice. However, the underlying mechanism is still not very clear.

Methods

The pharmacological methods including ELISA, immunofluorescence, and Western blot were used to investigate the role of geniposide on chronic unpredictable mild stress (CUMS)-induced depression mice.

Results

In this study, we found that geniposide could inhibit CUMS-induced depressive-like behaviors in mice. Geniposide is able to reduce the levels of ceramide and lower the activity of acid sphingomyelinase (ASM) in hippocampus; besides, ASM inhibitor (amitriptyline) can decrease the concentration of ceramide and ameliorate depressive-like behaviors of mice. Moreover, geniposide can also alleviate CUMS-induced hippocampal neuronal apoptosis and increase the phosphorylated form of PI3K, Akt, and GSK3β. Additionally, PI3K inhibitor (LY294002) can also abolish the neuroprotective effect of geniposide on hippocampal neurons in vitro.

Conclusions

These results indicate that geniposide exert a potential antidepressant-like effect on CUMS mice, and its effect might be associated with activated PI3K/Akt/GSK3β signaling, reduced the level of ceramide and hippocampal neuron apoptosis.

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Funding

This study was supported by Biomedical and Engineering cross youth fund of Shanghai Jiao Tong University (No. YG2021QN43).

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Author notes

  1. Meihua Wang, Lei Yang and Zhilin Chen are authors contributed equally to this work

Authors and Affiliations

  1. Department of Neurosurgery & Neurocritical Care, Huashan Hospital Affiliated To Fudan University, 958 Jinguang Road, Minhang District, Shanghai, 200040, China

    Meihua Wang, Lei Yang, Caihua Xi, Xing Wu, Gang Wu & Jin Hu

  2. Department of Neurology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China

    Meihua Wang

  3. Department of Neurology, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital Affiliated to Tongji University School of Medicine, Shanghai, 200081, China

    Zhilin Chen

  4. Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China

    Linlu Dai

  5. Department of Emergency, Xinhua Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China

    Yang Wang

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  1. Meihua Wang
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Wang, M., Yang, L., Chen, Z. et al. Geniposide ameliorates chronic unpredictable mild stress induced depression-like behavior through inhibition of ceramide-PP2A signaling via the PI3K/Akt/GSK3β axis. Psychopharmacology 238, 2789–2800 (2021). https://doi.org/10.1007/s00213-021-05895-8

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