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The protective effects of Mogroside V and its metabolite 11-oxo-mogrol of intestinal microbiota against MK801-induced neuronal damages

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Abstract

Rationale

Animal models, notably with non-competitive NMDA receptor antagonist MK801, are commonly used to investigate the mechanisms of schizophrenia and to pursue its mechanism-related drug discoveries.

Objectives

In the current study, we have extensively examined the protective effects of MogrosideV (MogV), a plant-derived three terpene glucoside known to exhibit anti-oxidative and anti-inflammatory activities.

Methods and Results

Here, we investigated its protective effects against neuronal damages elicited by MK-801 treatment. Our behavioral experimental results showed that MK-801-induced PPI deficits and social withdrawal were prevented by MogV treatment. Moreover, the cellular and neurochemical responses of MK-801 in medial prefrontal cortical cortex (mPFC) were also ameliorated by MogV treatment. Also, profiling metabolites assay through artificial intestinal microbiota was performed to identify bioactive components of MogV. An in vitro study of primary neuronal culture demonstrated that MogV and its metabolite 11-oxo-mogrol treatment prevented the MK-801-induced neuronal damages through the mechanisms of promoting neurite outgrowth, inhibiting cell apoptosis, and [Ca2+]i release. Additionally, 11-oxo-mogrol reversed inactivation of phosphorylation levels of AKT and mTOR induced by MK801.

Conclusions

These results suggest therapeutic potential of MogV for schizophrenia.

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Funding

This work was supported by the National Natural Science Foundation of China (grant numbers 81501153, 81571326), Feixiang Personnel Training Program of Shanghai Mental Health Center (grant number 2018-FX-02), Shanghai Sailing Project (grant number 17YF1416400) and Shanghai Key Laboratory of Psychotic Disorders (grant number 13dz2260500).

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Author notes

  1. Peijun Ju and Wenhua Ding equally contributed

Authors and Affiliations

  1. Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine; School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 201108, China

    Peijun Ju, Wenhua Ding, Jianhua Chen, Ying Cheng, Beibei Yang, Lanting Huang, Qiong Zhou, Cuizhen Zhu, **aobo Li, Mengyue Wang & **ghong Chen

  2. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Peijun Ju & **ghong Chen

  3. The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangdong, Guangzhou, China

    Wenhua Ding

  4. Anhui Mental Health Center, Hefei, Anhui Province, China

    Cuizhen Zhu

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  1. Peijun Ju
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  2. Wenhua Ding
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  3. Jianhua Chen
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  4. Ying Cheng
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  10. Mengyue Wang
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Contributions

Peijun Ju wrote the manuscript, analyzed data and performed the in vitro study part. Wenhua Ding, Beibei Yang and Ying Cheng carried out the behavioral tests. Chen Jianhua, Zhou Qiong and Cuizhen Zhu carried out the molecular studies. Lanting Huang and **aobo Li helped designing the experiments. **ghong Chen and Mengyue Wang designed and supervised the project and prepared the manuscript.

Corresponding authors

Correspondence to Mengyue Wang or **ghong Chen.

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ESM 1

Effects of MogV on gross histological change in control and MK801-treated mice, histological profiles were shown by HE staining (coronal sections). Scale bar: 500 μm. (TIF 957 kb) (PNG 184 kb)

ESM 2

Identification of metabolites from MogV after sequential metabolism by human intestinal bacteria (HIB). (TIF 384 kb) (PNG 112 kb)

ESM 3

Quantitative real-time RT-PCR analysis of CamK2αand Calbindin expression in primary neurons with distinct treatments (Control, MK801, MK801 + 0.1 μm 11-oxo-M, MK801 + 1 μm 11-oxo-M and MK801 + 10 μm 11-oxo-M), n = 3, *p < 0.05, **p < 0.01, ***p < 0.0001. (TIF 504 kb) (PNG 139 kb)

ESM 4

The effect of Olanzapine, Risperidone, Aripiprazole on the MK801-induced schizophrenia-like behaviors. (A) The effects of Olanzapine, Risperidone, Aripiprazole on the loss of sensorimotor gating functioning induced by MK801 in the acoustic startle response task. The percent of prepulse inhibition during 90 trials were recorded to compare in the normal naïve mice, Olanzapine, Risperidone, Aripiprazole-treated, MK801-treated, and MK801 + Olanzapine, Risperidone, Aripiprazoletreated group. At 79 dB, 85 dB, *p < 0.05 between MK801-treated and MK801 + Aripiprazole. (B) The comparison of NOR discrimination index in the normal naïve mice, Olanzapine, Risperidone, Aripiprazole-treated, MK801-treated, and MK801+ Olanzapine, Risperidone, Aripiprazole-treated mice respectively. *p < 0.05 between MK801-treated and MK801 + Aripiprazole. (C, D) Social behaviors of mice were compared in the normal naïve mice, Olanzapine, Risperidone, Aripiprazole-treated, MK801-treated, and MK801+ Olanzapine, Risperidone, Aripiprazole-treated mice respectively.In the three-chamber social interaction test, MK801+ Olanzapine, Risperidone, Aripiprazole-treated mice spent no significantly more time in mouse chamber and in sniffing mouse than that in object chamber (p > 0.05). MK801+ Olanzapine, Risperidone, Aripiprazole could not restore those social deficits induced by MK801 treatment. (E) Elevated plus maze were performed in the normal naïve mice, Olanzapine, Risperidone, Aripiprazole-treated, MK801-treated, and MK801+ Olanzapine, Risperidone, Aripiprazole-treated mice. The percentage of time in open arms were quantified. No significant differences were observed in MK801-treated and MK801+ Olanzapine, Risperidone, Aripiprazole groups. (F) Immobility in the normal naïve mice, Olanzapine, Risperidone, Aripiprazole-treated, MK801-treated, and MK801+ Olanzapine, Risperidone, Aripiprazole-treated mice was monitored for 5 min. *p < 0.05 between MK801-treated and MK801 + Aripiprazole. (TIF 6426 kb) (PNG 1457 kb)

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Ju, P., Ding, W., Chen, J. et al. The protective effects of Mogroside V and its metabolite 11-oxo-mogrol of intestinal microbiota against MK801-induced neuronal damages. Psychopharmacology 237, 1011–1026 (2020). https://doi.org/10.1007/s00213-019-05431-9

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