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Resveratrol exerts a protective effect in chronic unpredictable mild stress–induced depressive-like behavior: involvement of the AKT/GSK3β signaling pathway in hippocampus

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Abstract

Background

Chronic unpredictable mild stress (CUMS) is an important contributing factor for depression with inflammatory response alteration, neuron apoptosis, and decreased neurogenesis. Previous study reported that the administration of resveratrol alleviated depression by normalizing the increased proinflammatory cytokine levels and inhibiting apoptosis in the hippocampus. However, the upstream signaling pathway that regulates cytokines and apoptosis in the antidepressant effect of resveratrol remains unclear.

Objective

The objective of this study is to investigate the possible mechanism of the effect of resveratrol on depression.

Methods

Male Sprague Dawley rats were exposed to CUMS for four consecutive weeks to elicit depressive-like behavior. The rats in the drug treatment groups were injected with resveratrol (40 or 80 mg/kg/day) and fluoxetine (10 mg/kg/day) intraperitoneally for 4 weeks. Rats in two additional groups were administered LY294002 by bilateral stereotaxic microinjection into the lateral ventricle before resveratrol administration. Behavioral tests, including sucrose preference test, forced swim test, and open field test, were used after 4 weeks of a CUMS procedure to appraise depressive-like behavior. Then, the proinflammatory cytokines (TNF-α, IL-6, and IL-1β) in the hippocampus and prefrontal cortex (PFC) tissues of rats were measured. Apoptosis-related molecules such as Bax and Bcl-2 mRNA levels in the hippocampus were analyzed. Furthermore, p-Akt/Akt and p-GSK3β/GSK3β protein expression in the hippocampus were also measured.

Results

The results show that rats were subjected to CUMS procedure exhibited depressive-like behavior, increased TNF-α, IL-6, and IL-1β levels in hippocampus and PFC, alteration of Bax and Bcl-2 mRNA levels in hippocampus, decreased p-Akt/Akt and p-GSK3β/GSK3β protein expression in hippocampus, and an increased apoptotic cell percentage in the hippocampal CA1 region. However, resveratrol (40 or 80 mg/kg) treatment reversed these behavioral and molecular changes in CUMS rats. The positive control drug fluoxetine showed a similar effect as the resveratrol treatment. When rats were injected with LY294002 before resveratrol treatment, the antidepressant effect of resveratrol was significantly attenuated, TNF-α, IL-6 and IL-1β levels in hippocampus and PFC increased again, Bax mRNA levels increased and Bcl-2 mRNA levels decreased in hippocampus, and Akt/GSK3β protein expression in hippocampus decreased.

Conclusions

The findings in the present study suggest that the antidepressant effect of resveratrol treatment may act through activation of the Akt/GSK3β signaling pathway and then regulation of proinflammatory cytokine expression and alteration of apoptosis.

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Funding

The study was financially supported by the National Natural Science Foundation of China (No.81371196).

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Authors and Affiliations

  1. Department of Neurology, Zhongnan Hospital, Wuhan University, No.169, Donghu Road, Wuhan, 430071, Hubei, China

    Jun Shen, Chujie Qu, Linling Xu, Huimin Sun & Junjian Zhang

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  1. Jun Shen
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  2. Chujie Qu
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  3. Linling Xu
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  4. Huimin Sun
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  5. Junjian Zhang
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Corresponding author

Correspondence to Junjian Zhang.

Ethics declarations

All experiments were performed according to the NIH guidelines and approved by the Animal Ethics Committee of the Medical Department of Wuhan University.

Conflict of interest

The authors declare that they have no conflict of interest.

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Shen, J., Qu, C., Xu, L. et al. Resveratrol exerts a protective effect in chronic unpredictable mild stress–induced depressive-like behavior: involvement of the AKT/GSK3β signaling pathway in hippocampus. Psychopharmacology 236, 591–602 (2019). https://doi.org/10.1007/s00213-018-5087-1

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  • DOI: https://doi.org/10.1007/s00213-018-5087-1

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