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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.
Psychopharmacology (Berl). 2019 Feb; 236(2):591-602.P

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.

Authors+Show Affiliations

Department of Neurology, Zhongnan Hospital, Wuhan University, No.169, Donghu Road, Wuhan, 430071, Hubei, China.Department of Neurology, Zhongnan Hospital, Wuhan University, No.169, Donghu Road, Wuhan, 430071, Hubei, China.Department of Neurology, Zhongnan Hospital, Wuhan University, No.169, Donghu Road, Wuhan, 430071, Hubei, China.Department of Neurology, Zhongnan Hospital, Wuhan University, No.169, Donghu Road, Wuhan, 430071, Hubei, China.Department of Neurology, Zhongnan Hospital, Wuhan University, No.169, Donghu Road, Wuhan, 430071, Hubei, China. wdsjkx@163.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30374891

Citation

Shen, Jun, 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, vol. 236, no. 2, 2019, pp. 591-602.
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 (Berl). 2019;236(2):591-602.
Shen, J., Qu, C., Xu, L., Sun, H., & Zhang, J. (2019). 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(2), 591-602. https://doi.org/10.1007/s00213-018-5087-1
Shen J, 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 (Berl). 2019;236(2):591-602. PubMed PMID: 30374891.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Resveratrol exerts a protective effect in chronic unpredictable mild stress-induced depressive-like behavior: involvement of the AKT/GSK3β signaling pathway in hippocampus. AU - Shen,Jun, AU - Qu,Chujie, AU - Xu,Linling, AU - Sun,Huimin, AU - Zhang,Junjian, Y1 - 2018/10/29/ PY - 2017/12/12/received PY - 2018/10/18/accepted PY - 2018/10/31/pubmed PY - 2019/5/8/medline PY - 2018/10/31/entrez KW - Apoptosis KW - Chronic unpredictable mild stress KW - Proinflammatory cytokines KW - Resveratrol SP - 591 EP - 602 JF - Psychopharmacology JO - Psychopharmacology (Berl.) VL - 236 IS - 2 N2 - 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. SN - 1432-2072 UR - https://www.unboundmedicine.com/medline/citation/30374891/Resveratrol_exerts_a_protective_effect_in_chronic_unpredictable_mild_stress_induced_depressive_like_behavior:_involvement_of_the_AKT/GSK3β_signaling_pathway_in_hippocampus_ L2 - https://dx.doi.org/10.1007/s00213-018-5087-1 DB - PRIME DP - Unbound Medicine ER -