Resveratrol Exerts Antidepressant Properties In The Chronic Unpredictable Mild Stress Model Through The Regulation Of Oxidative Stress And MTOR Pathway In The Rat Hippocampus And Prefrontal

Background:As one of the top ten mental diseases in modern world,depression has an increasingly negative effect on people’s psychological health and normal lives.Moreover,there are some clinical performances,such as the disorder of neuronal system,altered weight,locomotor activity deficit and sleeping.Because of the growing competition level in the society,citizens face more physical and mental pressure and then they suffer from depression more easily.Therefore,it is significant for us to find the mechanism of depression and the method on how to reverse these disorders.Resveratrol is a phenolic compound enriched in Polygonum cuspidatum and also found abundantly in the skin of red wine and red grapes and then it has been reported that resveratrol is capable to cross the blood-brain barrier.Moreover,Numerous studies have demonstrated that resveratrol exerts a variety of bioactivities such as anti-inflammatory,antioxidant,anticancer and antiapoptotic,including signal pathways,mechanisms.There is also accumulating evidence showing that the antidepressant-like effects of resveratrol was mediated by the regulation of the central serotonin and noradrenaline levels and the related monoamine oxidase-A activities,as well as the activation of hippocampal brain-derived neurotrophic factor(BDNF).Resveratrol also showed the antidepressant-like effects in CUMS-induced depression model involving the regulation of serum corticosterone levels,up-regulating BDNF levels in the hippocampus and amygdala in rats.The hippocampus plays an important role in learning and memory and involves regulation of the hypothalamic-pituitary-adrenal axis,both of which are altered in depression.Moreover,the hippocampus has connections with the PFC and amygdala,which are more directly involved in emotion and cognition and thereby contribute to major symptoms of depression.However,the effects and mechanisms of resveratrol on hippocampus and PFC are not known.In the present study,we used CUMS as an animal model for depression to explore and the mechanisms underlying the antidepressant-like action of resveratrol by measuring oxidative stress parameters and phosphorylation of Akt/mTOR in the hippocampus and PFC.Objective:By the establishment of CUMS model,we can find the rats featured by depression through the behavioral test and figure out how resveratrol reverse the disordered behaviors.Moreover,we can know the change of imbalance between the productions of reactive oxygen species and explore the underlying mechanisms of the phosphorylation of Akt/mTOR in the CUMS model.Methods:Animals(180-200g)were randomly allocated to one of the following five groups:(1)control,(2)Resveratrol(80 mg/kg),(3)CUMS,(4)CUMS + Resveratrol(80 mg/kg),(5)CUMS + Ketamine(20 mg/kg).Expect the control group and resveratrol group,the other three groups should be treated by a variety of mild stressors.Resveratrol and PBS were administered once a day for 4 consecutive weeks.After 4 weeks,sucrose preference test,forced swim test and open field test were submitted.However,at the day after the last stressor was given,a single dose of ketamine was administrated 60 min before being behavior test as previously described.The malondialdehyde content,a quantitative measurement of lipid peroxidation,was measured using a commercial assay kit and the total superoxide dismutase was analyzed using a commercial assay kit by xanthinoxidase method.Western blot analysised the phospho-Akt/mTOR.Results:(1)A 4-week CUMS exposure significantly reduced the percentage of sucrose consumption,increased the immobility time in the FST in the stressed rats in comparison with the control.However,long-term treatment with resveratrol increased the sucrose preference and reduced the immobility time as compared to the CUMS-exposed rats animal.The CUMS rats showed significantly decreased activity in crossing and grooming,but not rearing in comparison to the control rats in OFT.Treatment with resveratrol significantly reversed the above mentioned behavioral alterations as compared to the CUMS group.(2)CUMS exposure significantly increased MDA levels in the hippocampus and PFC as compared to control rats.Resveratrol treatment caused a significant decrease in the MDA levels in hippocampus and PFC when compared to the CUMS group.(3)Between-groups comparisons showed SOD activity was significantly decreased in CUMS group as compared to control group in the hippocampus and PFC.Resveratrol treatment significantly improved the SOD activity in stressed mice brain as compared to stress vehicle treated group in the hippocampus and PFC.(4)In rats challenged with stress,phosphorylation levels of Akt/mTOR were markedly decreased in the hippocampus and PFC.Pre-treatment with resveratrol markedly reversed CUMS-reduced phosphorylation levels of Akt/mTOR in the hippocampus and PFC.Conclusion:The present study indicates that resveratrol have an important role in reversing the disordered behaviors,including reduced sucrose intake,locomotor activity deficit and increased immobility time.Resveratrol exhibited antidepressant-like properties in CUMS-induced depression model in rats.The action of resveratrol was mediated in part by its antioxidant mechanism,up-regulating phospho-Akt and phospho-mTOR levels in the hippocampus and PFC.