Antidepressant Effects Of Fisetin And The Mechanism Of Antidepressant In Treating Stressed-Ahi1 Mice

Currently depression is the most common psychiatric syndrome affecting over 350 million people worldwide.By 2020,depression will become the second leading cause of death.In addition,Depression has brought a heavy economic burden to the whole society,accounting for 10.3% of the total burden of the disease,mainly due to the high cost and side effects of antidepressants.At present the main reason for the limited treatment of depression is that the mechanism of depression is unknown.Although the researchers found that depression was associated with monoamines(5-hydroxytryptam,norepinephrine and dopamine),glutamate receptors,epigenetic modifications,hypothalamic-pituitary-adrenal(HPA)axis,inflammatory cytokines,and neurotrophic factors.These factors participate in the occurrence of the mechanism but lack of convincing evidence.The current treatment of depression is based on the hypothesis of the monoamine neurotransmitter imbalance and developed a series of antidepressants.Therefore,a series of antidepressants such as tricyclic antidepressants and selective serotonin reuptake inhibitors(SSRIs)have been developed.However,these antidepressants have substantial side effects.Therefore,it is great social significance to develop new effective antidepressants.In the first part,we studied the antidepressant mechanism of fisetin.Fisetin was found in fruits and vegetables and belongs to the class of flavonoids.It has been reported that it has antioxidative,anti-inflammatory and neuroprotective effects.Because of the above characteristics,fisetin has been considered as an effective drug for treating neurological diseases such as stroke,Huntington’s disease and Alzheimer’s disease.In theory,the anti-inflammatory properties of fisetin can inhibit chronic low-level inflammatory symptoms in depressive patients.Therefore,we are curious about the antidepressant effect of fisetin and its mechanism of action.Therefore,we experimented with two different models of depression to study the antidepressant effect of fisetin.In this article,we performed the model of spatial restraint stress in ICR mice and then treated them with fisetin.In the classic depression behavior test(tail suspension test and forced swimming test),we found that the immobility time will be reduced,indicating that it has a certain degree of antidepressant effect.At the same time,we injected the fisetin into a mouse model of depression in our laboratory(Ahi1 KO mice),which also slowed down its depressive behavior.Our groups has reported that Ahi1 KO mice have depressive behavior and can be considered as a very effective depressive model for exploring antidepressants.Since the TrkB signaling pathway is a classical and important signaling pathway in depression.Therefore,we examined the phosphorylation level of TrkB after administration and found that it increased and the total amount of TrkB remained unchanged.In our article,by administering an inhibitor of TrkB(K252a),we found that the depressive phenotype was not alleviated and that the phosphorylation level of TrkB did not increase.These results suggest that fisetin are antidepressant by activating the TrkB signaling pathway and have the potential to be effective drugs for the treatment of depression.The second part of the study is about the mechanism of of antidepressant in treating stressed-Ahi1 mice.In our research,we conducted spatial restraint stress in Ahi1 mice to simulate major depressive disorder,and study how antidepressants function through Ahi1 protein.In this paper,we confirmed that antidepressants are not sensitive to stressed-Ahi1 KO mice,and Ahi1 may be involved in the course of antidepressant treatment.First,we performed a spatial restraint stress for two weeks in Ahi1 mice.Behavioral tests showed that both Ahi1 Het and Ahi1 KO mice showed increased levels of depression,but Ahi1 KO mice had a smaller increase in the ratio.After three weeks of fluoxetine treatment,we observed that Ahi1 KO mice are insensitive to antidepressants.In addition we detected increased levels of Ahi1 protein and Hap1 protein in fluoxetine-treated Ahi1 Het mice by western blot,suggesting that Ahi1 may be involved in the antidepressant drug treatment process.Finally,we continued to investigate the mechanism of Ahi1 participation in antidepressant treatment.The results showed that the number of hippocampal neurons in stressed-Ahi1 Het and stressed-ICR mice treated with fluoxetine increased.It was reported that Cend1 protein can regulate the expression of hippocampal neurons in mice and find that Ahi1 protein interacts with Cend1 protein.We found that the decreased expression of Cend1 in the nucleus of Ahi1 KO mice suggests that Ahi1 plays an antidepressant role by regulating the expression of Cend1.These results suggest that Ahi1 could server as a biomarker in evaluating the efficiency of antidepressants,and also provides a new idea for the development of antidepressants.