Gastrodin Ameliorated Depression-like Behavior Of Mice Through JAK2-STAT3 Signaling Pathway

Objective:Depression is a kind of mental disorder,which is closely related to the abnormality of nervous system.Gastrodin is widely used in the treatment of nervous system diseases.To explore the antidepressant efficacy of gastrodin,the chronic unpredictable mild stress(CUMS)depression model of mice was constructed,gastrodin was administered to observe the effects of gastrodin on depression-like behavior mice model,and detect the expressions of key factors of JAK2-STAT3 signaling pathway to explore the antidepressant efficacy of gastrodin and the relation with the JAK2-STAT3 signaling pathway.Methods:In this study,forty Kunming mice were divided into control group and experimental groups.After 1 week of adaptive feeding,the mice in the experimental group went through chronic unpredictable mild stress(CUMS)stimulation for four weeks,and the mice in the control group were not treated;After 4 weeks,the mice in experimental and control group were tested for behavioral tests and weight changes.Behavioral experiments included tail suspension test(TST),forced swimming test(FST),sucrose preference test(SPT)and open field test(OFT).Then the model group was divided into three subgroups:CUMS+saline group,CUMS+fluoxetine group,and CUMS+gastrodin group.CUMS stimulation continued during 7th-8th weeks while three subgroups of mice were given different drug(saline,fluoxetine or gastrodin)intraperitoneally.In 9th week,behavioral changes and weight changes were re-examined to evaluate the antidepressant efficacy of gastrodin.And then the mice were sacrificed and brain tissue were moved for detecting by HE staining、immunohistochemistry,and Western blotting.Results:1.The results of behavioral tests and weight changes on 6th week showed that:compared to the control group,CUMS stimulation significantly decreased the weight gain(P<0.001),increased the immobility time in tail suspension test(TST)、forced swimming test(FST)(P<0.001,P<0.001),and decreased the percentage of sucrose intake(P<0.001).There was no difference in the total distance of open field test(OFT)between groups.2.The results of behavioral tests and weight changes on 9th week:(1)Body weight:Compared with the CUMS+saline group,the weight gain in CUMS+fluoxetine group and CUMS+gastrodin group increased significantly(P<0.001,P<0.001).(2)Forced swimming Test:compared with the control group,the immobility time of mice in CUMS+saline group increased significantly(P<0.001);Compared with CUMS+saline group,the immobility time of mice in CUMS+fluoxetine group and CUMS+gastrodin group were decreased significantly(P<0.001,P<0.001).(3)Tail Suspension Test:compared with the control group,the immobility time of mice in CUMS+saline group increased significantly(P<0.01);compared with CUMS+saline group,the immobility time of mice in CUMS+fluoxetine group and CUMS+gastrodin group decreased significantly(P<0.01,P<0.01);There was no significant difference between mice in CUMS+fluoxetine group and CUMS+gastrodin group.(4)Sucrose Preference Test:compared with the control group,the sucrose consumption rate of mice in CUMS+saline group decreased significantly(P<0.001);compared with CUMS+saline group,the sucrose consumption rate of mice in CUMS+fluoxetine group and CUMS+gastrodin group increased significantly(P<0.001,P<0.001).There was no significant difference between CUMS+fluoxetine group and CUMS+gastrodin group.3.Compared with the control group,the expressions of JAK2、STAT3、IL-1βprotein in cortex of CUMS+saline group significantly increased(P<0.01 or P<0.01 or P<0.01);compared with CUMS+saline group,the expressions of JAK2、STAT3 and IL-1β protein in CUMS+gastrodin group were significantly decreased(P<0.01 or P<0.01 or P<0.05);There was no significant difference in protein expressions between CUMS+fluoxetine group and CUMS+saline group.4.The results of HE staining showed that the mice in the control group had normal neuron structure,clear outline,large and round nucleus,clear nucleoli,uniform staining and dense arrangement in the cortex.Compared with the control group,some neurons in the CUMS+saline group were deformed triangularly,the cell structure was not clear,the nucleus shrank and dyed deeply.The morphology of neurons in CUMS+fluoxetine group and CUMS+gastrodin group was improved,which was close to those normal neurons.5.Immunohistochemical results showed that the expression of JAK2 protein in CUMS+saline group was significantly increased(P<0.001)when comparing with those in the control group,and the expression of JAK2 protein in CUMS+gastrodin group was significantly decreased,compared with those in CUMS+saline group(P<0.001);There was no significant difference in the expression of JAK2 protein between CUMS+fluoxetine group and CUMS+saline group.The expression of STAT3 protein in CUMS+saline group was significantly increased(P<0.05),compared with those of control group;Compared with CUMS+saline group,the expression of STAT3 protein in CUMS+gastrodin group was decreased significantly(P<0.01).There was no significant difference in the expression of STAT3 protein between CUMS+fluoxetine group and CUMS+saline group.Conclusion:1.CUMS could lead to depression-like behavior in mice,the model was successfully established.2.Gastrodin could effectively improve CUMS induced depression-like behavior in mice;Gastrodin has neuroprotective effect on cortex neurons in mice;Gastrodin could down-regulate the expressions of JAK2,STAT3 and IL-1β of CUMS mice.3.The improvement of gastrodin on depression-like behavior in mice might be related to the expressions of key proteins in JAK2-STAT3 signaling pathway.Gatrodin could reduce the inflammatory response of neurons in the cortex by down-regulating the expression level of JAK2,STAT3,and IL-1β,which played a protective role in neuron,and improved depressive-like behavior in mice.