Antidepressant Effect And Mechanisms Of Hypidone Hydrochloride (YL-0919)

Objective: To evaluate the antidepressant effect of YL-0919 by constructing a corticosterone(CORT)water-replacement model and a chronic social defeat stress(CSDS)model,and then to explore the antidepressant mechanism.Methods: Chronic corticosterone(CORT)water-replacement model was constructed,and the depressive-like behavior and the effects of YL-0919 were evaluated by sucrose preference test,open-field test,forced-swimming test,tail-suspension test,novelty-suppressed feeding test,and novel object recognition test.Chronic social defeat stress(CSDS)model was constructed,and the depressive-like behavior and the effects of YL-0919 were evaluated by social interaction test,elevated plus maze test,open field test,novelty-suppressed feeding test,novel object recognition test.Western blot was used to detect the expression of BDNF and PSD95 in hippocampus,and immunofluorescence was used to detect the number of DCX positive cells in hippocampus.Results: Evaluation of antidepressant effect of YL-0919: in the CORT water-replacement model: the immobility time of the CORT water-replacement group in the forced-swimming experiment and the tail-suspension experiment was significantly increased(P < 0.01),the sucrose preference was significantly decreased(P < 0.001)in the sucrose preference test,and the feeding latency was significantly increased(P < 0.001)in the novelty-suppressed feeding test.In the open field test,the time in the center was significantly decreased(P <0.01),and the mice had obvious cognitive impairment in the novel object recognition experiment(P < 0.001).Similar to fluoxetine,YL-0919 can significantly reverse these changes above.In the CSDS model: the Social Interaction proportion score of mice in the model group was significantly decreased(P < 0.01).Compared with the model group,YL-0919(2.5 mg/kg)could significantly reverse the decrease in the Social Interaction scale score(P < 0.05).Compared with the control group,the mice in the model group significantly decreased in the duration time in the central area in the open field(P < 0.01).Neither YL-0919 nor fluoxetine could reverse the decrease in the duration time in the central area.There was no significant difference in the total distance of mice in the open field test between the control group,the model group and the YL-0919 treatment group.Compared with the control group,the feeding latency of the mice in the model group increased significantly in the novelty-suppressed feeding test.Compared with the model group,YL-0919(2.5 mg/kg)and fluoxetine(10 mg/kg)could significantly reverse the feeding latency in mice(P < 0.05).Compared with the control group,the mice in the model group did not show obvious cognitive impairment,in the novel object recognition test;Research on the antidepressant mechanism of YL-0919,in the CORT water-replacement model,compared with the control group,the expression of PSD95 in the hippocampus of the CORT water-replacement group was significantly decreased(P < 0.01).YL-0919(1.25、2.5、5 mg/kg)or fluoxetine(10 mg/kg)could significantly reverse the above changes(P <0.05).Compared with the control group,the number of DCX positive cells in the DG of mice in the CORT water-replacement group decreased significantly(P < 0.05).Compared with the CORT water-replacement group,both YL-0919 and fluoxetine could significantly reverse the above changes(P < 0.05).In the CSDS model,compared with the control group,the expressions of BDNF and PSD95 in the hippocampus of the CSDS group were significantly decreased(P < 0.01).Compared with the CSDS group,Both YL-0919(2.5mg/kg)and fluoxetine(10 mg/kg)could significantly reverse the above changes(P < 0.05).Compared with the control group,the number of DCX positive cells in the DG of mice in the CSDS group decreased significantly(P < 0.05).Compared with the CSDS group,both YL-0919 and fluoxetine could significantly reverse the above changes(P < 0.05).Conclusion: Chronic treatment with YL-0919 showed significantly antidepressant effect,and can improve the cognitive function of mice in CORT and CSDS induced depressive-like behavior,which may be closely related to promoting hippocampal neural plasticity.