Study On The Antidepressant Effect And Mechanism Of Compound G11-5

Depression is a common mental disorder with high morbidity,high disability rate and high recurrence.The current therapeutic effects are unsatisfactory,urging the necessity to further explore the pathogenesis of depression and develop effective antidepressants.The active component of cinnamamide in piper laetispicum C.DC of Dai traditional medicine show good anti-depressant activity,but it is difficult to penetrate the blood-brain barrier.3-(3,4-Methylenedioxy-5-trifluoromethyl phenyl)-2E-propenoic acid isobutyl amide(G11-5)was derived from cinnamamide to enhance the lipid solubility.Previously,we found that G11-5 exhibited antidepressant effect in themice t learned helplessness model.The underlying mechanism might be relevant to mitochondrial autophagy,but needed to be further verified.To evaluate the antidepressant and anxiolytic effects of G11-5 in a varieties of animal models of depression.Moreover,the the pathogenesis of depression was investigated by proteomics strategy in the mice social defeat stress model.Social defeat stress,acute restraint stress and chronic restraint stress were established in C57BL6/J male mice.The efficacy of compound G11-5 was evaluated through social interaction test,open field test,elevated plus maze test,forced swim test and staircase test.Western Blotting was used to detect the expression of mitochondrial autophagy-related proteins TSPO,VDAC1,Parkin and Beclin1 and mitochondrial transportation-related proteins KIFC2 in the midbrain of mice in the social defeat stress model.The olfactory bulb tissues of mice model of social defeat stress were analyzed by using unlabeled proteomics method.G11-5 significantly increased the proportion of time spent in the interaction zone in the social defeat stress model mice(P<0.01),indicating that G11-5 significantly alleviated the social avoidance behavior of mice in the model of social defeat stress.Meanwhile,G11-5significantly reduced the immobility time in the forced swim test of mice with chronic restraint stress model(P<0.05),with antidepressant effect.Western blotting results showed that the expressions of mitochondrial autophagy-related proteins TSPO,VDAC1,Parkin and Beclin1 and mitochondrial transportation-related proteins KIFC2 in the midbrain of the mice in the social defeat stress model were significantly reduced compared with the control group(P<0.01).Moreover,G11-5 up-regulated the expression of the above proteins to a certain extent.Proteomics analysis showed that the expression of 498 proteins were significantly changed in the social defeat stress model mice compared with the control group.Among them,62 proteins were up-regulated and 436 were down-regulated.G11-5 exhibited obvious antidepressant effect with a mechanism relavant to the recovery of mitophagy and mitochondrial axonal transport in the mouse midbrain.Proteomic studies revealed that mitochondrial dysfunction,abnormal synaptic vesicle circulation,abnormal metabolism and imbalance of endoplasmic reticulum protein contributed to pathogenesis in the model mice of social defeat stress.