| BackgroundDepression is a serious neuropsychiatric disease which is one of the leading cause of death and disability.It is a serious threat to human health and brings great spiritual and economic burden to families and society.WHO estimates that depression will be world’s second largest diseases in 2020.It also is a risk factor for some other diseases,such as diabetes,cancer,ischemia,epilepsy and cardiovascular diseases.Although depression is a serious threat to people’s health,the current understanding of the pathogenesis of depression is not ideal.Considering the depression may be related to multiple brain regions and various types of cells dysfunction,it makes the study of the pathogenesis of depression and effective antidepressant treatment become more difficult.Although antidepressant treatments for the majority of the patients have certain curative effect,there are still 20% to 30% of patients with no response,in addition,more patients lack of ideal therapeutic effect.Recent studies have shown that agmatine,the production of arginine after decarboxylation,is involved in regulating the mood of the body.In the rodent depression model,agmatine is considered to have a good antidepressant effect.As a kind of endogenous neuromodulator,agmatine have an extensive function in the brain(including blocking membrane calcium ion channels and nitric oxide synthase(NOS)and NMDA receptors,activation of some of postsynaptic receptor including nicotinic receptors,imidazoline I1,I2,adrenergic receptor alpha 2 receptor,serotonin 5-HT2 A and 5-HT3 receptors,etc.).As the same of ketamine and monoamine antidepressants,agmatine’s antidepressant mechanism is also not clear,and considering the it’s extensive biological function in the brain,the study of it’s specific antidepressant mechanism becomes more difficult.As an endogenous substance,agmatine has the important benefit of not finding or having very small side effects in the treatment of depression.Considering the agmatine as an endogenousneuromodulator in the body,especially in the brain regions which are highly correlated with depression,it’s synthesis and metabolism will play an important role of antidepressant,and in these key brain regions of depression,enzymes that can change the metabolic level of agmatine are likely to be a new target for the treatment of depression.ObjectiveWe research whether agmatine metabolic processes in the brain is involved in the experimental rats depressant like behavior changes,explore it’s change in the specific area of the brain,and through Interference with the expression of agmatinase,observe changes in depression behavior.Methods(1)The effect of exogenous agmatine on the depressive behavior of rats with chronic restraint stress.First,we established the chronic restraint stress model of depression.The rats were randomly divided into control group(control),chronic restraint stress group(CRS)and chronic restraint stress plus agmatine group(CRS +agmatine).The drug group was given exogenous agmatine by intraperitoneal injection.The effects of agmatine on depression behavior in rats with CRS were observed by open field test and forced swimming test.(2)To verify the expression of agmatinase in the brain region of depression in rats and the changes after chronic restraint stress.The tissue sections of the hippocampus and prefrontal cortex were observed by immunofluorescence technique.By using of western blot,we respectively compared the agmatinase express level in PFC and hippocampus of control and CRS these two different groups.(3)The effect on depression behavior in CRS rats was observed by using AAV to interfere with the expression of agmatinase in the hippocampus of the rats.By injecting different AAV,the experimental rats were randomly divided into the control-eGFP group,the CRS-eGFP group and the CRS-shAGMAT group.Then we used open field test and forced swimming test to observe changes in depression behavior.Results(1)Compared with control group,the average residence time of CRS group in the center region of open field is significantly decreased and the average immobility time of CRS group in the forced swimming test increased significantly,the differences were statistically significant(P < 0.05).After three weeks,20 mg/(kg*day)agmatine intraperitoneal injection,the average residence time of CRS-agmatine groups in open field center region,and the average immobility time in the forced swimming test compared to Control group had no obvious change,there was no statistically significant difference(P > 0.05).(2)By using immunofluorescence(IF),we found that agmatinase had abundant expression in both the cortical prefrontal cortex and the hippocampus,these regions are closely related to depression.Compared with the control group,the expression of agmatinase in the hippocampus of rats in the CRS group was significantly increased(P<0.05),while there was no significant change in the area of the prefrontal cortex.(3)Compared with other two groups,the rats of CRS-eGFP group showed a significantly reduction of the average residence time in the central region of open field test and the average immobility time of CRS-eGFP group in the forced swimming test increased significantly,and the differences were statistically significant(P < 0.05).Compared with the control-eGFP group,the CRS-shAGMAT group showed no significant difference in the average time spent in the central area of the open field and the immobility time of the forced swimming test.Conclusion(1)Exogenous agmatine can reverse the depressant like behavior induced by chronic restraint stress in rats.(2)Agmatinase is widely distributed in the hippocampus and prefrontal cortex in rats.(3)Chronic restraint stress can induce a significant increase in the expression of agmatinase in the hippocampus.(4)Interference with the expression of agmatinase can reversed the depressant like behavior induced by chronic restraint stress in rats. |
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