| Objective:Depression is a kind of psychiatric disorder. It is reported that the incidence of the depression reached 7%. It has become a severe disease which threaten people's health.Based on the previous study, stress is considered to be a motivation of many psychiatric disorders including depression. Atrophy of hippocampus, a target locus of stress action, is thought to contribute to the depression. In a recent study, atrophy of the human hippocampus and synapse was found in depression patients. After treated with thymoleptics, the synaptic atrophy in hippocampus could be reversed or prevented. The same result was also obtained in animal studies. However, the mechanism of the development and recovery of hippocampal atrophy in is still poorly understood. Recently, the close attention has been paid to the cAMP–response element binding protein (CREB) which may play an important role in the development of the depression.CREB, a kind of transcription factor activated by phosphorylation, can regulate the transcriptional level of many cytokines which play an important role in neurogenesis. Brain derived neurogenesis factor (BDNF) is a member of neurotrophic family, and plays an important role in neuronal survival, growth, prevention of neurodegeneration and so on. As the expression of BDNF is regulated by CREB, CREB is also highly involved in the synaptic plasticity. It has been demonstrated that the level of p-CREB in dentate gyrus decreased in depression rats. But after treatment with antidepressant agents for a long time, the level of p-CREB in dentate gyrus increased remarkably.Venlafaxine is a kind of nontricyclic antidepressant that has shown its therapeutic effects in clinical practice. Venlafaxine can increase the BDNF level in hippocampus and improve behavior. Valproate (VPA), an effective antiepileptic drug, is one of the most commonly used mood stabilizers for the treatment of mania in bipolar disorder. In recent studies, VPA has been found to have the neurotrophic effects. Chronic treatment with VPA is known to increase the level of p-CREB in rat hippocampus. Given that CREB is involved in the development and relief of depression, it is unknown whether VPA plays the antidepressive role by increasing the level of p-CREB in hippocampus. In the present study, we aim to know whether the change of CREB is responsible for the development of stress-induced depression and whether VPA plays the antidepressive role by increasing the p-CREB level in hippocampus.Method: Part 1: Adult male Sprague-Dawley (SD) rats weighing 180-220 g (obtained from the Experimental Animal Center of Hebei Medical University) were were randomly divided into a control group (n=14) and a chronic unexpected stress group (n=14). Rats in the stressed group were subjected to 7 kinds of stress. Stress (started at 9 o'clock a.m ) was administered once per day for a period of 21 days. The stresses included: swimming in 4oC water for 6 min, tail pinch for 1 min, foot shock (35V, 5-s duration per 1 min) for 30 min, high speed horizontal shaking for 50 min, food deprivation for 24h, water deprivation for 24 h, restrained for 2 h. On 22th day, 8 rats in each group were selected for body weight measurement and behavior test (including Open-field test and MWM test), and the rest rats of each group were sacrificed for immunohistochemical analyses. Part 2: Adult male SD rats (selected in the same way as Part 1) were divided into 5 groups randomly, 14 rats in each group. They were treated with saline (1 ml/kg), VPA (20 mg/kg),VPA (50 mg/kg), VPA (100 mg/kg) and VPA (200 mg/kg) respectively. Rats in all group received a (at 8:30 a.m) i.p injecton everyday for 21 days. After half an hour of the injection, rats were subjected to the same stress stimulation as Part 1. On 22th day, 8 rats in each group were selected for behavior test, and the rest rats of each group were sacrificed for immunohistochemical analyses.Results: Weight of the rats in control group is higher than that in stress group. In the Open-field test, both horizontal movement and vertical movement of rats in stress group were less than those in control group. In MWM test, the escape latency of rats in control group was shorter than that of stress group. During the 60 sec probe trial, the time spent in searching for the platform by rats in stress group in the platform quadrant was less than that in control group. In dentate gyrus, a reduction of phosphorylated–CREB–immunoreactive cells was observed in the stress group, as compared to control group. In Part 2, weight of rats in saline group was lower than that in Venlafaxine group. The automatic movement and spatial memory of the rats in Venlafaxine group were improved remarkably. Phosphorylated–CREB–immunoreactive cells in dentate gyrus also were increased after treatment with Venlafaxine. VPA (200 mg/kg) show the same effect as that of Venlafaxine. VPA (100 mg/kg) could only partially improve the behavioral score and the p-CREB level in dentate gyrus. Its medical effect was inferior to that of Venlafaxine. VPA(50 mg/kg)had no effect on depression.Conclusion: The decreased level of p-CREB in dentate gyrus is the molecular mechanism of the depression. Venlafaxine can improve depression symptom by increasing the level of p-CREB in dentate gyrus. Valproate can reverse depression caused by the chronic unexpected stress through inducing the CREB phosphorylation in dentate gyrus. The medical effects of Valproate rely on its dose. |
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