Effects Of Aspirin Combined With Fluoxetine On The Behaviors Of Rats With Chronic Unpredictable Mild Stress-induced Depression And Its Possible Mechanism

OBJECTIVETo observe the effects of aspirin and fluoxetine on behaviors, the serum levels of IL-6 and TNF-α, the number of neuron and expressions of PKA in hippocampus and cerebral cortex of rats with chronic unpredictable mild stress-induced depression. And to discuss whether aspirin and fluoxetine have anti-depression effect and its possible mechanisms.METHODSFifty-six SD rats were devided into seven groups: normal group, model group, fluoxetine4mg/kg+aspirin10mg/kg group, fluoxetine4mg/kg group, fluoxetine2mg/kg+ aspirin10mg/kg group, fluoxetine2mg/kg group, aspirin10mg/kg group.Rats were exposed to alternative stress for 21 days to induce depression.To record the weight of each rat in the experimental section first, 21st day and compare the weight gain of rat in each group. The changes of behaviors in rat were observed by determing autonomous activity, sugar water consumption, immobility time in tail suspension and spatial learning and memory capacity. Using the radio immunoassay(RIA) to detect serum level of IL-6 and TNF-α, HE staining was used to observe changes of the number of neurons in hippocampus and cerebral cortex of rats. The expression of PKA in hippocampus and cerebral cortex was analyzed by immunohistochemistry determination.RESULTS1.Effect of Aspirin and Fluoxetine on body weight of rats with CUMS depression model.On the 21st day, compared with normal group, the weight gain decreased markedly in model group; compared with model group, the weight gain increased in fluoxetine4mg/kg+aspirin10mg/kg group; compared with fluoxetine4mg/kg group, the weight gain increased in fluoxetine4mg/kg+aspirin10mg/kg group, there has no difference in statistical in fluoxetine2mg/kg+aspirin10mg/kg group.2. Effect of Aspirin and Fluoxetine on behaviors of rats with CUMS depression model.(1)On the 21st day, compared with normal group, autonomic activities decreased markedly in model group; compared with model group, autonomic activities increased in fluoxetine4mg/kg+aspirin10mg/kg group; compared with fluoxetine4mg/kg group, there has no difference in statistics in fluoxetine2mg/kg+aspirin10mg/kg group. (2)On the 21st day, compared with normal group, the immobility time in tail suspension increased markedly in model group; compared with model group, the immobility time in tail suspension decreased in fluoxetine4mg/kg+aspirin10mg/kg group; compared with fluoxetine4mg/kg group, there has no difference in statistics in fluoxetine2mg/kg+ aspirin10mg/kg group.(3)Compared with normal group, the consumption of sugar water decreased markedly in model group; compared with model group, the consumption of sugar water increased in fluoxetine4mg/kg+aspirin10mg/kg group; compared with fluoxetine4mg/kg group, there has no difference in statistics in fluoxetine2mg/kg+aspirin10mg/kg group.(4)In the water maze test, compared with normal group, the escape latent period and explore time of original platform area increased markedly in model group; compared with model group, the escape latent period and explore time of original platform area decreased in fluoxetine4mg/kg+aspirin10mg/kg group; compared with fluoxetine4mg/kg group, the escape latent period and explore time of original platform area decreased in fluoxetine4mg/kg+aspirin10mg/kg group, there has no difference in statistics in fluoxetine2mg/kg+aspirin10mg/kg group.3. Effect of Aspirin and Fluoxetine on serum level of IL-6 and TNF-αin rats with CUMS depression model.Compared with normal group, the level of serum IL-6 increased markedly in model group; compared with model group, the level of serum IL-6 decreased in fluoxetine4mg/kg + aspirin10mg/kg group; compared with fluoxetine4mg/kg group, there has no difference in statistics in fluoxetine2mg/kg+aspirin10mg/kg group. Compared with normal group, the level of serum TNF-αincreased markedly in model group; compared with model group, the level of serum TNF-αdecreased in fluoxetine4mg/kg + aspirin10mg/kg group; compared with fluoxetine4mg/kg group, the level of serum TNF-αdecreased in fluoxetine4mg/kg+aspirin10mg/kg group, there has no difference in statistics in fluoxetine2mg/kg+aspirin10mg/kg group.4. Effect of Aspirin and Fluoxetine on the number of neuron in hippocampus and cerebral cortex of rats with CUMS depression model. Compared with normal group, the number of neuron in hippocampus and cerebral cortex decreased markedly in model group; compared with model group, the number of neuron in hippocampus and cerebral cortex increased in fluoxetine4mg/kg+ aspirin10mg/kg group,fluoxetine4mg/kg group,fluoxetine2mg/kg+aspirin10mg/kg group5. Effect of Aspirin and Fluoxetine on the expression of PKA in hippocampus and cerebral cortex of rats with CUMS depression model.(1)Hippocampus: Compared with normal group, gray value of positive cells increased while average optical density decreased in model group; compared with model group, gray value of positive cells decreased while average optical density increased in fluoxetine4mg/kg+aspirin10mg/kg group; compared with fluoxetine4mg/kg group, there has no difference in statistics in fluoxetine2mg/kg+aspirin10mg/kg group.(2)Cerebral cortex: Compared with normal group, gray value of positive cells increased while average optical density decreased in model group; compared with model group, gray value of positive cells decreased while average optical density increased in fluoxetine4mg/kg+aspirin10mg/kg group; compared with fluoxetine4mg/kg group, average optical density decreased in fluoxetine2mg/kg+aspirin10mg/kg group. CONCLUSIONS1. Fluoxetine(4mg/kg) combined with aspirin(10mg/kg) could improve behaviors of rats with the chronic stress depression model, which has a better anti-depressive effect than fluoxetine(4mg/kg) group.2. Fluoxetine(4mg/kg) combined with aspirin(10mg/kg) could influence neuroplasticity through regulating the unbalance of cytokines, the number of neuron and expression of PKA in hippocampus and cerebral cortex. This is possible mechanism of antidepressant effect of aspirin combined with fluoxetine3. The anti-depressive effect of Fluoxetine(2mg/kg) combined with aspirin(10mg/kg) group was similar correspondent with fluoxetine(4mg/kg) group, the combination of aspirin and fluoxetine which decreased the adverse effects of fluoxetine may provide a laboratory basis for clinic.