| Depressive disorder is a psychological disease with high pathogenicity, disability andsuicide rate, which is becoming a serious problem of society and public health.Anti-depression agents, such as selective serotonin reuptake inhibitor （SSRI） isrecommended as a main therapy. However, these agents have limitations, including adelayed onset of action and various adverse drug reactions, such as sexual dysfunctionand weight increase. A novel class of antidepressants has dual activities as a partialagonist of the5-HT1Areceptor and a selective serotonin reuptake inhibitor（SerotoninPartial Agonist and Reuptake Inhibitor，SPARI） that has attracted a great deal ofinterest because of its advantage of shorter onset and less safety concerns. YL-0919isa SPARI being developed by Beijing Institute of Pharmacology and Toxicology. Withits new medicine patent, YL-0919has completely new chemical structure andemerges as a promising anti-depression agent, however little is known about its targetmechanism.Objective:1. To evaluate the anti-depression effect of YL-0919by establishing the rats chronicstress models.2. To evaluate the learning and memory effect of YL-0919by the object recognitiontest in rats and step down test in mice.3. To observe the effect of YL-0919on neurogenesis and neuroplasticity in the dentategyrus of hippocampus in chronically stressed rats.Methods:1. The rats chronic stress models were established and then the behavior changes wereexplored using the open field test, sucrose preference test and novelty-suppressedfeeding test.2. The object recognition test in rats and the step down test in mice were used toevaluate the effect of YL-0919on the changes of learning and memory.3. Immunocytochemistry method was applied to evaluate the effect of YL-0919onthe changes of neurogenesis in hippocampal dentate gyrus.4. Golgi staining was applied to evaluate the effect of YL-0919on the dendriticcomplexity in hippocampal dentate gyrus. Results:1. The locomotor activity and the sucrose preference of chronically stressed rats wereboth significantly decreased, and the latency to novelty-suppressed feeding wasincreased, while administration of fluoxetine （10mg/kg, ig） or YL-0919（2.5mg/kg,1.25mg/kg, ig） reversed those effects. These findings indicate that YL-0919reveals promising anti-depression effect on the rats chronic stress models.2. The administration of donepezil （2mg/kg, ig） or YL-0919（1.25mg/kg, ig）increased the Recognition Index in the object recognition test in rat significantly. Theadministration of donepezil （5mg/kg, ig） or YL-0919（1.25～2.5mg/kg, ig）increased the step-down latency in the step down test in mice significantly, while itdidn’t show the same effect of fluoxetine （5～10mg/kg, ig） or duloxetine （5～10mg/kg, ig）.3. The number of BrdU positive cells in hippocampal dentate gyrus was significantdecreased in chronically stressed rats for28d, while chronic administration withfluoxetine （10mg/kg, ig） or YL-0919（1.25mg/kg,2.5mg/kg, ig） couldsignificantly increase the number of BrdU positive cells. Such findings suggest thatchronic administration with YL-0919will promote neurogenesis.4. The dendritic branch and length and spine density of dentate gyms of hippocampusin model group were significantly reduced, while chronic administration withfluoxetine or YL-0919prevented the stressed induced decrease of dendritic branchand length and spine density, and increased the dendritic complexity.Conclusions:1. YL-0919produced reliable anti-depressive effect on the chronically stressed ratmodels.2. YL-0919produced reliable effect of improving learning and memory on the objectrecognition model in rats and the step down model in mice, while first-lineanti-depression agents fail to reveal such effect.3. YL-0919could up-regulate hippocampal neurogenesis in chronically stressed rat,which showed that up-regulation of hippocampal neurogenesis could be responsiblefor anti-depressive effect of YL-0919.4. YL-0919could up-regulate dendritic branch, spine density and dendriticcomplexity in chronically stressed rat. The dendritic complexity of dentate gyms ofhippocampus pyramidal neurons may contribute to the pathophysiology of depressionand the anti-depression-like effect of YL-0919may be related to the protection of neurons.In conclusion, these findings indicate that YL-0919as a SPARI, produced reliableeffect of improving learning and memory and anti-depression with could be related toup-regulation of hippocampal neurogenesis and neuroplasticity. YL-0919is apromising anti-depressive agent and it would be meaningful and challenging todevelop this compound to be a novel anti-depressive drug. |
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