新型磷酸二酯酶-4（PDE4）抑制剂罗氟普兰抗抑郁效应的机制研究

项目名称： 新型磷酸二酯酶-4（PDE4）抑制剂罗氟普兰抗抑郁效应的机制研究

项目编号： No.81503043

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 程玉芳

作者单位： 南方医科大学

项目金额： 17.9万元

中文摘要： 本实验室已证实新型磷酸二酯酶-4（PDE4）抑制剂罗氟普兰具有高效的酶抑制活性，在动物模型中有良好的抗抑郁效应，且不具有传统抑制剂致呕吐的不良反应。现有的数据支持罗氟普兰抑制PDE4酶水解cAMP，升高细胞内cAMP水平，激活cAMP/PKA/CREB信号通路，但是关于罗氟普兰是否影响或调节抑郁症的小胶质细胞活化这一环节仍不清楚。本项目拟采用慢性抑郁症动物模型，探讨抑郁状态下前额皮质和齿状回部位的小胶质细胞形态学、活化、凋亡等方面的变化，验证罗氟普兰的抗抑郁效应与小胶质细胞之间的关系。以原代培养的小胶质细胞为实验对象，分别用特异性的抑制剂阻断cAMP的生成、抑制PKA活性进一步证实罗氟普兰干预小胶质细胞活化与cAMP/PKA、β肾上腺素受体之间的相关性，探索罗氟普兰改善抑郁症状是否依赖于调节小胶质细胞的活化，阐明小胶质细胞在形态与功能上的改变在罗氟普兰抗抑郁效应中的分子调节机制。

中文关键词： 抗抑郁；PDE4抑制剂；小胶质细胞；分子机制

英文摘要： The data from our lab shows new phosphodiesterase-4(PDE4) specific inhibitor roflupram can improve depressive-like symptoms both in tailing suspension test and forced swimming test in mice with high enzyme inhibition efficacy. And also roflupram does not cause any nausea or emesis which is the severe side effects with classical PDE4 inhibitor. Considering the highly specific selectivity of PDE4, we speculate the possible mechanism of roflupram is due to the activation of cAMP/PKA/CREB signaling cascades through inhibiting the hydrolysis of intracellular cAMP. The current project is designed to investigate whether the antidepressant roflupram might involve microglial activation. .To elucidate the possible mechanism for microglial activation and cAMP/PKA signaling pathways contributes to roflupram as an antidepressant, chronic unpredictable mild stress induced depressive mice were used, then morphological analysis of microglia in prefrontal cortex and dentate gyrus was determined with staining. Additionally, primary microglia were isolated from mice brain and collected for further investigation. With the intervene of adenlyate cyclase inhibitor SQ-22536 or PKA inhibitor Rp-cAMPs, we try to examine the effects of roflupram on microglial activation is dependent on cAMP/PKA. The results provide direct evidence that microglial alterations in morphology and function underlie the elucidating the antidepressant mechanism of roflupram.

英文关键词： Antidepressant;PDE4 inhibitor ;Microglia;molecular mechanism