基于调节GABA/ Glu系统平衡研究TSPO配体YL-IPA08的抗PTSD作用机制

Posttraumatic stress disorder (PTSD) is the most common mental disorder after the traumatic event. Recent evidences suggested, the imbalance between Glu and GABA was the important causal factors in the precipitation of PTSD. We have previously found that, YL-IPA08, a new TSPO ligand, exerted a notable anti-PTSD effect in several experimental animal models. And also, YL-IPA08 could reverse the imbalance between Glu and GABA in hippocampus induced by PTSD. With the method of behavioral pharmacology, molecular biology and cell biology, the aim of this study is to explore whether the balance between Glu and GABA is necessary for YL-IPA08’s anti-PTSD effect. There are two critical questions included in this study. At first, whether the normalization of imbalance between Glu and GABA was an important pathogenesis of PTSD. Then, whether the anti-PTSD effects of YL-IPA08 depends on the normalization of imbalance between Glu and GABA. All in all, our results would shed light on the mechanisms for YL-IPA08’s anti-PTSD and provide a rational and conceptual foundation for strategies for anti-PTSD drugs discovery and development.

创伤后应激障碍（PTSD）是继发于重大应激事件之后发病率最高的精神心理疾患。近来研究发现，Glu和GABA系统失衡与PTSD 的发生关系密切。本课题组前期研究证实，TSPO 配体YL-IPA08在多种行为学模型上具有良好的抗PTSD作用，并且可以逆转PTSD模型大鼠海马Glu和GABA系统失衡。本研究拟通过行为药理学、分子生物学、细胞生物学等多种手段，探讨YL-IPA08抗PTSD 作用与其Allo之间的关系，重点考察：①脑内GABA/ Glu系统功能失衡是否是PTSD发生的关键机理；②调节前额叶-海马-杏仁核神经回路中GABA/ Glu系统平衡是否是YL-IPA08抗PTSD作用的关键步骤。本研究为阐明YL-IPA08抗PTSD作用提供实验依据，为深入研究PTSD 的发病机理及抗PTSD 药物筛选奠定基础。

Glu和GABA系统失衡与PTSD的发生关系密切。本研究发现，TSPO配体YL-IPA08主要是通过调节神经类固醇，继而调节 GABA/ Glu 系统平衡，发挥抗 PTSD 作用。利用TSPO基因敲除小鼠以及药理学技术发现，干扰 GABA/ Glu 系统平衡可阻断YL-IPA08的抗PTSD效应。本研究除了按计划完成YL-IPA08的快速抗PTSD效应研究外，还补充研究了YL-IPA08对小胶质细胞功能和5-HT的影响，从而使研究更具有现实意义。研究成果已经在Neuropharmacology（2018，2020，2021）等SCI期刊发表论文5篇，相关研究结果的其他SCI文章正在投稿中。本项目按计划圆满完成，取得系列新的发现，并为基于TSPO的非单胺能新型抗PTSD候选新药研究奠定了基础。