转位蛋白18KDa介导芍药苷抗创伤后应激性障碍作用机制研究

Post-traumatic Stress Disorder (PTSD) has become a serious public health problem. However, it still lacks the specific treatments in the clinic. The effects of paeoniflorin on PTSD had not been reported. Therefore, it is important to explore the effect of paeoniflorin on the prevention and treatment of PTSD. Our previous study found that paeoniflorin had the significant anti-PTSD-like effects. In addition, paeoniflorin was found to had selective affinity in translocator protein 18KDa (TSPO), and increased the level of allopregnanolone. Moreover, paeoniflorin had no benzodiazepines-like side effects. The present study aim to explore the anti-PTSD-like mechanisms of paeoniflorin that were associated with TSPO. The anti-PTSD-like effects of paeoniflorin were determined by various animal models. Moreover, we explored the role of TSPO and biosynthesis of neurosteriods in the anti-PTSD-like effects of paeoniflorin in animals and cells levels to provide theoretical and experimental basis for the anti-PTSD-like effects of paeoniflorin.

创伤后应激性障碍 (Post-traumatic stress disorder, PTSD) 已成为严重的公共卫生问题，但临床上仍缺乏PTSD特异性治疗药物。芍药苷抗PTSD效应尚未见报。据此，研究芍药苷防治PTSD效应对突破该领域新药研究具有重要意义。我们前期研究发现芍药苷具有显著抗PTSD样行为学效应。同时发现芍药苷高亲合于18KDa转位蛋白 (Translocator protein, TSPO)，并可上调四氢孕酮水平，同时不具有苯氧氮卓类样副作用。本研究将继续以TPSO为芍药苷抗PTSD效应作用机制研究核心。采用多种经典PTSD动物模型，深入探讨TPSO在芍药苷抗PTSD样行为效应中的作用。并通过整体水平和细胞水平，探讨TSPO以及下游四氢孕酮生物合成在芍药苷的抗PTSD样行为作用机制中的作用，为芍药苷抗PTSD的临床应用提供理论和实验基础。

鉴于目前仍缺乏防治PTSD的特异性治疗药物和现有的防治PTSD的化学药物所存在的毒副作用，研究尝试探讨中药（单体）在防治该精神障碍的药理效应和潜在作用机制。研究通过PTSD模型继续评价芍药苷抗PTSD样行为效应。结果提示芍药苷具有缓解PTSD样行为药效不是通过影响其自发活动产生的。18KDa转位蛋白 (Translocator protein, TSPO) 与PTSD的发病相关。在前期调研和项目的资助下，研究团队发表SCI论文《Translocator protein 18 kDa: a potential therapeutic biomarker for post traumatic stress disorder》，系统综述TSPO与PTSD发病的相关性。据此，研究进一步通过分子对接技术和配体结合实验分别验证了芍药苷与TSPO具有亲合力。此外，TSPO和四氢孕酮的拮抗剂可分别阻断芍药苷抗PTSD样行为药效。研究提示芍药苷的抗PTSD样行为药效与TSPO及四氢孕酮的介导相关。进一步通过提取动物相关脑区和血样本分析得芍药苷的药效与调节HPA轴相关激素水平，脑区中四氢孕酮和部分单胺递质水平相关。在此基础上，研究团队把相关的研究成果整理并发表SCI论文《Anxiolytic-like effects of paeoniflorin in an animal model of post traumatic stress disorder》。在动物行为实验和组织学分析的基础上，研究进一步在细胞水平评价芍药苷的药理效应与TSPO及其下游四氢孕酮水平变化的相关性。结果显示芍药苷具有神经保护作用，体现在其提高神经细胞的存活率。然而，该药理效应可被TSPO和四氢孕酮的拮抗剂分别阻断。据此，继续研究分析药物处理后TSPO下游神经类固醇（如孕烯醇酮、孕酮和四氢孕酮）的变化。结果显示芍药苷可提高孕酮和四氢孕酮水平，但该效应可被TSPO，孕酮和四氢孕酮的拮抗剂分别阻断。结果也提示芍药苷的神经保护作用与TSPO和四氢孕酮的介导有关，并通过整理数据发表SCI论文《Cytoprotective effects of paeoniflorin are associated with translocator protein 18 kDa》。.总括而言，项目的执行基本上按照计划书中内容进行。在项目