R-氯胺酮经TGF-β信号通路抗抑郁作用机制研究

Major depression disorder is a common mental disorder, characterized by persistent low mood. Although the antidepressant effect of ketamine is fast and effective, its potential for widespread clinical use is limited by psychotomimetic side effects and abuse liability. R-ketamine shows greater potency and longer lasting antidepressant effects than ketamine in animal models of depression, but its antidepressant mechanism is not clear yet. Our previous data demonstrated that R-ketamine upregulated the TGF-β signaling pathway, and TGF-β pathway inhibitor can interfere with the antidepressant effect of R-ketamine. These results suggest that TGF-β pathway plays a role in the antidepressant effects of R-ketamine. Based on our previous work, this project intends to find out the interaction between R-ketamine and TGF-β signal pathway through animal models and cytological methods, explore how R-ketamine target to TGF-β1, TGF-β receptor I and TGF-β receptor II, and declare the mechanism of TGF-β1-TGF-β receptor I-TGF-β receptor II regulate Smad. This study provides experimental evidence and theoretical basis for the mechanism of R-ketamine’s antidepressant effect, helps to find more effective and safe new antidepressants based on the mechanism.

抑郁障碍是一种以心境低落为主要临床表现的常见精神疾病。氯胺酮抗抑郁作用具有快速、有效等特点，但潜在成瘾性、抗抑郁疗效短等缺点限制其临床应用。与氯胺酮相比，R-氯胺酮有更持久的抗抑郁作用，且成瘾危害小，但其抗抑郁机制目前尚不明确。本课题组前期发现，R-氯胺酮治疗上调抑郁小鼠海马TGF-β信号通路分子表达，治疗前使用TGF-β通路抑制剂可以干扰R-氯胺酮抗抑郁作用，提示TGF-β信号通路可能是R-氯胺酮抗抑郁作用靶点。基于前期工作，本项目拟利用抑郁动物模型和细胞学方法深入研究R-氯胺酮与TGF-β信号通路分子间相互作用，探讨R-氯胺酮如何作用于TGF-β1、TβRI、TβRII并使其处于激活状态，调控Smad蛋白在R-氯胺酮抗抑郁中的作用机制。通过对R-氯胺酮作用于TGF-β信号通路研究，将为R-氯胺酮抗抑郁机制研究提供实验证据和理论依据，有助于基于该机制发现更加长效、安全的新型抗抑郁药物。

本项目通过模式动物研究结合体外细胞实验等研究方法，阐明R-氯胺酮如何激活TGF-β信号通路进而发挥快速抗抑郁作用的分子机理。本研究结果为R-氯胺酮抗抑郁机制研究提供了实验证据和理论依据。一系列的动物实验结果表明，侧脑室注射TGF-β1蛋白治疗后慢性社会失败应激抑郁小鼠情绪明显改善，且治疗效果和R-氯胺酮无明显差异。R-氯胺酮通过作用于TGF-β信号通路从而达到抗抑郁的作用。当直接使用TGF-β1蛋白侧脑室注射也可以达到同样的抗抑郁效果。这一结果为今后使用TGF-β1蛋白作为抗抑郁剂提供了理论依据。今后本课题组还将在临床中继续探索，力争实现成果转化，早日临床应用。