益肾调气法对卒中后抑郁、焦虑、痴呆发生发展的防治作用研究

According to the national planning for major diseases early prevention of traditional Chinese medicine and two academicians' guidance, our former clinical and basic researches have found that symptom groups of cognitive disorder, thinking hysteresis, hypomnesis and somnipathy after stroke and even the subsequent developments of vascular depression, vascular anxiety and vascular dementia, both contained kidney deficiency and liver depression pathogenesis in their dynamic evolutionary processes.Furthermore, we have found the abnormal changes of emotional disorders in behavior, as well as nerve substances and energy metabolism, the expressions of post-receptor signals were all closely related to PapeZ loop and neuroendocrine immune system also played an important regulatory role. Based on the above, we propose hypothesis in this project that Papez loop is a critical foundation of post stroke psychosis which can be early prevented and treated by tonifying kidney and regulating qi. We are going to discuss the specific roles of Papez loop in different diseases by observing behavioral, neuroanatomical, pathophysiological and neurobiological changes of post stroke psychoses in different periods dynamically and take the method of tonifying kidney and regulating qi as interventions to annotate the effect of prevention and therapy. We are going to apply similar method in different diseases with the same mechanism to achieve the destination of preventing the development of disease while it begins and explore the inner mechanism for its occurrence.

根据国家对重大疾病中医药早期预防的规划，结合两位院士指导和多年来的基础研究及临床实践发现的脑卒中后认知障碍、思维迟滞、记忆力减退、睡眠障碍等症状组群乃至发展为血管性抑郁、血管性焦虑和血管性痴呆等疾病，在其动态演变过程中共同存在着肾虚肝郁的病机；同时发现Papez环路与情志障碍的行为学、神经物质及能量代谢、受体后信号表达等方面的异常改变密切相关，神经内分泌系统也具有重要调控作用。本项目在此基础上，提出Papez环路是卒中后精神疾患发生发展的重要基础，益肾调气法可起到早期干预、早期防治的作用这一假说。通过动态观察脑血管病后精神症状组群不同时间段发生发展的行为学、神经解剖学、病理生理学及神经生物学机制，探讨Papez环路在不同疾病中的具体作用，并以益肾调气法对其进行干预，诠释益肾调气法的预防治疗作用，从异病同治的角度入手，达到既病防变得目的，寻找其发生的内在机理。

本项目在前期基础上进行了更为深入的探索，前期发现脑卒中后认知障碍、思维迟滞、记忆力减退、睡眠障碍等症状组群乃至发展为血管性焦虑、抑郁、痴呆等疾病，在其发展过程中存在肾虚肝郁的病机；同时发现Papez环路与情志障碍的行为学、生物学以及能量代谢学等方面的异常关系密切。项目通过建立缺血性脑卒中和出血性脑卒中动物模型，复合不同应激刺激建立PSD、PSA以及VaD模型，行为学方面出现活动力的减弱、探索力的减低、兴趣与奖赏的减退，记忆能力下降、面对逃脱反应下降等改变，脑组织形态学方面亦有相应结构损伤发生。该模型较好地模拟了卒中后精神症状组群及至发展为卒中后抑郁、焦虑、甚至痴呆发病的病因以及发病的状态，可为深入研究 卒中后精神障碍的发病机制及新药研发等提供良好的研究平台。 卒中后精神障碍模型大鼠从病理形态学、影像、免疫-内分泌及分子生物学存在海马、乳头体，杏仁核，纹状体等相关Paperz 环路的继发性损伤，破坏相关组织白质纤维束完整性，影响情绪调节环路功能的实现，影响神经传导等正常功能的发挥，提示PSA、PSD、VaD的发生与 Paperz 环路密切相关。而应用益肾调气法为辨治原则的中药颐脑解郁方灌胃后模型得到相关方向的改善，颐脑解郁方能够减轻海马、前额叶皮质微结构受损程度，改善局部组织病理状态，促进相关因子和激素水平的正向调节，具有阻断脑卒中进一步发展为卒中后精神疾病的作用；同时能够修复卒中后精神疾病海马、前额叶区域纤维束完整性，对PSD、PSA及VaD具有一定治疗作用。此为益肾调气法治疗 PSD、PSA、VaD提供了依据，也为本法治疗的药效学研究奠定了一定基础。