基于“肾脑相关”理论探讨熟地黄通过“线粒体-肠道菌群”途径调控ADHD神经元发育的机制研究

The latest evidence indicated that mitochondrial dysfunction (such as energy metabolism disturbance, oxidative stress and apoptosis) and gut microbiota can lead to the neurodevelopmental delay in the children and adolescent with ADHD, Chinese medicine with the effectiveness of invigorating the kidney and filling the marrow could ameliorate the mitochondrial dysfunction, but which had not been applied in the study of ADHD. we found the Radix Rehmanniae Praeparata is the most used Chinese medicine in treating ADHD, and the Chinese medicine can regulate the metabolite of energy metabolism in the blood, urine and prefrontal cortex into the normal, we speculaed that Radix Rehmanniae Praeparata may improve the neurodevelopmental delay via the above mechanism. This study will adopt the ADHD model rats, oxygen-glucose deprivation /reoxygenation neural stem cell and platelet-mediated transmitochondrial cell model, and then adopt the micro-PET, flow cytometry, immunofluorescence and other methods to oberve the effect of Radix Rehmanniae Praeparata on the pathomorphology, the genes regulating the neural proliferation, differention, and migration, mitochondrial structure and function, gut microbiota and their metabolites in the main functional brain area, we put forward the new regulation pattern that invigorating the kidney and filling the marrow can improve the neurodevelopmental delay corresponding to marrow sea insufficiency in TCM via regulating mitochondrial dysfunction and gut microbiota, and then relieve the core symptoms of ADHD. This study is to explore the scientific implications of Chinese medicine in treating ADHD, and is of important significance to innovate and develop the Chinese medicine theory.

最新证据表明线粒体功能障碍(能量代谢障碍、氧化应激、凋亡)及肠道菌群共同介导了注意缺陷多动障碍(ADHD)患儿神经元发育障碍；补肾填髓中药可改善线粒体功能障碍，但未见于ADHD研究中。我们前期发现熟地黄为治疗ADHD核心中药，中药又可调控ADHD模型鼠体液及前额叶能量代谢产物分布状态回归正常，以此推测熟地黄可能从以上途径改善神经元发育障碍。因此，本项目拟采用ADHD模型鼠、氧糖剥夺/再复氧神经干细胞、转线粒体细胞模型，应用micro-PET、流术细胞术、免疫荧光等技术，结合“肾脑相关”理论，观察熟地黄对主要功能脑区病理形态学，神经元增殖、分化及迁移等调控基因，线粒体结构及功能，肠道菌群及其代谢产物等的调控，建立并验证“补肾填髓→线粒体功能障碍/肠道菌群→神经元发育障碍(髓海不充/阴静不足)→ADHD核心症状（阳动有余）”的新型调控模式。本课题对创新发展中医理论体系具有重要意义。

线粒体功能障碍(能量代谢障碍、氧化应激、凋亡)及肠道菌群共同介导了注意缺陷多动障碍(ADHD)患儿神经元发育障碍；补肾填髓中药可改善线粒体功能障碍，但未见于ADHD研究中。我们前期发现熟地黄为治疗ADHD核心中药，中药又可调控ADHD模型鼠体液及前额叶能量代谢产物分布状态回归正常，以此推测熟地黄可能从以上途径改善神经元发育障碍。因此，本项目采用ADHD模型鼠、氧糖剥夺/再复氧神经干细胞、转线粒体细胞模型，应用micro-PET、流术细胞术、免疫荧光等技术，结合“肾脑相关”理论，观察熟地黄对主要功能脑区病理形态学，神经元增殖、分化及迁移等调控基因，线粒体结构及功能，肠道菌群及其代谢产物等的调控。结果发现，熟地黄能显著减少SHR大鼠多动、冲动行为，提高其空间学习、记忆能力，改善前额叶皮质神经元排列散乱、形态结构异常等情况；促进前额叶皮质线粒体和髓鞘结构的完整；对介导神经元发育的转录因子/调控蛋白有广泛调控作用，其优势调控靶点可能在BDNF/TrkB、Cdk5/p35和FGF/FGFR等信号通路；保护前额叶皮质线粒体功能，并能提高其能量代谢水平，同时能抑制内源性凋亡信号通路，减少神经元凋亡；并分别基于氧糖剥夺/再复氧神经干细胞及转线粒体细胞模型证实熟地黄可改善神经干细胞增殖、分化、迁移，改善线粒体形态及能量代谢；可调控肠道微生物群落种类及丰度，不同程度调控短链脂肪酸、脑肠肽的表达而调控线粒体功能及神经元发育。此项目验证了“补肾填髓→线粒体功能障碍/肠道菌群→神经元发育障碍(髓海不充/阴静不足)→ADHD核心症状（阳动有余）”的新型调控模式，对创新发展中医理论体系具有重要意义。

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