基于认知功能修复的补肾治法方药抗LOD研究的新视角：CP衰老—叶酸脑转运—海马神经发生

Late-onset depression(LOD)is a common senile disease with higher risk of dementia, which seriously affects the life quality of the elderly people and aggravates the burden of both family and society. Cognitive function impairment is one of the main reasons for increasing the difficulty of LOD treatment. Taking the cognitive function impairment as the breakthrough point, from a new perspective of "Plexus choroid(CP) aging-Folate's brain transport-Hippocampal neurogenesis- Cognitive function", we put forward the scientific hypothesis: "kidney-tonifying therapy and prescription could exert effective and integral anti-LOD effects by improving CP aging, enhancing folate's brain transporter, promoting hippocampal neurogenesis and repairing cognitive function. By in vivo and in vitro experiments, in LOD model rats, the effects of kidney-tonifying therapy and prescription(Erxiantang) on structure and function of CP, folate's brain transporter and the stem cell proliferation and differentiation in DG area of hippocampus were investigated, thereby clarifying the targets and mechanisms of anti LOD effects of kidney-tonifying therapy and prescription. The study would not only enrich and innovate of the theory of "kidney-brain system" in traditional Chinese medicine, but also innovatively apply kidney-tonifying therapy and prescription into prevention and treatment of mental illness in the elderly people. The study is helpful to further clarify and reveal the scientific value, characteristics and advantages of kidney-tonifying therapy and prescription in prevention and treatment of mental disease. In addition, the study would provide scientific evidence for translational medicine research on kidney-tonifying therapy and prescription in the prevention and treatment of LOD.

晚发型抑郁症（LOD）是常见的老年病，极易发展为老年痴呆症，严重影响老年人的生活质量并加剧患者家庭和社会的负担。认知功能损害是增加LOD治疗难度的主要原因之一。本课题以认知功能损害为切入点，从“脉络丛（CP）衰老—叶酸脑转运—海马神经发生—认知功能”这一新视角，提出“补肾治法方药可通过改善CP衰老，增强叶酸脑转运，促进海马神经发生，进而修复认知功能，发挥其整体有效的抗LOD效应”的科学假说。通过整体实验和体外实验，探讨补肾治法方药二仙汤对LOD大鼠CP结构与功能、叶酸脑转运、海马DG区神经干细胞增殖分化的影响，阐明中医补肾治法方药发挥整体有效抗LOD效应的作用靶点及机理。本研究不仅对中医“肾—脑髓体系”理论有所丰富和创新，而且也是对补肾治法方药在老年性精神疾病防治中的创新运用。本研究亦将为今后补肾治法方药防治 LOD的转化医学研究提供科学依据。

迟发性抑郁症（LOD）是常见的老年病，认知功能损害是增加LOD治疗难度的主要原因之一，海马萎缩是LOD的神经解剖学标志，而神经发生障碍和神经元凋亡都是引起海马萎缩的重要原因，促进海马神经发生可改善认知功能。衰老会影响脉络丛（choroid plexus，CP）导致其紧密连接发生改变和转运功能出现障碍从而改变脑脊液（cerebrospinal fluid，CSF）的成分，进而影响海马神经发生。因此，本课题以认知功能损害为切入点，提出科学假说：补肾治法方药可通过改善CP衰老，增强叶酸脑转运，促进海马神经发生，进而修复认知功能。.基于以上，我们采用自然衰老大鼠 结合CUMS复制LOD模型，观察补肾方对LOD大鼠认知功能、抑郁症状、脉络丛结构和叶酸转运功能、CSF成分及海马神经发生的影响。同时，结合体外实验，观察补肾方对高浓度皮质酮合并D-氨基半乳糖胺条件下原代脉络丛上皮细胞结构和叶酸转运功能的影响；探索各组大鼠CSF对高浓度皮质酮合并D-氨基半乳糖胺条件下原代海马神经干细胞增殖、分化的影响。.结果提示，整体实验表明，LOD大鼠出现明显的抑郁样症状和认知功能障碍，脉络丛紧密连接被破坏，叶酸转运功能下降，并且CSF组分发生变化，伴有海马神经发生障碍和海马神经元丢失的现象；经补肾方的治疗，可有效缓解抑郁样症状，改善认知障碍，提高叶酸转运，促进海马神经发生。体外研究表明，补肾方可有效维持高浓度皮质酮合并D-氨基半乳糖胺条件下原代脉络丛上皮细胞紧密连接，提高其叶酸转运功能；而补肾方组大鼠CSF有效促进了高浓度皮质酮合并D-氨基半乳糖胺条件下原代海马神经干细胞增殖、分化。.以上结果阐明中医补肾方可能通过维持CP紧密连接，增强叶酸脑转运，促进海马神经发生，进而修复认知功能，达到抗LOD的疗效。本研究不仅是对中医“肾—脑髓体系”理论的丰富和创新发挥，而且也是补肾治法方药在老年性精神疾病防治中的创新运用。