药对枳壳厚朴通过调控以海马5-HT1A受体为标靶的microRNAs的抗抑郁机制研究

The incidence of depression is increasing year by year and it becomes a serious global public health problem and prominent social problem. Characterized by multiple components, multiple targets, little toxic side-effects, the traditional Chinese medicine has advantages in depression treatment. 5-HT1A receptor is regulated by a variety of microRNAs, and it is also an important target for clinical treatment of depression. Our previous research has confirmed that the traditional spleen and stomach qi regulating herb pair — Fructus Aurantii and Magnolia Bark Decoction (FM) can achieve the antidepressant effect by raising the level of hippocampal 5-HT1ARmRNA. Based on the previous study, this project proposes a hypothesis that FM may have the antidepressant effect by affecting the expression of microRNAs targeting hippocampal 5-HT1A receptor. By replicating the depression rat model which received chronic unpredictable stress stimulus and integrating advanced techniques in the field of animal behavior, bioinformatics, molecular biology and so on, the project intends to screen and verify the microRNAs which targeting hippocampal 5-HT1A receptor regulated by herb pair FM and the absorbed components. What’s more, it is aimed at illustrating FM’s therapeutic material basis and deep antidepressant mechanism, which can provide more experimental basis for clinical treatment of depression from the aspect of regulating spleen and stomach qi, and it will also contribute to the research of the pathogenesis of depression and discovering a new drug.

抑郁症发病率逐年上升，已成为全球严重的公共卫生问题和突出的社会问题。中药以多成分、多靶点、毒副作用小为特点，在抑郁症治疗中有一定的优势。5-HT1A受体（5-HT1AR）是临床治疗抑郁症的一个重要靶点，5-HT1AR的表达与多种microRNAs密切相关。前期研究已证实：传统调理脾胃气机药对枳壳厚朴可通过上调海马5-HT1ARmRNA水平而达到抗抑郁作用。基于前期研究基础，本项目提出“枳壳厚朴可能通过调控以海马5-HT1AR为标靶的microRNAs的表达从而发挥抗抑郁作用”的假说。项目拟复制慢性不可预见应激抑郁模型，采用动物行为学、生物信息学、分子生物学等领域的先进技术筛选、验证药对枳壳厚朴及各吸收成分调控靶向海马5-HT1AR的microRNAs，从而阐明枳壳厚朴抗抑郁的药效物质基础及深层作用机制，为临床从脾治疗抑郁症提供更多实验依据，同时亦有助于抑郁症发病机制的研究及新药的发掘。

抑郁症发病率逐年上升，已成为全球严重的公共卫生问题和突出的社会问题。中药以多成分、多靶点、毒副作用小为特点，在抑郁症治疗中有一定的优势。内容：本项目研究枳壳厚朴对慢性应激抑郁大鼠海马中特异性miRNA表达的影响，并从miRNA及其通路网络水平探讨枳壳厚朴抗抑郁的作用机制。本研究通过基因芯片检测出抑郁模型组与正常对照组海马间表达差异的miRNA，将其和枳壳厚朴组与抑郁模型组海马间表达差异的miRNA相交集，得到20个共同表达差异miRNA，并经定量PCR验证，得到有效的验证miRNA共4个（rno-miR-1839-3p、rno-miR-1839-5p、rno-miR-194-5p、rno-miR-327）。因此，这4个miRNA有可能是枳壳厚朴的作用靶点，我们对其靶基因功能及信号通路进行深一步的分析。枳壳厚朴通过miRNA间接调控轴突导向因子、β-TGF等神经营养因子，从而改善神经元细胞的生长发育及分化，另一方面，还能通过Wnt信号通路，上调海马组织中的Wnt分子进而发挥抗抑郁作用，这一结论推进了中药在抑郁疾病中的应用，为抗抑郁治疗提供了一个新方向。