大叶仙茅组植物特征成分降木脂素的抗抑郁活性与作用机制研究

Depression is a serious mental disease for human with great hazards to both body and mind. Antidepressants now clinically used often have the shortcomings including narrow treatment spectrum, side-effects and poor efficacy. The norlignans with skeleton of Ph-5C-Ph are the characteristic compounds of the medicinal plants of Section Molineria with the function of kidney nourishment. Series of norlignans were identified and some of them were found good antidepressant activity in our previous work, and the compound crassifoside H showed high antidepressant activity by inhibited the over activation of HPA axis through effectively decreasing the level of CORT in serum and the expression of CRH in hypothalamus in CUMS rat. In this project, the antidepressant activities of all the norlignans obtained in our previous work will be systematically screened on the SH-SY5Y cell model induced by CORT, and the structure modification on the leading compounds will be carried out following the structure-activity relationship analysis. The probable mechanisms of the norlignans against depression of the CUMS combined with raise isolated rats will be studied on different levels of behavior, morphology, neuro-biochemistry, cytology and molecular biology by means of ELISA, QPCR, Western blot and Immunohistochemistry techniques. The aim of this project is to lay a solid foundation for the development of this class of norlignans to be one new antidepressant, and also to provide reasonable suggestions for the further utilization of the medicinal plants of Section Molineria.

抑郁症是严重危害人类身心健康的精神疾患。目前临床抗抑郁药存在治疗谱窄、毒副作用多、疗效不佳等缺陷。具有Ph-5C-Ph基本骨架的降木脂素是大叶仙茅组补肾药用植物的特征成分。前期研究积累系列降木脂素化合物，首次发现此类天然产物具有良好的抗抑郁作用，活性单体crassifoside H 可有效降低CUMS抑郁大鼠血清CORT水平和下丘脑CRH蛋白表达，抑制HPA轴过度激活。项目拟在前期研究基础上，采用CORT诱导的SH-SY5Y神经细胞损伤模型，系统开展降木脂素的抗抑郁活性评价，构效关系分析，并进行结构修饰与改造；运用大鼠CUMS结合孤养抑郁模型，借助ELISA、QPCR、Western blot和免疫组化等技术，从行为学、形态学、神经生化、细胞学、分子生物学等多层次阐明其抗抑郁的可能作用机制，为开发新型高效低毒抗抑郁天然药物奠定坚实的基础，为大叶仙茅组药用资源植物的合理利用提供重要依据。

抑郁症是严重危害人类身心健康的精神疾患。目前临床抗抑郁药治疗谱窄、毒副作用多、疗效不佳，从传统药用植物中发掘抗抑郁药物意义重大。大叶仙茅组药用植物降木脂素类特征成分，具有独特Ph-5C-Ph分子骨架，前期研究中显示出较好的抗抑郁作用。项目“大叶仙茅组植物特征成分降木脂素的抗抑郁活性与作用机制研究（31670353）”主要围绕降木脂素化合物的抗抑郁作用筛选评价、构效关系，前景化合物的抗抑郁活性与作用机制等展开工作。研究结果，仙茅属降木脂素具有较强抗抑郁活性，部分样品体外活性高于临床抗抑郁药物氟西汀，其中以葡基聚合型降木脂素crassifoside F, H和J活性最强，具有良好的抗抑郁潜力。在大鼠慢性不可预见温和应激（CUMS）实验研究中，Crassifoside H有效改善了CUMS模型大鼠的多种抑郁行为；降低CUMS大鼠血清皮质酮和下丘脑CRF蛋白表达，抑制HPA 轴过渡激活；增强CUMS模型大鼠5-HT1A受体敏感度；明显上调CUMS抑郁大鼠脑部海马区和前额皮层BDNF水平及p-ERK1/2表达，激活BDNF- ERK信号通路。Crassifoside H降低CUMS大鼠血清和海马炎性细胞因子TNF-α和IL-1水平；并抑制海马NLRP3炎性小体过度活化，因而，抑制神经细胞的炎性损伤，亦是其抗抑郁重要机制之一。此外，我们还发现仙茅经典名方“二仙汤”和其中主成分orcinol glucoside具有改善女性更年期抑郁症（PMD）作用，初步机制表明其抗PMD活性与雌激素调控之间存在的密切关联性。项目完成了预定计划，对降木脂素成分进行抗抑郁活性筛选与构效关系分析，阐明了前景化合物Crassifoside H抗抑郁作用机制，相关研究丰富了仙茅属植物化学成分与药理活性研究内容，为进一步从该属药用植物中进行抗抑郁或改善女性更年期抑郁症药物研发提供重要的理论依据。