金丝桃属中药抗抑郁多异戊烯基酰基间苯三酚类有效成分及其作用机制研究

Depression is a common mental disease, which pathogenesis is not clear. The incidence of depression is increasing year by year, and has become a serious social problem now. St. John’s Wort (SJW), the traditional Chinese medicine (TCM) of Hypericum perforatum, is the most commonly used antidepressant medicinal plant in Europe and the United States. One class of the effective components of SJW is polycyclic polyprenylated acylphloroglucinols (PPAP), which has been proved to act on multiple targets of depression. The preliminary phytochemical studies on some TCMs of the genus Hypericum with similar traditional efficacy as SJW suggest that the novel PPAPs from them show the antidepressant activity as well. Therefore, on the basis of our oriented research strategy for PPAPs, this project will start at the oriented discovery, systematic isolation, and structural identification of the antidepressant PPAPs from some TCMs of the genus Hypericum, such as H. patulum. Then, a variety of modern pharmacological methods will be used to clarify the targets, pathways, and the potential synergistic antidepressant mechanisms of active PPAPs. The aims of this project are the investigation of novel PPAPs with unique and multiple action targets, and the clarification of the material foundation and mechanism of TCMs with antidepressant activity. On the basis of the multiple action targets of PPAPs, the further preparation of active PPAPs groups could light the synergetic advantage of TCMs. It is also of great significance to reveal the scientific connotation of TCMs and lay the foundation for the development of new drugs with independent intellectual property rights.

抑郁症是一种发病机制尚不明确的常见精神疾病，发病率呈上升趋势，已发展成为一个严重的社会问题。圣约翰草，即传统中药贯叶金丝桃，是欧美最常用的抗抑郁植物药，其有效成分为能作用于多个抗抑郁靶标的多异戊烯基酰基间苯三酚（PPAP）。前期研究发现，金丝桃属部分与贯叶金丝桃有相似功效的中药也含有结构新颖且具有抗抑郁活性的PPAP类成分。本项目拟根据已建立的PPAP类定向研究策略，系统开展金丝梅等金丝桃属中药中抗抑郁活性PPAP类的定向识别、系统分离和结构测定，确定其单体有效成分。综合运用多种现代药理学方法阐明有效成分的作用靶点和通路，以及协同抗抑郁的作用机制。本项目致力于发现结构新颖、机制独特的抗抑郁单体有效成分，阐明抗抑郁中药的物质基础及其作用机制，并根据多靶点的特征制备有效成分组合物，体现中药治疗抑郁症的协同作用优势，这对揭示传统中药的科学内涵具有重要意义，并为具有自主知识产权新药的创制奠定基础。

抑郁症是一种日益常见的精神障碍，其对我国人民健康的影响位列5大非致死性疾病的第3位，现已成为一个受到广泛关注的社会问题。我们在前期研究中发现与著名抗抑郁植物药圣约翰草（贯叶金丝桃）有相似功效的金丝桃属中药中含有结构新颖多样且具有潜在抗抑郁活性的多异戊烯基酰基间苯三酚（Polycyclic Polyprenylated Acylphloroglucinol，PPAP）类成分。本项目在4年的研究执行期内，采用活性导向和基于HPLC-DAD、HPLC-Q-TOF/MSn、1H-NMR特征信号的定向分离方法，从川滇金丝桃果实、金丝梅叶子和花朵、金丝桃花朵和根、挺茎遍地金全草、栽秧花花朵和匙萼金丝桃等6种金丝桃属中药和药用植物中共分离鉴定PPAP类化合物239个，其中137个为新化合物，包括3类新骨架化合物。我们采用X-射线单晶衍射法（X-Ray）和电子圆二色谱法（ECD）、高斯理论计算、化学沟通等多种研究方法，确定了化合物的绝对构型。通过系统筛选所分离鉴定化合物的抗抑郁活性，我们发现hyperibone J（ZX-8）、hypercalin B（HB）、bzhyperforin（HF-42）等化合物具有显著的抗抑郁活性。其中ZX-8能够显著改善LPS诱导的急性抑郁样行为，改善LPS对小鼠模型海马体的损伤，降低抑郁模型小鼠海马和皮层中IL-6, IL-1α, TNF-β等炎症因子的含量，通过调节参与神经配体-受体关系的信号转导途径发挥抗抑郁作用。本项目现已发表标注的SCI论文13篇，其中在有机化学和天然产物研究领域权威杂志Organic Letters（IF: 6.005）发表研究论文2篇，在Organic Chemistry Frontiers、Journal of Natural Products、Phytochemistry等天然产物国际著名期刊7篇。发现的2类共3个新骨架化合物被Natural Product Reports评为国际热点化合物。本项目对金丝桃属中药抗抑郁价值的研究与开发具有重要意义，发现的PPAP类活性先导化合物为创制具有自主知识产权的新型抗抑郁药物奠定了基础。