附子中胺醇型C19-二萜生物碱的体内代谢特征及抗心肌细胞凋亡的机制研究

Aconiti Lateralis Radix Praeparata (Fuzi) is widely used in Chinese traditional medicine with long history，and known as the first one of reviving Yang for resuscitation with cardiac and anti-shock effects. The alkaloids in Fuzi are the main bioactive components. But Fuzi is also a toxic medicine, and the diester-diterpenoid alkaloids (DDAs) in it reveal acute toxicity. But aminoalcohol diterpenoid alkaloids (ADAs), the secondary hydrolysis products of DDAs, show little toxicity. Our research team firstly reported that the ADAs in Fuzi exhibited remarkable cardiac effect. However, the cardiac effect and anti-heart-failure effect of ADAs were only investigated in vitro, and the in vivo pharmacodynamic and pharmacokinetic characteristics are not clear. Therefore, in this proposal, we will study the in vivo pharmacodynamic and pharmacokinetic characteristics of ADAs after monomer administration and Fuzi decoction administration, and clarify the clinical anti-heart-failure effect of Fuzi in the aspect of characteristics in vivo of these effective substances. We will also investigate that how ADAs affect the Caspase-3 dependent apoptosis regulation on cardiomyocyte, and preliminarily interpret the molecular mechanisms of anti-cardiomyocyte apoptosis of ADAs. The above in-depth research of effective substances in Fuzi will contribute to illuminate the material basis of traditional efficacy of Fuzi, ensure the safety and effectiveness of clinical medication, and provide basic data of modern research and development of Fuzi.

附子是一味历史悠久、应用广泛的中药，具有强心、抗休克作用，被称为“回阳救逆第一品”。研究表明生物碱是其主要活性成分。附子同时也是一味有毒中药，其中的双酯型生物碱是剧毒物质。但双酯型生物碱的二级水解产物，胺醇型生物碱则几乎没有毒性。本课题组首次报道了胺醇型生物碱具有明显的强心作用。然而，目前其强心和抗心衰的药效研究仅局限在体外水平，体内药效作用特点及代谢特征尚不清楚。因此本项目拟在前期工作的基础上，研究附子中的胺醇型生物碱单体给药和附子水煎液给药后各成分的体内过程和体内药效特征，从药效物质体内作用特点的层面阐释附子临床抗心衰的疗效；研究该类生物碱对心肌细胞Caspase-3依赖的凋亡调控机制的影响，初步阐释该类化合物的抗心肌细胞凋亡的分子机制。以上对附子药效物质的深入研究将有助于阐明附子传统功效的物质基础，保障临床用药的安全有效，为附子的现代研究和开发提供基础性数据。

附子是一味历史悠久、应用广泛的中药，具有强心、抗休克作用，被称为“回阳救逆第一品”。本项目在前期发现胺醇型二萜生物碱具有明显的强心作用的基础上，继续研究了附子中的胺醇型生物碱单体给药和附子水煎液给药后5个胺醇型二萜生物碱的体内过程，结果表明多数胺醇型C19-二萜生物碱的生物利用度低，吸收少，但基本上是以原型形式存在于体内并发挥药效；从细胞水平和动物水平初步探讨了mesaconine抗心肌细胞凋亡的机制，结果表明其显著减少心肌细胞LDH释放，可改善阿霉素引起的细胞膜完整性破坏，可抑制阿霉素引起的心肌细胞凋亡，其原因是mesaconine影响了凋亡蛋白Bcl-2和Bax的表达，为寻找该类化合物发挥药效作用的靶点奠定了基础。在应用方面，已将附子中的单体成分mesaconine开发为抗慢性心力衰竭1类创新药，并转让给四川好医生药业集团有限公司，于2021年底向药审中心提交了原料药和胶囊剂的申报资料。若能成功开发出安全有效的抗慢性心衰1类新药，将使庞大的慢性心衰人群受益，造福人类。