钩吻生物碱抑制呼吸中枢的结构-毒性关系和毒理机制研究

Gelsemium elegans is mainly distributed in south China. Since the whole plant is toxic, eating very small amounts of the plant can cause death. In recent decades, the poisoning or death events caused by Gelsemium elegans are usually reported, which has caused at least hundreds of deaths. However, the related fundamental research of Gelsemium poisoning is still very weak. The toxic components and the toxicological mechanism are still unclear, resulting in ineffective clinical treatment. In the previous work, we found that both humantenine and gelsedine type alkaloids from Gelsemium elegans are responsible for its toxic. Preliminary mechanism studies have shown that the toxic components can pass through the blood-brain barrier and inhibit the neuronal discharge of brainstem slices. The above findings suggest that these alkaloids could act on the respiratory center to produce their toxicity. However, the toxicological mechanism and structure-toxicity relationship need to be further studied. This project is based on the previous work and to build a library of natural product analogues by further isolation of Gelsemium alkaloids. In addition, this project will study the toxicity, toxicological mechanism and structure-toxicity relationship of Gelsemium alkaloids, which will provide scientific information for the development of effective clinical treatment method.

钩吻广泛分布于我国南方地区，其全株均有剧毒，误食少量即可致人死亡。近几十年来，钩吻中毒或致死的事件屡见不鲜，已至少造成数百人死亡。然而，钩吻中毒的毒性成分不明确，毒理机制不清楚，限制了其临床救治。本课题组在前期研究中，对从钩吻枝叶和根中获得的单萜吲哚生物碱进行了初步的毒性评价，发现部分humantenine型和gelsedine型生物碱具有强烈毒性，并首次发现毒性成分可通过血脑屏障和抑制延髓脑片的神经放电，从而抑制呼吸中枢而产生毒性。本项目拟在前期工作基础上，进一步对钩吻植物不同部位的生物碱类成分进行分离和鉴定，评价它们对延脑呼吸中枢的抑制作用，阐明结构-毒性关系和毒理机制，为钩吻中毒临床救治的方案制定提供科学依据。

钩吻广泛分布于我国南方地区，其全株均有剧毒，误食少量即可致人死亡。然而，钩吻中毒的毒性成分不明确，毒理机制不清楚，限制了其临床救治。本项目在前期研究基础上，对钩吻的总生物碱部位进行了系统的化学成分研究，从中分离得到了118个生物碱类化合物，构建了humantenine 和gelsedine 型生物碱样品库。通过毒性筛选，发现6个毒性成分，其中钩吻素己的毒性最强，并首次发现Humantenine型生物碱是一类新型的天然毒素。结构-毒性分析表明，钩吻生物碱结构中单萜部分的笼状结构是其发挥毒性作用的必须结构单元。毒理机制研究表明，gelsenicine通过抑制呼吸中枢而导致死亡，其机制为激活GABAAR介导氯电流。注射荷包牡丹碱或一叶萩碱能够有效降低gelsenicine引发的死亡率，具有潜在的临床应用价值。