驱蛔中药的活性成分川楝素的生物效应

利用楝属植物皮和种子治疗消化道寄生虫病和防治农业虫害,早在两千年前的中国古代已有记载。川楝素（toosendanin,C30H38O11,FW=574）是我国科学家在上世纪五十年代从川楝皮提取、分离的一个用以代替进口驱蛔药山道年的三萜化合物。研究已证明川楝素具多种独特的生物效应和在科学研究、临床医学及农业上的应用价值。第一,川楝素以先易化后抑制的双相作用干扰神经递质释放,阻遏神经肌肉接头和中枢神经突触的突触传递。此作用可能是川楝素改变递质释放装置的Ca^2＋敏感性和使之最终完全消失的结果。第二,尽管川楝素与肉毒神经毒素阻遏神经肌肉接头传递的作用有许多相似,川楝素在离体和在体实验中均显示出极有效的抗肉毒神经毒素作用：川楝素可治愈致死量肉毒中毒的小鼠和猴;经川楝素孵育的离体神经肌肉标本,或由经一次川楝素注射的动物取出的神经肌肉标本具抵抗肉毒神经毒素作用的能力。已有证据表明抗肉毒神经毒素作用是通过川楝素阻隔肉毒神经毒素与其酶解底物SNARE蛋白的接近而实现的。第三,近年观察到川楝素还引发细胞分化和凋亡,抑制人的多种肿瘤细胞增殖。该作用是Ca^2＋依赖性的,有线粒体依赖的凋亡通路参与。第四,川楝素抑制多种K^＋通道,选择性地易化通过L型Ca^2＋通道的Ca^2＋流,并由此导致细胞内Ca^2＋浓度（[Ca^2＋]i）持续升高。川楝素对K^＋通道的抑制,对L型Ca^2＋通道的易化和由之引起的[Ca^]．升高和超载,是川楝素引发细胞分化和凋亡、抑制细胞增殖,以及川楝素产生神经递质双相变化和阻遏突触传递的机制。

Biological effects of toosendanin, an active ingredient of herbal vermifuge in Chinese traditional medicine

The fact that the fruit and bark of plant belonging to family Melia could be used as digestive tract-parasiticide and agricultural insecticide was recorded about two thousand years ago in ancient China.Toosendanin(TSN,C30H38O11,FW=574),a triterpenoid derivative,was extracted from the bark of Melia toosendan Sieb.et Zucc.by Chinese scientists in 1950's and used as an ascarifuge in China instead of imported sendanin.Studies have demonstrated that TSN possesses special biological actions as well as considerable various values in scientific research,clinic medicine and agriculture.The first is that by interfering with neurotransmitter release by causing an initial facilitation,TSN eventually blocks synaptic transmission at both the neuromuscular junction and central synapses.The action might result from TSN-induced Ca2+-sensitivity change and final elimination of transmitter release machinery.The second is that despite sharing many similar actions with botulinum neurotoxin(BoNT)on blocking neuromuscular transmission,TSN has a markedly antibotulismic action in vivo and in vitro:TSN-treatment saves the botulism mice or monkeys from death;TSN-incubation in vitro or TSN-injection in vivo endows neuromuscular junction with a high tolerance to BoNT.Studies suggest that the antibotulismic action is achieved by preventing BoNT from approaching its enzymatic substrate,SNARE protein.The third,in recent years,it is also observed that TSN can induce differentiation and apoptosis in several cell lines,and suppress proliferation of various human cancer cells.The TSN-induced differentiation is Ca2+-dependent and the mitochondria-dependent apoptosis pathway is involved in the TSN-induced apoptosis.The fourth is that TSN inhibits various K+ channels and selectively facilitates Ca2+ current through L-type Ca2+ channels and hence elevates [Ca2+]i.The TSN-induced [Ca2+]i increase and overload could be responsible for the TSN-induced biphasic effect on neurotransmitter release,cell differentiation,apoptosis as well as the cytotoxicity of TSN.