石杉碱甲衍生物预防梭曼中毒的研究  

Protective effect of Huperzine A derivatives against soman intoxication

作　　者：崔雅岚 张瑞华 靳倩 石童 王陈 陈学军 李丽琴 CUI Ya-lan;ZHANG Rui-hua;JIN Qian;SHI Tong;WANG Chen;CHEN Xue-jun;LI Li-qin(State Key Laboratory of NBC Protection for Civilian,Beijing 102205)

机构地区：[1]国民核生化灾害防护国家重点实验室,北京102205

出　　处：《中南药学》2021年第12期2502-2507,共6页Central South Pharmacy

摘　　要：目的研究石杉碱甲(Hup A)衍生物石杉碱甲-水杨醛(Hup A-SA)和石杉碱甲-反式肉桂醛(Hup A-TCA)对神经性毒剂梭曼(GD)的体外、体内预防效应及安全性。方法采用改良Ellman法体外测定Hup A及其衍生物Hup A-SA和Hup A-TCA对乙酰胆碱酯酶(AChE)的抑制效应及对GD的体外预防效应。小鼠灌胃给予Hup A(2 mg·kg^(-1))、Hup A-SA(2.86 mg·kg^(-1))和Hup A-TCA(2.94 mg·kg^(-1)),分别于给药后12、24 h肌内注射1×LD;剂量的GD,观察并记录各组小鼠的中毒症状及死亡情况。小鼠灌胃给予Hup A(4~10 mg·kg^(-1))、Hup A-SA(15~55 mg·kg^(-1))和Hup A-TCA(5~40 mg·kg^(-1)),记录小鼠的中毒症状及14 d内的死亡情况,使用Bliss法计算半数致死剂量(LD;)。结果 Hup A、Hup A-SA、Hup A-TCA均浓度依赖性地抑制AChE活性,其半数抑制浓度(IC;)分别为(0.36±0.05)、(1.36±0.03)和(0.62±0.03)μmol·L^(-1)。3种药物与AChE预孵育,均可显著提高GD的IC;值;体内预防给药12 h后以GD攻击,3种药物小鼠存活率均提高,分别为66.67%、75%和100%;预防给药24 h后以GD攻击,2个衍生物组仍有部分动物存活,而Hup A组动物全部死亡,2种衍生物体内预防GD的时效性较Hup A更长。急性毒性研究显示,3种药物小鼠灌胃的LD;值分别为7.20、45.75和16.42 mg·kg^(-1),衍生物安全性提高。结论 Hup A-SA和Hup A-TCA均通过可逆地抑制AChE活性发挥GD中毒预防作用,预防时间较Hup A长,且安全性更高。Objective To determine the in vitro and in vivo intoxication and safety of Hup A derivatives (Hup A-SA and Hup A-TCA) against soman (GD).Methods Modified Ellman method was applied in vitro to determine the inhibiting effect of Hup A and its derivatives on AChE and their preventive effect against soman intoxication.The mice were pretreated with Hup A (2 mg·kg^(-1)),Hup A-SA (2.86 mg·kg^(-1)),and Hup A-TCA (2.94 mg·kg^(-1)) orally.The poisoning symptoms and death rates of each group were observed and recorded 12 h or 24 h after challenged with 1×LD;dose of GD (im).In the acute toxicity study,the mice were given Hup A,Hup A-SA or Hup A-TCA orally.Their poisoning symptoms and death rates within 14 d were recorded,and the median lethal doses (LD;) were calculated by Bliss method.Results Hup A,Hup A-SA and Hup A-TCA all inhibited the activity of AChE in a concentration-dependent manner with IC;values at (0.36±0.05) μmol·L^(-1),(1.36±0.03) μmol·L^(-1)and (0.62±0.03) μmol·L^(-1),respectively.The IC;values of GD inhibiting AChE pretreated with Hup A,Hup A-SA or Hup A-TCA were increased significantly as compared with those of the non-pretreated groups.The mice were pretreated with prophylactic drugs of Hup A,Hup A-SA or Hup A-TCA 12 hours in advance improved the survival rates of mice challenged with GD,and the survival rates of mice were 66.67%,75%,and 100%,respectively.If given 24 hours in advance,some mice in the two derivative groups survived,while all mice died in the Hup A group.The effective time of preventing soman in the two derivatives groups was longer than that of Hup A group.The LD;values of the mice given Hup A,Hup A-SA and Hup A-TCA orally were 7.20 mg·kg^(-1),45.75 mg·kg^(-1)and 16.42 mg·kg^(-1),respectively,and the safeties of the derivatives were enhanced.Conclusion The Hup A-SA and Hup A-TCA can prevent GD poisoning by reversibly inhibiting the activity of AChE,with longer prevention time and safer effect than those of Hup A.

关 键 词：石杉碱甲 衍生物 神经性毒剂 梭曼 预防作用 

分 类 号：R285.5[医药卫生—中药学]