左旋盐酸去甲基苯环壬酯对大鼠和小鼠震颤与行为的影响  

Effect of l-demethyl phencynonate hydrochloride on tremor and behavior of rats and mice

作　　者：闫加庆[1] 李昕[1] 王丽韫[1] 闫海涛[1] 何新华[1] 仲伯华[1] 郑建全[1] 

机构地区：[1]军事医学科学院毒物药物研究所生化药理研究室,北京100850

出　　处：《中国药理学与毒理学杂志》2011年第4期333-338,共6页Chinese Journal of Pharmacology and Toxicology

基　　金：国家"重大新药创制"科技重大专项(2009ZX09102-007)~~

摘　　要：目的评价抗胆碱药左旋盐酸去甲基苯环壬酯(R-DM8021)的帕金森病(PD)治疗作用。方法 ①使用脑单侧立体定向注射6-羟基多巴胺(6-OHDA)损毁大鼠中脑黑质-多巴胺神经元的方法建立PD动物模型。观察大鼠单次ig给予R-DM80210.2,0.5,1.0和2.0mg.kg-1旋转行为;观察大鼠连续ig给予R-DM80210.2,0.5和2.0mg.kg-121d对大鼠旋转行为;观察大鼠连续ig给予R-DM80210.2,0.5和2.0mg.kg-17d后自发活动情况。②昆明小鼠ig给予R-DM80210.25～40mg.kg-1,30min后ip给予氢溴酸槟榔碱35mg.kg-1,观察肌肉震颤持续时间。③C57BL/6小鼠ip给予MPTP30mg.kg-17d建立MPTP帕金森病模型,ig给予R-DM80215,10和20mg.kg-1后观察小鼠自发活动情况。结果①与6-OHDA损毁模型对照组相比,单次ig给予R-DM80210.2,0.5,1.0和2.0mg.kg-1分别使APO诱导的旋转次数增加(17.3±4.5)%、(29.8±9.3)%、(30.2±13.9)%和(31.7±5.5)%;苯海索3.0,5.0和10.0mg.kg-1组分别增加(18.8±4.8)%、(22.2±17.3)%和(36.9±10.0)%。连续给药21d,大鼠APO诱导的旋转次数显著增加(P<0.01),并维持在稳定的水平。与等剂量的苯海索相比,R-DM8021对APO诱导旋转的作用更强。建模成功后,大鼠10min内自发活动路程较正常组显著降低(P<0.01),连续给予R-DM8021和苯海索7d可明显提高大鼠自发活动路程,R-DM8021对大鼠自发活动的改善效果显著优于等剂量的苯海索(P<0.01)。②ip给予槟榔碱35mg.kg-1,小鼠出现明显肌肉震颤,持续时间为(8.9±1.0)min,R-DM8021和苯海索均可剂量依赖性地降低小鼠肌肉震颤持续时间,两药对槟榔碱致小鼠肌肉震颤持续时间抑制作用的ED50分别为(6.87±1.33)mg.kg-1和(41.14±9.31)mg.kg-1,两者相比具有显著性差异(P<0.01)。③ip连续给予MPTP7d,小鼠3min内自发活动路程较正常组显著降低,连续ig给予R-DM8021和苯海索3d可明显提高小鼠自发活动路程,R-DM8021对小鼠自发活动的改善效果显著优于等剂量的苯海索(P<0.01)。结论 R-DM8021对3种模型PD均�OBJCETIVE To evaluate the therapeutic effect of anticholinergic agents l-demethyl phencynonate hydrochloride（R-DM8021） and trihexyphenidyl on Parkinson′s disease（PD） model animals.METHODS ① The cerebral unilateral stereotactic directionally injection of 6-Hydroxydopamine（6-OHDA） was given to substantia nigra-striatum neurons of rats.The rotation test evoked by apomorphine（APO） and locomotor activity were observed in the rat model after single and chronic treatment（21 d） with R-DM8021 0.2-2.0 mg·kg-1 and trihexyphenidyl.② R-DM8021 0.25-40 mg·kg-1 was ig given to mice and arecoline hydrobromide 35 mg·kg-1 was ip given 30 min later before the duration of tremor was recorded.③ C57BL16 mice PD model was established after mice were ip given 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine（MPTP） consecutively for 7 d and locomotor activity was observed after administration of R-DM8021 5-20 mg·kg-1.RESULTS ① Compared with the model control group,single administration of R-DM8021 0.2,0.5 and 2.0 mg·kg-1 increased rotation times evoked by APO by（17.3±4.5）%,（29.7±9.3）%,（30.2±13.7）% and（31.7±5.5）%,and for trihexyphenidyl 3.0,5.0 and 10.0 mg·kg-1 by（18.8±4.8）%,（22.1±17.3）% and（36.9±9.9）% by trihexyphenidyl 3.0,5.0 and 10.0 mg·kg-1.The rotation times kept increasing during R-DM8021 treatment for 21 d.② Mice exhibited apparent tremor after arecoline hydrobromide administration.The duration was decreased significantly in R-DM8021 and trihexyphenidyl groups.ED50 of inhibition on duration time of R-DM8021 and trihexyphenidyl was（6.87±1.33）mg·kg-1 and（41.14±9.31）mg·kg-1,respectively.③ Compared with normal control group,locomotor activity in MPTP model group significantly decreased.After treatment with R-DM8021 5.0,10.0 and 20.0 and trihexyphenidyl 20.0 mg·kg-1 for 3 d,the locomotor activity of mice showed obvious improvement.CONCLUSION R-DM8021 shows better therapeutic effect on 3 PD models than trihexyphenidyl.

关 键 词：盐酸去甲苯环壬酯 抗胆碱药 苯海索 帕金森病 

分 类 号：R964[医药卫生—药理学] R971.5[医药卫生—药学]