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

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-DM8021 0.2,0.5,1.0和2.0 mg·kg旋转行为;观察大鼠连续ig给予R-DM8021 0.2.0.5和2.0 mg·kg21 d对大鼠旋转行为;观察大鼠连续ig给予R-DM8021 0.2,0.5和2.0mg·kg7 d后自发活动情况.②昆明小鼠ig给予R-DM8021 0.25～40 mg·kg,30 min后ip给予氢溴酸槟榔碱35 mg·kg,观察肌肉震颤持续时间.③C57BL/6小鼠ip给予MPTP 30 mg·kg 7 d建立MPTP帕金森病模型.ig给予R-DM8021 5,10和20 mg-kg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-DM8021 0.2,0.5,1.0和2.0 mg·kg分别使APO诱导的旋转次数增加(17.3 4±4.5)%、(29.8±9.3)%、(30.2±13.9)%和(31.7±5.5)%;苯海索3.0,5.0和10.0 mg·kg组分别增加(18.8±4.8)%、(22.2±17.3)%和(36.9±10.0)%.连续给药21 d,大鼠APO诱导的旋转次数显著增加(P,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ED分别为(6.87±1.33)mg·kg和(41.14±9.31)mg·kg,两者相比具有显著性差异(P<0.01).③ip连续给予MPTP7 d,小鼠3 min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3 d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均有治疗作用且效果均优于苯海索.%OBJCETIVE To evaluate the therapeutic effect of anticholinergic agents l-demethyl phencynonate hydrochloride (R-DM8021) and trihexyphenidyl on Parkinson's disease (PD) modelanimals. METHODS ① The cerebral unilateral stereotactic directionally injection of6-hydroxydopamine (6-OHDA) was given to substantia nigra-striatum neurons of rats. The rotationtest 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. ②R-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.