Andringa G, van Oosten R V, Unger W, Hafmans T G, Veening J, Stoof J C, Cools A R
Department of Psychoneuropharmacology, University of Nijmegen, Nijmegen, The Netherlands.
Eur J Neurosci. 2000 Aug;12(8):3033-43. doi: 10.1046/j.1460-9568.2000.00181.x.
The ability of CGP 3466B to attenuate the behavioural and morphological consequences of experimentally induced cell death was investigated in a recently updated animal model of Parkinson's disease. 6-Hydroxydopamine was infused bilaterally into the substantia nigra pars compacta of rats that were pretreated with desimipramine. Treatment with CGP 3466B (0.0014-1.4 mg/kg, injected subcutaneously) or its solvent was begun 2 h after the 6-OHDA injection, and maintained twice daily for 14 days. After a washout period of 14 days, changes in motor behaviour were evaluated, using the open field test (analysis of normal and abnormal stepping, e.g.) and the paw test (analysis of retraction time of limbs). Changes in learning and memory were evaluated with the help of the Morris water maze task. Following immunocytochemical staining of tyrosine hydroxylase, the extent of the lesion was quantified using a computerized system. CGP 3466B prevented all deficits produced by 6-hydroxydopamine (6-OHDA), though at different doses. It prevented: abnormal stepping (0.0014-0.014 mg/kg); increased forelimb and hindlimb retraction time (0.014-0.14 mg/kg and 0.0014-0.14 mg/kg, respectively); delayed learning (1.4 mg/kg); and reduced tyrosine hydroxylase immunoreactivity in the substantia nigra (0.0014-0.014 mg/kg). CGP 3466B (0.0014-0.14 mg/kg) induced no deficits in sham-treated rats. CGP 3466B (1.4 mg/kg), however, did not show any benefit on motor deficits in 6-OHDA-lesioned rats, and induced abnormal movements and decreased the tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta and the ventral tegmental area of sham-lesioned animals. It is concluded that CGP 3466B prevents all 6-OHDA-induced behavioural and immunocytochemical deficits, though at different doses. CGP 3466B is suggested to be a valuable agent for inhibiting the dopaminergic degeneration in patients with Parkinson's disease.
在最近更新的帕金森病动物模型中，研究了CGP 3466B减轻实验性诱导细胞死亡的行为和形态学后果的能力。将6-羟基多巴胺双侧注入用去甲丙咪嗪预处理的大鼠黑质致密部。在6-OHDA注射后2小时开始用CGP 3466B（0.0014 - 1.4mg/kg，皮下注射）或其溶剂进行治疗，并每天维持两次，持续14天。在14天的洗脱期后，使用旷场试验（例如分析正常和异常步态）和爪子试验（分析肢体回缩时间）评估运动行为的变化。借助莫里斯水迷宫任务评估学习和记忆的变化。在酪氨酸羟化酶免疫细胞化学染色后，使用计算机系统对损伤程度进行量化。CGP 3466B可预防6-羟基多巴胺（6-OHDA）产生的所有缺陷，尽管剂量不同。它预防了：异常步态（0.0014 - 0.014mg/kg）；前肢和后肢回缩时间增加（分别为0.014 - 0.14mg/kg和0.0014 - 0.14mg/kg）；学习延迟（1.4mg/kg）；以及黑质中酪氨酸羟化酶免疫反应性降低（0.0014 - 0.014mg/kg）。CGP 3466B（0.0014 - 0.14mg/kg）在假手术处理的大鼠中未诱导出缺陷。然而，CGP 3466B（1.4mg/kg）对6-OHDA损伤大鼠的运动缺陷没有显示出任何益处，并且在假损伤动物的黑质致密部和腹侧被盖区诱导了异常运动并降低了酪氨酸羟化酶免疫反应性。得出的结论是，CGP 3466B可预防所有6-OHDA诱导的行为和免疫细胞化学缺陷，尽管剂量不同。CGP 3466B被认为是抑制帕金森病患者多巴胺能变性的一种有价值的药物。
