Andringa G, Cools A R
Department of Psychoneuropharmacology, Faculty of Medicine, University of Nijmegen, The Netherlands.
J Neural Transm Suppl. 2000(60):215-25. doi: 10.1007/978-3-7091-6301-6_14.
The propargylamine CGP 3466B prevents dopamine cell death both in vitro and in rodent models of Parkinson's disease. The present study investigates the efficacy of this compound to prevent the behavioral consequences of dopaminergic cell death in the best animal model of Parkinson's disease, the bilaterally MPTP-treated monkey. Rhesus monkeys were bilaterally treated with MPTP, using a two-step procedure: 2.50 mg MPTP was infused into the left carotid artery followed by a second bolus of 1.25 mg into the right carotid artery, 8 weeks later. Subcutaneous injection of either 0.014 mg/kg CGP 3466B (n = 4) or its solvent (distilled water; n = 4), twice daily for fourteen days, started two hours after the second MPTP infusion. A Parkinson rating scale was assessed for the evaluation of the effects. After the first MPTP treatment, the monkeys developed mild to moderate parkinsonian symptoms. The second MPTP treatment strongly increased the severity of Parkinson scores in all control monkeys, as assessed on day 3, 7, 14, 21, 28 and 35 after the second MPTP treatment. In contrast, CGP 3466B nearly completely prevented the increase of parkinsonian symptoms after the second MPTP treatment. The therapeutic effects of CGP 3466B were still present after a washout period of 3 weeks, implying that the effects were not symptomatic. These data are the first to show that the systemic administration of CGP 3466B is able to prevent the development of MPTP-induced motor symptoms in primates. This compound may have great value for inhibiting the progression of the neurodegenerative process in patients with Parkinson's disease.
炔丙胺CGP 3466B在体外和帕金森病啮齿动物模型中均可防止多巴胺能细胞死亡。本研究在帕金森病最佳动物模型——双侧MPTP处理的猴子中，探究了该化合物预防多巴胺能细胞死亡行为后果的疗效。恒河猴采用两步法进行双侧MPTP处理：8周后，先向左侧颈动脉注入2.50 mg MPTP，然后向右侧颈动脉注入1.25 mg的第二次大剂量注射。在第二次MPTP注入两小时后开始，连续十四天每天两次皮下注射0.014 mg/kg CGP 3466B（n = 4）或其溶剂（蒸馏水；n = 4）。通过评估帕金森评定量表来评价效果。首次MPTP处理后，猴子出现了轻度至中度帕金森症状。第二次MPTP处理后，在第3、7、14、21、28和35天评估时，所有对照猴子的帕金森评分严重程度大幅增加。相比之下，CGP 3466B几乎完全阻止了第二次MPTP处理后帕金森症状的加重。在3周的洗脱期后，CGP 3466B的治疗效果仍然存在，这意味着其效果并非对症治疗。这些数据首次表明，全身性给予CGP 3466B能够预防灵长类动物中MPTP诱导的运动症状的发展。该化合物对于抑制帕金森病患者神经退行性过程的进展可能具有重要价值。
