The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce parkinsonism in man and non-human primates. Monoamine-oxidase B (MAO-B) has been reported to be implicated in both MPTP-induced parkinsonism and Parkinson's disease, since selegiline (L-deprenyl), an irreversible MAO-B inhibitor, prevents MPTP-induced neurotoxicity in numerous species including mice, goldfish and drosophyla. However, one disadvantage of this substance relates to its metabolism to (-)-methamphetamine and (-)-amphetamine. Rasagiline (R-(+)-N-propyl-1-aminoindane) is a novel irrevesible MAO-B-inhibitor, which is not metabolized to metamphetamine and/or amphetamine. The present study compared the effects of high doses of selegiline and rasagiline (10 mg/kg body weight s.c.) on MPTP-induced dopaminergic neurotoxicity in a non-human primate (Callithrix jacchus) model of PD. Groups of four monkeys were assigned to the following six experimental groups: Group I: Saline, Group II: Selegiline/Saline, Group III: Rasagiline/Saline, Group IV: MPTP/Saline, Group V: Rasagiline/MPTP, Group VI: Selegiline/MPTP. Daily treatment with MAO-B-inhibitors (either rasagiline or selegiline, 10 mg/kg body weight s.c.) was initiated four days prior to MPTP-exposure (MPTP-HCl, 2 mg/kg body weight subcutaneously, separated by an interval of 24 hours for a total of four days) and was continued until the end of the experiment, i.e. 7 days after the cessation of the MPTP-injections, when animals were sacrificed. MPTP-treatment caused distinct behavioural, histological, and biochemical alterations: 1. significant reduction of motor activity assessed by clinical rating and by computerized locomotor activity measurements; 2. substantial loss (approx. 40%) of dopaminergic (tyrosine-hydroxylase-positive) cells in the substantia nigra, pars compacta; and 3. putaminal dopamine depletion of 98% and its metabolites DOPAC (88%) and HVA (96%). Treatment with either rasagiline or selegiline markedly attenuated the neurotoxic effects of MPTP at the behavioural, histological, and at the biochemical levels. There were no significant differences between rasagiline/MPTP and selegiline/MPTP-treated animals in respect to signs of motor impairment, the number of dopaminergic cells in the substantia nigra, and striatal dopamine levels. As expected, both inhibitors decreased the metabolism of dopamine, leading to reduced levels of HVA and DOPAC (by >95% and 45% respectively). In conclusion, rasagiline and selegiline at the dosages employed equally protect against MPTP-toxicity in the common marmoset, suggesting that selegiline-derived metabolites are not important for the neuroprotective effects of high dose selegiline in the non-human MPTP-primate model in the experimental design employed. However, unexpectedly, high dose treatment with both MAO-inhibitors caused a decrease of the cell sizes of nigral tyrosine hydroxylase positive neurons. It remains to be determined, if this histological observation represents potential adverse effects of high dose treatment with monoamine oxidase inhibitors.

译文

神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 已被证明可诱导人类和非人类灵长类动物的帕金森病。据报道,单胺氧化酶B (mao-b) 与MPTP诱导的帕金森病和帕金森氏病有关,因为不可逆的mao-b抑制剂司来吉兰 (L-异戊二烯基) 可防止MPTP诱导的神经毒性。包括小鼠,金鱼和鱼肉。然而,该物质的一个缺点是其代谢为 (-)-甲基苯丙胺和 (-)-苯丙胺。雷沙吉兰 (R-()-N-propyl-1-aminoindane) 是一种新型的不可救性MAO-B-抑制剂,其不代谢为异丙胺和/或苯丙胺。本研究比较了高剂量司来吉兰和雷沙吉兰 (10 mg/kg体重s.C.) 对非人灵长类动物 (Callithrix jacchus) PD模型中MPTP诱导的多巴胺能神经毒性的影响。将四只猴子分为以下六个实验组: 第一组: 盐水,第二组: 司来吉兰/盐水,第三组: 雷沙吉兰/盐水,第四组: MPTP/盐水,第五组: 雷沙吉兰/MPTP,第六组: 司来吉兰/MPTP。在MPTP暴露 (MPTP-HCl,皮下2 mg/kg体重) 前四天开始每日使用MAO-B抑制剂 (雷沙吉兰或selegiline,10 mg/kg体重,间隔24小时,共4天),并一直持续到实验结束,即在MPTP注射停止后7天,当动物被处死时。MPTP治疗引起了明显的行为,组织学和生化改变: 1.通过临床评分和计算机运动活动测量评估的运动活动显着减少; 2.黑质中多巴胺能 (酪氨酸羟化酶阳性) 细胞的大量损失 (约40%); 和3.壳核多巴胺耗竭98% 及其代谢物DOPAC (88%) 和HVA (96%)。用雷沙吉兰或司来吉兰治疗可显着减弱MPTP在行为,组织学和生化水平上的神经毒性作用。雷沙吉兰/MPTP和司来吉兰/MPTP处理的动物在运动障碍的迹象,黑质中多巴胺能细胞的数量以及纹状体多巴胺水平方面没有显着差异。如预期的那样,两种抑制剂都降低了多巴胺的代谢,导致HVA和DOPAC水平降低 (分别> 95% 和45%)。总之,雷沙吉兰和司来吉兰在普通mar猴中同样可以防止MPTP毒性,这表明司来吉兰衍生的代谢产物对于在非人MPTP-灵长类动物模型中使用的高剂量司来吉兰的神经保护作用并不重要。然而,出乎意料的是,两种MAO抑制剂的高剂量治疗均导致黑质酪氨酸羟化酶阳性神经元的细胞大小减小。如果该组织学观察结果代表单胺氧化酶抑制剂高剂量治疗的潜在不良反应,还有待确定。

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