Kupsch A, Sautter J, Schwarz J, Riederer P, Gerlach M, Oertel W H
Ludwig-Maximilians-University, Klinikum Grosshadern, Department of Neurology, München, Germany.
Brain Res. 1996 Nov 25;741(1-2):185-96. doi: 10.1016/s0006-8993(96)00917-1.
The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce parkinsonism in man and non-human primates. Hypotheses concerning the mechanism of action of MPTP have been related to the pathogenesis of nigral cell death in Parkinson's disease. For instance, alterations of calcium influxes have been reported to be implicated in both MPTP-induced parkinsonism and Parkinson's disease. Recently, we reported that nimodipine, a blocker of L-type calcium channels, prevents dopaminergic MPTP-induced neurotoxicity in C57B1/6 black mice. The present study extended these rodent findings to the non-human primate model of Parkinson's disease and assessed the effects of nimodipine, continuously applied by pellet for 18 days, on behavioural, biochemical and histological parameters, following systemic application of MPTP in common marmosets (Callithrix jacchus). The experimental design involved five groups of common marmosets and a total of 24 animals. Monkeys assigned to group I (n = 4) received subcutaneously implanted vehicle pellets 7 days prior to subcutaneous saline injections (control). Monkeys of group II (n = 4) were treated with nimodipine pellets (80 mg) and saline injections. Marmosets in group III (n = 8) were treated with vehicle pellets and received 4 times MPTP (MPTP-HCl, 2 mg/kg body weight subcutaneously, separated by an interval of 24 h for a total of 4 days). Monkeys in group IV (n = 4) and V (n = 4) were treated as group-III animals except for the implantation of nimodipine pellets (80 mg and 120 mg, respectively) 7 days prior to toxin exposure. In common marmosets MPTP induced severe parkinsonian symptoms, a pronounced dopamine depletion in the caudate-putamen (more than 99% of control) and a loss of tyrosine hydroxylase immunoreactive cells in the substantia nigra (50% percent of control) 7 days after MPTP-administration. Pretreatment with nimodipine (120 mg pellets) did neither attenuate the behavioural impairments in MPTP-treated animals nor antagonize the striatal neurotoxin-induced dopamine depletion, but almost completely prevented (in a dose-dependent manner) the MPTP-induced decrease of nigral tyrosine hydroxylase immunoreactive cells. These data suggest that application of nimodipine, during the observation period of 7 days, protects against MPTP-induced neurotoxicity in common marmosets at the cellular nigral level, but not at the synaptic striatal level, implicating differential mechanisms of actions of MPTP-induced neurotoxicity at the nigral versus the striatal level.
神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）已被证明可在人类和非人类灵长类动物中诱发帕金森症。关于MPTP作用机制的假说与帕金森病中黑质细胞死亡的发病机制有关。例如，据报道钙内流的改变与MPTP诱导的帕金森症和帕金森病都有关。最近，我们报道了L型钙通道阻滞剂尼莫地平可预防C57B1/6黑小鼠中多巴胺能MPTP诱导的神经毒性。本研究将这些啮齿动物的研究结果扩展到帕金森病的非人类灵长类动物模型，并评估了在普通狨猴（Callithrix jacchus）全身应用MPTP后，通过颗粒持续给药18天的尼莫地平对行为、生化和组织学参数的影响。实验设计包括五组普通狨猴，共24只动物。分配到第一组（n = 4）的猴子在皮下注射生理盐水前7天接受皮下植入的载体颗粒（对照）。第二组（n = 4）的猴子用尼莫地平颗粒（80 mg）和生理盐水注射治疗。第三组（n = 8）的狨猴用载体颗粒治疗，并接受4次MPTP（MPTP-HCl，2 mg/kg体重皮下注射，间隔24小时，共4天）。第四组（n = 4）和第五组（n = 4）的猴子除在毒素暴露前7天植入尼莫地平颗粒（分别为80 mg和120 mg）外，治疗方式与第三组动物相同。在普通狨猴中，MPTP给药7天后可诱发严重的帕金森症状、尾状核-壳核中明显的多巴胺耗竭（超过对照的99%）以及黑质中酪氨酸羟化酶免疫反应性细胞的丢失（对照的50%）。用尼莫地平（120 mg颗粒）预处理既不能减轻MPTP处理动物的行为损伤，也不能拮抗纹状体神经毒素诱导的多巴胺耗竭，但几乎完全预防了（呈剂量依赖性）MPTP诱导的黑质酪氨酸羟化酶免疫反应性细胞减少。这些数据表明，在7天的观察期内应用尼莫地平可在普通狨猴的黑质细胞水平上保护其免受MPTP诱导的神经毒性，但在纹状体突触水平上则不能，这意味着MPTP诱导的神经毒性在黑质和纹状体水平上的作用机制不同。
