German D C, Nelson E L, Liang C L, Speciale S G, Sinton C M, Sonsalla P K
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas 75235-9070, USA.
Neurodegeneration. 1996 Dec;5(4):299-312. doi: 10.1006/neur.1996.0041.
The neurotoxin MPTP has been used to create an animal model of Parkinson's disease in the mouse, in part, because it causes a significant loss of dopaminergic neurons in the substantia nigra (nucleus A9). The purpose of the present study was to determine whether MPTP also causes degeneration of midbrain dopaminergic neurons in nuclei A8 and A10 in the mouse, as occurs in humans with Parkinson's disease. Two commonly used strains of mice were used: FVB/N and C57BL/6. MPTP was administered in cumulative doses of 50-300 mg/kg. Seven days later, dopamine concentrations were measured in the striatum using high performance liquid chromatography, and midbrain dopaminergic neurons were identified using an antibody against tyrosine hydroxylase. The cell locations were mapped with a computer imaging system. In the FVB/N strain, there was a dose-dependent decrease in striatal dopamine concentrations. Although the highest dose (300 mg/kg) caused an 86% reduction in striatal dopamine concentrations, there was only a moderate and non-significant loss of midbrain dopaminergic neurons. In the C57BL/6 strain, however, a high dose of MPTP (240 mg/kg) caused a significant reduction in both striatal dopamine concentrations (95%), and midbrain dopaminergic cells; 69% loss of nucleus A8 cells, 75% loss of nucleus A9 cells, and in nucleus A10 subnuclei there was 42% loss of ventral tegmental area cells, 55% loss of interfascicular nucleus cells, and no loss of cells in the central linear nucleus. These data (1) provide further evidence for differential susceptibility to MPTP toxicity among different mouse strains, (2) indicate that a significant depletion of striatal dopamine is not necessarily due to degeneration of midbrain dopaminergic neurons, (3) provide the precise locations of midbrain dopaminergic cells that are vulnerable to MPTP, which will aid future studies that seek to determine the mechanism/s by which-MPTP selectively destroys only certain midbrain dopaminergic neurons, and (4) indicate that MPTP produces midbrain dopaminergic neuronal degeneration in the same nuclei in the C57BL16 mouse that degenerate in humans with Parkinson's disease.
神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）已被用于建立小鼠帕金森病动物模型，部分原因是它会导致黑质（A9核）中多巴胺能神经元大量丧失。本研究的目的是确定MPTP是否也会导致小鼠中脑A8和A10核中的多巴胺能神经元退化，就像帕金森病患者那样。使用了两种常用的小鼠品系：FVB/N和C57BL/6。MPTP以50 - 300 mg/kg的累积剂量给药。7天后，使用高效液相色谱法测量纹状体中的多巴胺浓度，并使用抗酪氨酸羟化酶抗体鉴定中脑多巴胺能神经元。细胞位置通过计算机成像系统进行定位。在FVB/N品系中，纹状体多巴胺浓度呈剂量依赖性下降。尽管最高剂量（300 mg/kg）导致纹状体多巴胺浓度降低了86%，但中脑多巴胺能神经元仅有中度且不显著的丧失。然而，在C57BL/6品系中，高剂量的MPTP（240 mg/kg）导致纹状体多巴胺浓度（95%）和中脑多巴胺能细胞显著减少；A8核细胞丧失69%，A9核细胞丧失75%，在A10核亚核中，腹侧被盖区细胞丧失42%，束间核细胞丧失55%，中央线性核细胞未丧失。这些数据（1）为不同小鼠品系对MPTP毒性的易感性差异提供了进一步证据，（2）表明纹状体多巴胺的显著耗竭不一定是由于中脑多巴胺能神经元的退化，（3）提供了易受MPTP影响的中脑多巴胺能细胞的精确位置，这将有助于未来旨在确定MPTP仅选择性破坏某些中脑多巴胺能神经元的机制的研究，（4）表明MPTP在C57BL/6小鼠中与帕金森病患者中退化的相同核团中产生中脑多巴胺能神经元变性。
