The neurotoxin MPTP causes degeneration of specific nucleus A8, A9 and A10 dopaminergic neurons in the mouse
The neurotoxin MPTP causes degeneration of specific nucleus A8, A9 and A10 dopaminergic neurons in the mouse
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DOI：
10.1006/neur.1996.0041
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发表时间：
1996-12-01
期刊：
影响因子：
--
通讯作者：
Sonsalla, PK
中科院分区：
文献类型：
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作者：
German, DC;Nelson, EL;Sonsalla, PK
神经毒素MPTP已被用来在小鼠身上建立帕金森氏病的动物模型，部分原因是它导致黑质(A9核)中的多巴胺能神经元的显著损失。本研究的目的是确定MPTP是否也导致小鼠中脑A8和A10核多巴胺能神经元退化，就像人类帕金森病一样。两种常用的小鼠品系：FVB/N和C578L/6。MPTP的累积剂量为50-300 mg/kg。7天后，用高效液相色谱法测定纹状体中的多巴胺浓度，并用酪氨酸羟基酶抗体鉴定中脑多巴胺能神经元。用计算机成像系统绘制细胞位置图。在FVB/N株中，纹状体多巴胺浓度呈剂量依赖性下降。虽然最高剂量(300 mg/kg)导致纹状体多巴胺浓度下降86%，但中脑多巴胺能神经元只有中度和非显著的损失。在C57BL/6株中，高剂量MPTP(240 mg/kg)可使纹状体多巴胺浓度(95%)和中脑多巴胺能细胞数均显著减少，A8核丢失69%，A9核丢失75%，A10亚核腹侧被盖区细胞丢失42%，束间核丢失55%，中央线形核无细胞丢失。这些数据(1)提供了进一步的证据证明MPTP在不同品系的小鼠之间对MPTP毒性的不同敏感性，(2)表明纹状体多巴胺的显著耗竭并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准确位置，这将有助于未来的研究，试图确定MPTP选择性破坏中脑多巴胺能神经元的机制/S，以及(4)MPTP在C57BL16小鼠中引起中脑多巴胺能神经元变性，这是帕金森病患者在人类中变性的C57BL16小鼠。(C)1996年学术出版社有限公司
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 C578L/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. (C) 1996 Academic Press Limited