TIME-COURSE AND MORPHOLOGY OF DOPAMINERGIC NEURONAL DEATH CAUSED BY THE NEUROTOXIN 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE
TIME-COURSE AND MORPHOLOGY OF DOPAMINERGIC NEURONAL DEATH CAUSED BY THE NEUROTOXIN 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE
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DOI：
10.1016/1055-8330(95)90015-2
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发表时间：
1995-09-01
期刊：
影响因子：
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通讯作者：
PRZEDBORSKI, S
中科院分区：
文献类型：
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作者：
JACKSONLEWIS, V;JAKOWEC, M;PRZEDBORSKI, S
1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)诱导的多巴胺(DA)神经元死亡的机制尚不清楚，甚至在小鼠中是否发生神经元死亡也不清楚。体外研究表明，MPTP的活性代谢产物1-甲基-4-苯基吡啶离子(MPP(+))可通过细胞凋亡来杀死神经元。在此，我们研究了MPTP是否在体内诱导了小鼠DA神经元的死亡，其机制是否与细胞凋亡有关。C57/bl小鼠每隔2小时4次腹腔注射不同剂量的MPTP，在不同的时间点处死小鼠，进行中脑酪氨酸羟化酶(TH)免疫组织化学、银染和尼氏染色。我们发现MPTP可诱导黑质致密部(SNPC)和腹侧被盖区(VTA)神经元的破坏。变性活跃期于注射后12h开始，持续至4d。在此期间，TH阳性神经元的减少幅度大于Nissl染色的神经元，这表明MPTP可以在不破坏神经元的情况下导致TH的丢失。此后，两种技术的神经元计数相等，没有进一步的DA神经元丢失。死亡的神经元表现为胞浆内嗜酸性粒细胞缩小，胞核深染。双重染色显示仅在SNPC和VTA的TH阳性神经元中有变性神经元。未观察到MPTP作用的时间点和剂量的细胞凋亡。此外，原位标记没有发现DNA断裂的证据。本研究表明，MPTP小鼠模型复制了帕金森病模型中DA神经元变性的几个关键特征，并且没有体内证据表明，使用这种特定的注射范式，MPTP通过凋亡来杀死DA神经元。(C)1995年学术出版社有限公司
Mechanisms responsible for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine (DA) neuronal death remain unknown and in mice it is even unclear whether neuronal death does occur. In vitro studies suggest that 1-methyl-4-phenylpyridinium ion (MPP(+)), the active metabolite of MPTP, kills neurons by apoptosis. Herein, we investigated whether MPTP induces DA neuronal death in vivo in mice and whether the mechanism is that of apoptosis. C57/bl Mice received different doses of MPTP administered in four intraperitoneal injections every 2 hours and were sacrificed at different time points for analyses of tyrosine hydroxylase (TH) immunohistochemistry, silver staining, and Nissl staining within the mesencephalon. We found that MPTP induces neuronal destruction in the substantia nigra pars compacta (SNpc) and the ventral tegmental area (VTA). The active phase of degeneration began at 12 h postinjection and continued up to 4 days. During this period, there was a greater decrease in TH-defined neurons than in Nissl-stained neurons suggesting that MPTP can cause a loss in TH without necessarily destroying the neuron. Thereafter, neuronal counts by both techniques equalized and there was no further loss of DA neurons. Dying neurons showed shrunken eosinophilic cytoplasm and shrunken darkly stained nuclei. Double staining revealed degenerating neurons solely among TH positive neurons of SNpc and VTA. At no time point and at no dose of MPTP was apoptosis observed. In addition, in situ labelling revealed no evidence of DNA fragmentation. This study demonstrates that the MPTP mouse model replicates several key features of neurodegeneration of DA neurons in PD and provides no in vivo evidence that, using this specific paradigm of injection, MPTP kills DA neurons by apoptosis. (C) 1995 Academic Press Limited