Muthane U, Ramsay K A, Jiang H, Jackson-Lewis V, Donaldson D, Fernando S, Ferreira M, Przedborski S
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
Exp Neurol. 1994 Apr;126(2):195-204. doi: 10.1006/exnr.1994.1058.
The present study demonstrates that the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes significantly greater reductions in striatal dopamine levels in C57/bl mice than in CD-1 mice, thus confirming a greater sensitivity of the C57/bl mice to MPTP. To determine the possible reasons for this difference in MPTP sensitivity between these two mouse strains, we have compared both the organization and the number of substantia nigra (SN) neurons, the primary target of MPTP, in C57/bl and in CD-1 mice using immunostaining for tyrosine hydroxylase (TH) and calbindin-D28k (calbindin). In saline-injected animals, there is a significantly lower number of SN TH-positive and calbindin-positive neurons in C57/bl than CD-1 mice; no significant differences in the numbers of these neurons are found in the ventral tegmental area between the two strains. In MPTP-injected animals, the reductions in SN TH-positive neurons are significantly greater in C57/bl than in CD-1 mice. In contrast, MPTP does not cause any significant changes in the numbers of SN calbindin-positive neurons in either strain. The present study shows that C57/bl mice which have fewer SN TH-positive neurons are more sensitive to MPTP-induced toxicity than CD-1 mice. This observation suggests a possible inverse relationship between SN TH-positive neuron number and MPTP sensitivity. If correct, this hypothesis may be of major importance for Parkinson's disease since it is suggested that individuals at risk of developing this neurodegenerative disorder may have lower numbers of SN TH-positive neurons to start with. The present study also shows that SN calbindin-positive neurons are spared following MPTP administration. However, the observed difference in SN calbindin-positive neuron numbers does not account for the differential sensitivity to MPTP between these two mouse strains.
本研究表明，神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）导致C57/bl小鼠纹状体多巴胺水平的降低幅度显著大于CD-1小鼠，从而证实C57/bl小鼠对MPTP更为敏感。为了确定这两种小鼠品系对MPTP敏感性差异的可能原因，我们使用酪氨酸羟化酶（TH）和钙结合蛋白-D28k（钙结合蛋白）免疫染色，比较了C57/bl和CD-1小鼠中MPTP的主要靶标黑质（SN）神经元的组织结构和数量。在注射生理盐水的动物中，C57/bl小鼠中SN TH阳性和钙结合蛋白阳性神经元的数量显著低于CD-1小鼠；在这两个品系的腹侧被盖区，这些神经元的数量没有显著差异。在注射MPTP的动物中，C57/bl小鼠中SN TH阳性神经元的减少幅度显著大于CD-1小鼠。相比之下，MPTP对这两个品系中SN钙结合蛋白阳性神经元的数量均未引起任何显著变化。本研究表明，SN TH阳性神经元数量较少的C57/bl小鼠比CD-1小鼠对MPTP诱导的毒性更敏感。这一观察结果表明SN TH阳性神经元数量与MPTP敏感性之间可能存在反比关系。如果这一假设正确，那么它可能对帕金森病具有重要意义，因为有迹象表明，有患这种神经退行性疾病风险的个体最初可能就有较少的SN TH阳性神经元。本研究还表明，MPTP给药后SN钙结合蛋白阳性神经元未受影响。然而，观察到的SN钙结合蛋白阳性神经元数量差异并不能解释这两种小鼠品系对MPTP的不同敏感性。
