Date I, Felten D L, Felten S Y
Department of Neurobiology and Anatomy, University of Rochester School of Medicine, NY 14642.
Brain Res. 1990 Jun 11;519(1-2):266-76. doi: 10.1016/0006-8993(90)90088-s.
The long-term effect of the parkinsonism-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central monoaminergic neurons in young (2-3 months) and aging (12 months) C57BL/6 mice has been studied using neurochemical and immunocytochemical techniques. MPTP treatment (4 x 20 mg/kg i.p. given 12 h apart) resulted in significant depletion of dopamine (DA) concentration in the striatum, substantia nigra, nucleus accumbens, and olfactory tubercle 1 week after treatment in both young and aging mice. Although a decreased DA concentration in the ventral tegmental area was not seen in young mice, aging mice did show a significant decrease. The extent of decrease of DA concentration was greater in aging mice than in young mice in all areas investigated except in dorsal striatum. The long-term effect of MPTP on DA neurons in young mice included considerable recovery of DA concentration in both nigrostriatal and mesolimbic DA systems following the initial profound depletion; such recovery was minimal in aging mice, even 3 months after MPTP treatment. In young mice treated with MPTP, no significant change of norepinephrine (NE) or serotonin (5-HT) concentration was observed in any area investigated while a significant decrease of NE and 5-HT concentration was seen in several brain areas investigated in aging mice. Immunocytochemical analysis revealed that the MPTP injection resulted in marked disappearance of tyrosine hydroxylase (TH)-immunoreactive (IR) fibers in striatum of both young and aging mice 1 week following treatment. Partial recovery of TH-IR fibers was seen 5 weeks or 3 months after MPTP treatment in young mice, while no such apparent recovery was seen in aging mice. Aging mice also showed significant decrease in the number of TH-positive cell bodies in the substantia nigra and ventral tegmental area through all periods investigated, while such a significant decrease was only seen in the substantia nigra of young mice 1 week after treatment. We conclude that aging mice are more sensitive to MPTP and show more widespread damage to the monoaminergic systems than young mice, suggesting that MPTP-treated aging mice provide a more useful model for studying anatomical and neurochemical characteristics of Parkinson's disease than young mice.
利用神经化学和免疫细胞化学技术，研究了帕金森病诱导性神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）对年轻（2 - 3个月）和老龄（12个月）C57BL/6小鼠中枢单胺能神经元的长期影响。MPTP处理（腹腔注射，4×20 mg/kg，间隔12小时给药）导致年轻和老龄小鼠在处理后1周时，纹状体、黑质、伏隔核和嗅结节中的多巴胺（DA）浓度显著降低。虽然在年轻小鼠中未观察到腹侧被盖区DA浓度降低，但老龄小鼠确实出现了显著降低。除背侧纹状体外，在所有研究区域中，老龄小鼠DA浓度的降低程度均大于年轻小鼠。MPTP对年轻小鼠DA神经元的长期影响包括，在最初深度耗竭后，黑质纹状体和中脑边缘DA系统中的DA浓度有相当程度的恢复；而在老龄小鼠中，即使在MPTP处理3个月后，这种恢复也很微小。在用MPTP处理的年轻小鼠中，在所研究的任何区域均未观察到去甲肾上腺素（NE）或5-羟色胺（5-HT）浓度有显著变化，而在老龄小鼠所研究的几个脑区中，NE和5-HT浓度出现了显著降低。免疫细胞化学分析显示，MPTP注射导致处理后1周时，年轻和老龄小鼠纹状体中酪氨酸羟化酶（TH）免疫反应性（IR）纤维明显消失。在年轻小鼠中，MPTP处理5周或3个月后可见TH-IR纤维部分恢复，而老龄小鼠未见这种明显恢复。在所有研究时期，老龄小鼠黑质和腹侧被盖区中TH阳性细胞体数量也显著减少，而在年轻小鼠中，仅在处理后1周时黑质中出现这种显著减少。我们得出结论，老龄小鼠对MPTP更敏感，并且与年轻小鼠相比，单胺能系统受损更广泛，这表明MPTP处理的老龄小鼠比年轻小鼠为研究帕金森病的解剖学和神经化学特征提供了更有用的模型。
