Ueda S, Aikawa M, Ishizuya-Oka A, Yamaoka S, Koibuchi N, Yoshimoto K
Department of Histology and Neurobiology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan.
Neuroscience. 2000;95(2):389-98. doi: 10.1016/s0306-4522(99)00451-0.
Oxidant stress has been implicated in the pathogenesis of Parkinson's disease. To test the oxidant stress hypothesis of dopaminergic degeneration, age-related changes in the mesostriatal dopamine neuron system were compared between zitter mutant rats which have abnormal metabolism of oxygen species in the brain and Sprague-Dawley rat as a control using the neurochemistry and immunohistochemistry. Dopamine content in the caudate-putamen, nucleus accumbens and olfactory tubercle of zitter rats decreased significantly with age, and was lower than that found in corresponding age-matched controls. In the zitter rats, the reduction of dopamine was more prominent in the caudate-putamen than in the nucleus accumbens and olfactory tubercle. A characteristic decline of tyrosine hydroxylase-immunoreactive fibers in the caudate-putamen of the zitter rat was also observed. In the dorsolateral caudate-putamen, reduction of tyrosine hydroxylase-immunoreactive fibers was observed in the matrix-like area, whereas in the ventromedial caudate-putamen the reduction occurred in the patch-like areas. Degeneration of tyrosine hydroxylase-immunoreactive fibers which was characterized by swollen varicosities and clustered fibers was observed in the caudate-putamen and nucleus accumbens and preceded loss of normal tyrosine hydroxylase-immunoreactive fibers in the caudate-putamen. Thus, the depletion of dopamine in the terminal areas is related to axonal degeneration. However, there was no degenerative tyrosine hydroxylase-immunoreactive fibers in the olfactory tubercle at any examined age, but reductions of tyrosine hydroxylase-immunoreactive fibers and dopamine contents were noted in the olfactory tubercle after four months-of-age. Since the zitter rats have an abnormal oxygen metabolism, the degeneration of tyrosine hydroxylase-immunoreactive fibers could result from an accumulation of superoxide species. The present results provide support for the oxidant stress hypothesis of dopaminergic neuronal degeneration and further indicate the region-specific vulnerability of the nigrostriatal dopamine system.
氧化应激与帕金森病的发病机制有关。为了验证多巴胺能神经元变性的氧化应激假说，利用神经化学和免疫组织化学方法，比较了脑内氧代谢异常的颤抖突变大鼠与作为对照的斯普拉格-道利大鼠中脑纹状体多巴胺神经元系统的年龄相关变化。随着年龄增长，颤抖大鼠尾状核-壳核、伏隔核和嗅结节中的多巴胺含量显著降低，且低于相应年龄匹配的对照大鼠。在颤抖大鼠中，尾状核-壳核中多巴胺的减少比伏隔核和嗅结节更明显。还观察到颤抖大鼠尾状核-壳核中酪氨酸羟化酶免疫反应性纤维有特征性减少。在背外侧尾状核-壳核的基质样区域观察到酪氨酸羟化酶免疫反应性纤维减少，而在腹内侧尾状核-壳核的斑块样区域出现减少。在尾状核-壳核和伏隔核中观察到以肿胀的曲张和聚集纤维为特征的酪氨酸羟化酶免疫反应性纤维变性，且早于尾状核-壳核中正常酪氨酸羟化酶免疫反应性纤维的丧失。因此，终末区域多巴胺的耗竭与轴突变性有关。然而，在任何检查年龄的嗅结节中均未发现变性的酪氨酸羟化酶免疫反应性纤维，但在4月龄后嗅结节中观察到酪氨酸羟化酶免疫反应性纤维和多巴胺含量减少。由于颤抖大鼠存在异常的氧代谢，酪氨酸羟化酶免疫反应性纤维的变性可能是由于超氧阴离子的积累所致。目前的结果为多巴胺能神经元变性的氧化应激假说提供了支持，并进一步表明黑质纹状体多巴胺系统存在区域特异性易损性。
