DOES NEUROMELANIN CONTRIBUTE TO THE VULNERABILITY OF CATECHOLAMINERGIC NEURONS IN MONKEYS INTOXICATED WITH MPTP
DOES NEUROMELANIN CONTRIBUTE TO THE VULNERABILITY OF CATECHOLAMINERGIC NEURONS IN MONKEYS INTOXICATED WITH MPTP
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DOI：
10.1016/0306-4522(93)90349-k
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发表时间：
1993-09-01
期刊：
影响因子：
3.3
通讯作者：
AGID, Y
中科院分区：
文献类型：
--
作者：
HERRERO, MT;HIRSCH, EC;AGID, Y
神经黑色素是灵长类中脑神经元衰老过程中积累的儿茶酚胺代谢的副产物，它是否导致帕金森病中多巴胺能神经元亚群的选择性易感性，这一问题已经被提出。1-甲基-4-苯基吡啶（MPP+）是1-甲基，4-苯基，1,2,3,6-四氢吡啶（MPTP）的代谢物，对多巴胺能神经元有毒，特别是在灵长类动物中，产生类似于帕金森病观察到的运动综合征。为了检验这种神经毒素是否优先影响黑化神经元，我们分析了食蟹猴中脑MPTP中毒后黑化和非黑化儿茶酚胺能神经元的存活情况。实验在6只长期接受MPTP治疗的动物（2只严重残疾，4只中度残疾）和2只年龄匹配的对照猴子身上进行。在整个中脑的有规则间隔的切片上检查了两类神经元：用酪氨酸羟化酶免疫组织化学鉴定的儿茶酚胺能神经元和用马森方法可视化的含有神经黑色素的神经元。利用计算机辅助图像分析，估计了不同中脑儿茶酚胺能细胞组中每种类型神经元的总数。在对照动物的中脑中，并非所有儿茶酚胺能神经元都含有神经黑色素。与酪氨酸羟化酶阳性神经元总数相比，黑质致密部（81.5%）和蓝斑部（98%）黑质外侧部（70%）、儿茶酚胺能细胞组A8（50%）和腹侧被盖区（41.5%）黑化神经元的比例较高，而在中央灰质中几乎为零。在mptp治疗的猴子中，儿茶酚胺能神经元损失的严重程度在不同的中脑细胞组中是不同的，尽管严重和轻度残疾的猴子的强度相似。发现mptp中毒动物中脑不同细胞组多巴胺能神经元的丢失与其正常含有的黑化神经元百分比之间存在相关性（r = 0.98; P = 0.04）。儿茶酚胺能神经元在蓝斑（唯一研究的去肾上腺素能细胞组）中的损失百分比低于从多巴胺能细胞组中获得的相关曲线。总之，这些发现表明：(i)多巴胺能神经元比去甲肾上腺素能神经元更容易受到mptp毒性的影响；（ii）在多巴胺能神经元中，含有神经黑色素的神经元更容易受到影响，表明神经黑色素可能在mptp毒性中起作用。然而，神经黑色素可能只是神经毒素诱导的神经元死亡的因素之一，因为一些黑化的神经元也能在mptp中毒中存活。
The question has been raised as to whether neuromelanin, a by-product of catecholamine metabolism which accumulates during aging in primate midbrain neurons, contributes to the selective vulnerability of subgroups of dopaminergic neurons in Parkinson's disease. 1-Methyl-4-phenylpyridinium (MPP+) a metabolite of 1-methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP) is toxic to dopaminergic neurons, particularly in primates, producing a motor syndrome similar to that observed in Parkinson's disease. To test whether this neurotoxin preferentially affects melanized neurons, the survival of melanized and non-melanized catecholaminergic neurons was analysed after MPTP intoxication in the midbrain of the cynomolgus monkey (Macaca fascicularis). Experiments were performed on six animals chronically treated with MPTP (two were severely disabled, four moderately affected) and two age-matched control monkeys.Two populations of neurons were examined on regularly spaced sections throughout the midbrain: catecholaminergic neurons, identified by tyrosine hydroxylase immunohistochemistry and neuromelanin-containing neurons, visualized by Masson's method. The total number of neurons of each type was estimated in the different midbrain catecholaminergic cell groups using computer assisted image analysis. In the midbrains of control animals not all catecholaminergic neurons contained neuromelanin. The percentage of melanized neurons compared to the total population of tyrosine hydroxylase-positive neurons was high in the substantia nigra pars compacta (81.5%) and in the locus coeruleus (98%), intermediate in the substantia nigra pars lateralis (70%), in the catecholaminergic cell group A8 (50%), and in the ventral tegmental area (41.5%) and almost nil in the central gray substance. In MPTP-treated monkeys, the severity of the loss of catecholaminergic neurons was variable within the different midbrain cell groups, though of similar intensity in severely and mildly disabled monkeys. A relationship was found between the loss of dopaminergic neurons in the different mesencephalic cell groups of MPTP-intoxicated animals and the percentage of melanized neurons they normally contain (r = 0.98; P = 0.04). The percentage loss of catecholaminergic neurons in the locus coeruleus, the only noradrenergic cell group studied, was lower than expected from the correlation curve obtained for dopaminergic cell groups.Altogether, these findings indicate: (i) that dopaminergic neurons are more vulnerable to MPTP-toxicity than noradrenergic neurons; and (ii) that among dopaminergic neurons, those containing neuromelanin are more susceptible, indicating a possible role of neuromelanin in MPTP-toxicity. Nevertheless, neuromelanin may only represent one of the factors involved in the neurotoxin-induced neuronal death, since some nigral melanized neurons also survive MPTP-intoxication.