Attenuation of 6-hydroxydopamine-induced dopaminergic nigrostriatal lesions in superoxide dismutase transgenic mice
Attenuation of 6-hydroxydopamine-induced dopaminergic nigrostriatal lesions in superoxide dismutase transgenic mice
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DOI：
10.1016/s0306-4522(97)00665-9
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发表时间：
1998-08-01
期刊：
影响因子：
3.3
通讯作者：
Cadet, JL
中科院分区：
文献类型：
--
作者：
Asanuma, M;Hirata, H;Cadet, JL
6-羟基多巴胺是一种神经毒素，可引起啮齿类动物黑质纹状体多巴胺能通路的变性。它的毒性被认为涉及产生超氧阴离子继发于其自氧化。为了研究Cu，Zn-超氧化物歧化酶活性过度表达对6-羟基多巴胺诱导的多巴胺能神经元损伤的影响，我们测量了6-羟基多巴胺对纹状体和黑质多巴胺转运蛋白和黑质酪氨酸羟化酶免疫反应神经元的Cu，Zn-超氧化物歧化酶转基因小鼠的影响。在非转基因小鼠脑室内注射6-羟基多巴胺（50 μ g），在注射后两周处死的小鼠的大脑两侧产生纹状体区大小的减少和脑室的扩大。此外，6-羟基多巴胺引起纹状体和黑质[I-125]RTI-121标记的多巴胺转运蛋白显着减少，不仅在注射侧，而且在非转基因小鼠的非注射侧;这与这些小鼠两侧黑质中酪氨酸羟化酶免疫反应性多巴胺神经元的细胞数量和大小减少有关。与此相反，超氧化物歧化酶转基因小鼠对6-羟基多巴胺的神经毒性作用的保护，与纯合子转基因小鼠表现出几乎完全的protection.These结果提供了进一步的支持超氧阴离子的作用，6-hydroxydopamine的毒性作用。它们还提供了进一步的证据，表明活性氧可能是儿茶酚胺神经退行性作用的主要决定因素。
6-Hydroxydopamine is a neurotoxin that produces degeneration of the nigrostriatal dopaminergic pathway in rodents. Its toxicity is thought to involve the generation of superoxide anion secondary to its autoxidation. To examine the effects of the overexpression of Cu,Zn-superoxide dismutase activity on 6-hydroxydopamine-induced dopaminergic neuronal damage, we have measured the effects of 6-hydroxydopamine on striatal and nigral dopamine transporters and nigral tyrosine hydroxylase-immunoreactive neurons in Cu,Zn-superoxide dismutase transgenic mice. Intracerebroventricular injection of 6-hydroxydopamine (50 mu g) in non-transgenic mice produced reductions in the size of striatal area and an enlargement of the cerebral ventricle on both sides of the brains of mice killed two weeks after the injection. In addition, 6-hydroxydopamine caused marked decreases in striatal and nigral [I-125]RTI-121-labelled dopamine transporters not only on the injected side but also on the non-injected side of non-transgenic mice; this was associated with decreased cell number and size of tyrosine hydroxylase-immunoreactive dopamine neurons in the substantia nigra pars compacta on both sides in these mice. In contrast, superoxide dismutase transgenic mice were protected against these neurotoxic effects of 6-hydroxydopamine, with the homozygous transgenic mice showing almost complete protection.These results provide further support for a role of superoxide anion in the toxic effects of 6-hydroxydopamine. They also provide further evidence that reactive oxygen species may be the main determining factors in the neurodegenerative effects of catecholamines.