Parkinson's disease (PD) is the second common neurodegenerative disorder. Deficit of the nigro-striatal dopaminergic neurons causes the motor symptoms of PD. While the oxidative stress is thought to be deeply involved in the etiology of PD, molecular targets for the oxidative insults has not been fully elucidated. 6R-5,6,7,8-Tetrahydrobiopterin (BH4) is a cofactor for tyrosine hydroxylase (TH), the rate-limiting enzyme for production of dopamine, and easily oxidized to its dihydro-form. In this study, we examined the alteration in the metabolism of BH4 caused by a parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP reduced the dopamine content and the in vivo activity of TH in the striatum prior to degeneration of the dopaminergic neurons. We found that administration of BH4 could restore the dopamine content and in vivo TH activity in the striatum of MPTP-treated mice. Unexpectedly, when BH4 was administered with MPTP, BH4 contents in the brain were far higher than those injected without MPTP even at 23 h after the last injection. Because MPTP has been shown to increase ROS production in the dopaminergic neurons, we assumed that the increased ROS oxidizes BH4 into its dihydro-form, excreted from the dopaminergic neurons, taken-up by the neighboring cells, reduced back to BH4, and then accumulated in the brain. We also investigated the action of MPTP in mice lacking quinonoid-dihydropteridine reductase (Qdpr), an enzyme catalyzing regeneration of BH4 from quinonoid dihydrobiopterin. The dopamine depletion induced by MPTP was severer in Qdpr-deficient mice than in wild-type mice. The present data suggest that perturbation of the BH4 metabolism would be the cause of early and persistent dopamine depletion in the striatum.

中文翻译：

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给予四氢生物蝶呤恢复了由MPTP的急性作用引起的纹状体中多巴胺的下降。

帕金森氏病（PD）是第二种常见的神经退行性疾病。黑质纹状体多巴胺能神经元的缺乏会导致PD的运动症状。尽管人们认为氧化应激与PD的病因密切相关，但尚未完全阐明氧化损伤的分子靶标。6R-5,6,7,8-四氢生物蝶呤（BH4）是酪氨酸羟化酶（TH）的辅助因子，酪氨酸羟化酶是生产多巴胺的限速酶，容易氧化成二氢形式。在这项研究中，我们检查了帕金森氏神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）引起的BH4代谢变化。MPTP降低了多巴胺能神经元变性之前纹状体中的多巴胺含量和TH的体内活性。我们发现，施用BH4可以恢复MPTP处理的小鼠纹状体中的多巴胺含量和体内TH活性。出乎意料的是，当BH4与MPTP一起使用时，即使在最后一次注射后23小时，大脑中的BH4含量也远高于未注射MPTP的情况。由于已显示MPTP增加多巴胺能神经元中ROS的产生，因此我们假设增加的ROS将BH4氧化成其二氢形式，从多巴胺能神经元中排出，被邻近细胞吸收，还原为BH4，然后积累在大脑中。我们还研究了MPTP在缺乏醌类-二氢蝶呤还原酶（Qdpr）的小鼠中的作用，该酶催化从醌类双氢生物蝶呤再生BH4。Qdpr缺陷型小鼠中MPTP引起的多巴胺耗竭比野生型小鼠严重。