The neuroprotective effect of tetrahydrobiopterin

描述(申请人提供)：虽然帕金森病(PD)可能有多种病因，但核心致病特征是多巴胺能神经元退化，特别是黑质致密部(SNPC)中的多巴胺能神经元，具有共同的最终通路，涉及氧化损伤、线粒体功能障碍或两者兼而有之。因此，人们可能假设SNPC中的多巴胺能神经元选择性地容易受到氧化应激和/或线粒体破坏的影响，了解这种选择性的机制可能会揭示其发病机制。然而，我们的数据显示，培养的腹侧中脑多巴胺能神经元具有增强的抗氧化能力，因为它们比非多巴胺能神经元更能抵抗氧化应激，如谷胱甘肽耗竭和过氧化氢处理。此外，它们增强的抗氧化能力反映在比非多巴胺能神经元更低的活性氧(ROS)和更高的还原型谷胱甘肽水平上。我们假设，增强的抗氧化能力对于可能受到多巴胺及其代谢产物增加的氧化应激的多巴胺能神经元的生存至关重要。我们推测，这种天生的抗氧化能力的破坏使它们容易受到额外的环境侮辱，从而导致选择性退化。我们注意到，腹侧中脑多巴胺能神经元抗氧化能力的增强是由于四氢生物蝶呤(BH4)，它是产生多巴胺的酶酪氨酸羟基酶的辅助因子，但也降低了超氧化物歧化水平，部分是直接清除作用，并调节线粒体功能。首先，我们将研究BH4对线粒体生物能量学和功能的影响，包括启动死亡途径。其次，我们将研究BH4在NO和超氧化物生成以及在调节其他内源性抗氧化系统中的作用。第三，BH4对1-甲基-4-苯基-1，2，3，6-四氢吡啶、鱼藤酮毒性和谷胱甘肽耗竭等帕金森病模型的神经保护作用将在体内和器官切片培养中进行测试，使用缺乏BH4生产的HPH-1小鼠。

DESCRIPTION (provided by applicant): While multiple etiologies are likely to account for Parkinson's disease (PD), the core pathogenic feature is degeneration of dopaminergic neurons, particularly those in the substantia nigra pars compacta (SNpc), with shared common final pathways involving oxidative damage, mitochondrial dysfunction, or both. Therefore, one may hypothesize that dopaminergic neurons in the SNpc are selectively vulnerable to oxidative stresses and/or mitochondrial disruption and understanding the mechanism of this selectivity may reveal the pathogenesis. However, our data show that ventral mesencephalic dopaminergic neurons in culture have an enhanced antioxidant capacity, as they are better able to resist oxidative stresses such as glutathione depletion and peroxide treatment than nondopaminergic neurons. In addition, their enhanced antioxidant capacity is reflected in lower reactive oxygen species (ROS) and higher reduced glutathione levels than nondopaminergic neurons. We hypothesize that an enhanced antioxidant capacity is essential for the survival of dopaminergic neurons that may be subjected to increased oxidative stress exerted by dopamine and its metabolites. We postulate that disruption of this innate antioxidant capacity makes them vulnerable to additional environmental insults and thereby leads to selective degeneration. We noted that the enhanced antioxidant capacity in ventral mesencephalic dopaminergic neurons is due to tetrahydrobiopterin (BH4), which is the cofactor for tyrosine hydroxylase, the enzyme producing dopamine, but also lowers superoxide levels, partly be direct scavenging effect and modulates mitochondrial function. First, We will study the effect of BH4 on mitochondrial bioenergetics and function including initiation of death pathways. Second, we will examine the role of BH4 on NO and superoxide generation and in modulating other endogenous antioxidant systems. Third, the neuroprotective function of BH4 against PD models such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, rotenone toxicity, and glutathione depletion will be tested in vivo and in organotypic slice cultures, using hph-1 mice that are deficient in BH4, production.