Immobilization stress causes increases in tetrahydrobiopterin, dopamine, and neuromelanin and oxidative damage in the nigrostriatal system
Immobilization stress causes increases in tetrahydrobiopterin, dopamine, and neuromelanin and oxidative damage in the nigrostriatal system
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DOI：
10.1111/j.1471-4159.2005.03342.x
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发表时间：
2005-10-01
影响因子：
4.7
通讯作者：
Hwang, O
中科院分区：
文献类型：
--
作者：
Kim, ST;Choi, JH;Hwang, O
氧化应激被认为有助于帕金森病的病理生理学，其中黑质纹状体多巴胺能（DA）神经元经历变性。鉴定有助于产生氧化应激和这些细胞的脆弱性的内源性分子对于理解这种疾病的病因至关重要。暴露于四氢生物蝶呤（BH 4），DA合成的强制性辅因子，以前观察到造成DA细胞的氧化损伤。为了证明这一观察结果的生理相关性，我们研究了体内是否真的会发生BH4和DA的过度产生，如果确实如此，这是否会导致黑质纹状体系统的氧化损伤。束缚应激（IMO）使BH4和DA及其合成酶酪氨酸羟化酶和GTP环化水解酶I升高。这是伴随着升高的脂质过氧化和蛋白结合醌，抗氧化酶的活性。氧化应激指数的这些增加似乎是由于BH4合成增加，因为它们在给予BH4合成抑制剂2，4-二氨基-6-羟基-嘧啶后被消除。IMO还引起神经黑色素的积累和黑质纹状体系统的变性。这些结果表明，严重的应激可增加BH 4和DA，并导致体内DA神经元的氧化损伤，表明与帕金森病有关。
Oxidative stress is believed to contribute to the pathophysiology of Parkinson's disease, in which nigrostriatal dopaminergic (DA) neurons undergo degeneration. Identification of endogenous molecules that contribute to generation of oxidative stress and vulnerability of these cells is critical in understanding the etiology of this disease. Exposure to tetrahydrobiopterin (BH4), the obligatory cofactor for DA synthesis, was observed previously to cause oxidative damage in DA cells. To demonstrate the physiological relevance of this observation, we investigated whether an overproduction of BH4 and DA might actually occur in vivo, and, if it did, whether this might lead to oxidative damage to the nigrostriatal system. Immobilization stress (IMO) elevated BH4 and DA and their synthesizing enzymes, tyrosine hydroxylase and GTP cyclohydrolase I. This was accompanied by elevation of lipid peroxidation and protein-bound quinone, and activities of antioxidant enzymes. These increases in the indices of oxidative stress appeared to be due to increased BH4 synthesis because they were abolished following administration of the BH4 synthesis inhibitor, 2,4-diamino-6-hydroxy-pyrimidine. IMO also caused accumulation of neuromelanin and degeneration of the nigrostriatal system. These results demonstrate that a severe stress can increase BH4 and DA and cause oxidative damages to the DA neurons in vivo, suggesting relevance to Parkinson's disease.