Biomarkers of Oxidative Stress in Parkinson's Disease

描述（由申请人提供）：本申请涉及广泛的挑战领域（03）：验证和特定挑战主题03- at -102：抗氧化生物标志物。氧化应激生物标志物的开发和验证，可用于评估体内膳食补充剂的抗氧化作用。帕金森病（PD）以及其他神经退行性疾病与氧化损伤有关。在PD中，黑质中还原性谷胱甘肽的早期减少，以及脂质，蛋白质和DNA氧化标记物的增加。许多实验室报告了PD患者血浆和脑脊液氧化应激生物标志物的增加。我们最近发现PD患者血浆中尿酸降低，8-羟基-2-脱氧鸟苷（8-OHdG）升高。目前，我们正在进行一项针对帕金森病的抗氧化营养补充剂辅酶Q10 （CoQ10）的III期临床试验。600名新诊断的未服药的帕金森病患者被随机分配到安慰剂组，每天服用1200mg辅酶q10或2400 mg辅酶q10。患者每3个月使用统一帕金森病评定量表（UPDRS）进行评估，直到他们需要多巴胺能治疗或完成16个月。我们建议在基线、治疗1、8和16个月时测量几种氧化损伤标志物。我们将测量血浆8-羟色胺，丙二醛，抗坏血酸，尿酸，氧化和还原辅酶q10，氧化和还原谷胱甘肽的水平。所有样品将使用高效液相色谱与库仑阵列检测的代谢组学分析进行检查。这样可以检测到多达2000个具有电化学活性的小分子。单个峰值的测量将与氧化损伤的已建立的标记相关联，如8-OHdG，丙二醛和氧化/还原谷胱甘肽的比例，以确定是否可以识别出更敏感和特定的氧化应激新生物标记。生物标志物将与PD患者的临床改善相关，通过UPDRS评分进行评估。这些研究将建立现有氧化损伤生物标志物的相对效用，并可能导致新的生物标志物的发展，这将有助于评估体内膳食补充剂的抗氧化效果，并有助于评估其对人体健康的有效性。因此，这些研究可能有助于确定大量可能影响人类健康的饮食干预措施的有效性。

DESCRIPTION (provided by applicant): This application addresses broad challenge area (03): Validation and Specific Challenge Topic 03-AT-102: Antioxidant biomarkers. Development and validation of biomarkers of oxidative stress that could be used to assess the antioxidant effects of dietary supplements in vivo. Parkinson's Disease (PD) as well as other neurodegenerative diseases are associated with oxidative damage. In PD, there is an early reduction in reduced glutathione in the substantia nigra, as well as increases in markers of lipid, protein and DNA oxidation. A number of laboratories have reported increases in plasma and cerebrospinal fluid biomarkers of oxidative stress in PD. We recently found reduced uric acid and increased 8-hydroxy-2-deoxyguanosine (8-OHdG) in plasma of PD patients. We are presently carrying out a phase III clinical trial of the antioxidant nutritional supplement coenzyme Q10 (CoQ10) in PD. Six hundred newly diagnosed unmedicated PD subjects are being randomized to placebo, 1200mg of CoQ10 or 2400 mg of CoQ10 daily. Patients are assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) every 3 months until they require dopaminergic therapy or they complete 16 months. We propose to measure several markers of oxidative damage at baseline, 1, 8 and 16 months of therapy. We will measure plasma levels of 8-OHdG, malondialdehyde, ascorbic acid, uric acid, oxidized and reduced CoQ10, and oxidized and reduced glutathione. All samples will be examined using metabolomic profiling using HPLC with coulometric array detection. This results in detection of up to 2000 small molecules, which are electrochemically active. The measurements of individual peaks will be correlated with those of established markers of oxidative damage such as 8-OHdG, malondialdehyde and the ratio of oxidized/reduced glutathione, to see if more sensitive and specific novel biomarkers of oxidative stress can be identified. The biomarkers will be correlated with clinical improvements in PD patients as assessed using UPDRS scores. These studies will establish the relative utility of existing biomarkers of oxidative damage, and may lead to the development of novel biomarkers, which will be useful in assessing the efficacy of the antioxidant effects of dietary supplements in vivo, and will help in assessing their effectiveness with respect to human health. As such, these studies may be useful in establishing the effectiveness of a large number of dietary interventions, which may impact human health. Public Health Relevance: This study proposes to identify biomarkers of oxidative stress to facilitate in vivo study of the antioxidant effects of the dietary supplement coenzyme Q10 (CoQ10). We intend to comprehensively evaluate a panel of established markers of oxidative damage and to utilize metabolic profiling to identify novel markers of oxidative stress. We will examine the relative sensitivity of these biomarkers in relationship to clinical efficacy of CoQ10 in a phase III clinical trial in Parkinson's Disease. The development of useful biomarkers to assess oxidative stress in relationship to human health, has the potential of having a major impact in the development of therapies to treat and prevent neurodegenerative diseases. These biomarkers may be useful in assessing therapeutic interventions in numerous other human illnesses in which oxidative stress plays an important role.