Biomarkers of Oxidative Stress in Parkinson's Disease

帕金森病氧化应激的生物标志物

• 批准号: 7933687
• 负责人: M FLINT BEAL
• 金额: $ 71.8万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7933687
• 关键词: 3-nitrotyrosine; Address; Aftercare; Antioxidants; Area; Ascorbic Acid; Atherosclerosis; Attention; Biochemical Markers; Biological Markers; Cerebrospinal Fluid; Clinical; Clinical Trials; Coenzyme Q10; DNA; Deoxyguanosine; Detection; Development; Diet; Dietary Intervention; Disease; Effectiveness; Environment; Epidemiologic Studies; Glutathione Disulfide; Health; High Pressure Liquid Chromatography; Human; Individual; Intake; Isoprostanes; Laboratories; Lead; Lipids; Malignant Neoplasms; Malondialdehyde; Measurement; Measures; Mediterranean Diet; Metabolic; Mitochondria; Neurodegenerative Disorders; Newly Diagnosed; Oxidative Stress; Parkinson Disease; Patients; Phase III Clinical Trials; Placebos; Plasma; Play; Proteins; Randomized; Reduced Glutathione; Relative (related person); Reporting; Role; Sampling; Sensitivity and Specificity; Substantia nigra structure; Testing; Therapeutic Intervention; Treatment Efficacy; Uric Acid; Validation; clinical efficacy; cohort; dietary supplements; fruits and vegetables; in vivo; metabolomics; novel; novel marker; oxidation; oxidative damage; prevent; public health relevance; small molecule; therapy development

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.

描述（由申请人提供）：此申请地址为广泛的挑战领域（03）：验证和特定挑战主题102-102：抗氧化生物标志物。氧化应激的生物标志物的开发和验证，可用于评估体内饮食补充剂的抗氧化作用。帕金森氏病（PD）以及其他神经退行性疾病与氧化损伤有关。在PD中，黑质中的谷胱甘肽还原早期减少，以及脂质，蛋白质和DNA氧化标记的增加。许多实验室报告了PD中氧化应激的血浆和脑脊液生物标志物的增加。最近，我们发现PD患者血浆中的尿酸减少，并增加了8-羟基-2-脱氧糖苷（8-OHDG）。我们目前正在PD中进行抗氧化剂营养补充剂Q10（COQ10）的III期临床试验。六百个新诊断的未经药物的PD受试者被随机分配到安慰剂，每天1200毫克的COQ10或2400 mg COQ10。使用统一的帕金森氏病评级量表（UPDRS）对患者进行每3个月的评估，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1、8和16个月的治疗时测量几个氧化损伤标记。我们将测量8-OHDG，丙二醛，抗坏血酸，尿酸，氧化和降低的COQ10的血浆水平，并氧化和减少谷胱甘肽。所有样品将使用与库米阵列检测的HPLC使用代谢组分析进行检查。这导致检测多达2000个小分子，这些分子具有电化学活性。单个峰的测量将与已建立的氧化损伤标记物相关，例如8-OHDG，丙二醛和氧化/还原的谷胱甘肽的比率，以查看是否可以鉴定出更敏感和特定的新型氧化应激生物标记物。生物标志物将与使用UPDRS评分评估的PD患者的临床改善相关。这些研究将确定现有的氧化损伤生物标志物的相对效用，并可能导致新型生物标志物的发展，这将有助于评估体内饮食补充剂的抗氧化作用的功效，并将有助于评估其对人类健康的有效性。因此，这些研究可能有助于确定大量饮食干预措施的有效性，这可能会影响人类健康。 公共卫生相关性：本研究提议鉴定氧化应激的生物标志物，以促进体内研究饮食补充剂辅酶Q10（COQ10）的抗氧化作用。我们打算全面评估氧化损伤的既定标志物，并利用代谢分析来识别氧化应激的新颖标志物。我们将研究这些生物标志物在帕金森氏病的III期临床试验中，这些生物标志物与coq10的临床功效的相对敏感性。开发有用的生物标志物来评估与人类健康关系的氧化应激，具有对治疗和预防神经退行性疾病的疗法产生重大影响的潜力。这些生物标志物可能有助于评估许多其他人类疾病的治疗干预措施，其中氧化应激起着重要作用。