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）：本申请解决了广泛的挑战领域 (03)：验证和特定挑战主题 03-AT-102：抗氧化生物标志物。开发和验证氧化应激生物标志物，可用于评估膳食补充剂的体内抗氧化作用。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，黑质中的还原型谷胱甘肽早期减少，脂质、蛋白质和 DNA 氧化标记物增加。许多实验室报告称，PD 患者的血浆和脑脊液氧化应激生物标志物有所增加。我们最近发现PD患者血浆中的尿酸降低，并且8-羟基-2-脱氧鸟苷(8-OHdG)增加。我们目前正在进行抗氧化剂营养补充剂辅酶Q10（CoQ10）治疗PD的III期临床试验。 600 名新诊断的未接受药物治疗的帕金森病受试者被随机分配到安慰剂、每天 1200 毫克辅酶 Q10 或 2400 毫克辅酶 Q10 组。每 3 个月使用统一帕金森病评定量表 (UPDRS) 对患者进行一次评估，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 8-OHdG、丙二醛、抗坏血酸、尿酸、氧化型和还原型 CoQ10、以及氧化型和还原型谷胱甘肽的血浆水平。所有样品都将使用 HPLC 和库仑阵列检测进行代谢组学分析。这样可以检测多达 2000 个具有电化学活性的小分子。各个峰的测量结果将与已确定的氧化损伤标记物（例如 8-OHdG、丙二醛和氧化/还原型谷胱甘肽的比率）的测量值相关联，以了解是否可以识别出更敏感和更特异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开发，这将有助于评估膳食补充剂体内抗氧化作用的功效，并有助于评估其抗氧化作用的有效性。尊重人类健康。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。 公共健康相关性：本研究旨在确定氧化应激的生物标志物，以促进膳食补充剂辅酶 Q10 (CoQ10) 抗氧化作用的体内研究。我们打算全面评估一组已确定的氧化损伤标记物，并利用代谢谱来识别新的氧化应激标记物。我们将在帕金森病的 III 期临床试验中检查这些生物标志物与 CoQ10 临床疗效的相对敏感性。开发有用的生物标志物来评估与人类健康相关的氧化应激，有可能对治疗和预防神经退行性疾病的疗法的开发产生重大影响。这些生物标志物可能有助于评估氧化应激在其中发挥重要作用的许多其他人类疾病的治疗干预措施。