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：抗氧化剂生物标志物。开发和验证可用于评估膳食补充剂体内抗氧化作用的氧化应激生物标志物。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。许多实验室报告了PD患者血浆和脑脊液中氧化应激生物标志物的增加。我们最近发现PD患者的血浆中尿酸降低和8-羟基-2-脱氧鸟苷（8-OHdG）升高。我们目前正在进行抗氧化营养补充剂辅酶Q10（CoQ 10）在PD中的III期临床试验。600名新诊断的未经药物治疗的PD受试者被随机分配到安慰剂组，每天1200 mg CoQ 10或2400 mg CoQ 10。患者每3个月使用统一帕金森病评定量表（Unified Parkinson's Disease Rating Scale，简称DPRS）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、1个月、8个月和16个月治疗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、氧化和还原辅酶Q10以及氧化和还原谷胱甘肽的血浆水平。将使用HPLC和库仑阵列检测，采用代谢组学分析对所有样本进行检查。这导致检测多达2000个电化学活性的小分子。将单个峰的测量值与已建立的氧化损伤标志物（如8-OHdG、丙二醛和氧化型/还原型谷胱甘肽的比率）的测量值相关联，以观察是否可以鉴定出更灵敏和特异的氧化应激的新型生物标志物。生物标志物将与PD患者的临床改善相关，如使用PDRS评分评估的。这些研究将建立氧化损伤的现有生物标志物的相对效用，并可能导致新的生物标志物的开发，这将有助于评估膳食补充剂在体内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可能影响人类健康的饮食干预措施的有效性。 公共卫生相关性：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（CoQ 10）的抗氧化作用的体内研究。我们打算全面评估一组已建立的氧化损伤标志物，并利用代谢谱来确定新的氧化应激标志物。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CoQ 10临床疗效的相对敏感性。开发有用的生物标志物来评估氧化应激与人类健康的关系，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。

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.