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：抗氧化生物标记物。开发和验证氧化应激的生物标志物，可用于评估膳食补充剂在体内的抗氧化效果。帕金森病(PD)和其他神经退行性疾病都与氧化损伤有关。在帕金森病患者中，黑质还原型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。一些实验室已经报告了帕金森病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患者血浆尿酸降低，8-羟基-2-脱氧鸟苷(8-OHdG)升高。我们目前正在进行抗氧化性营养补充剂辅酶Q10(CoQ10)治疗帕金森病的第三阶段临床试验。600名新诊断的未服用药物的帕金森病患者被随机分配到安慰剂、1200毫克辅酶Q10或2400毫克辅酶Q10。每3个月使用统一帕金森氏病评定量表(UPDRS)对患者进行评估，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个月、8个月和16个月时测量几个氧化损伤的标志物。测定血浆8-OHdG、丙二醛、抗坏血酸、尿酸、氧化还原辅酶Q10、氧化还原谷胱甘肽水平。所有样品都将通过使用带有库仑阵列检测的高效液相色谱进行代谢组分析进行检测。这导致检测到多达2000个小分子，这些小分子具有电化学活性。单峰的测量将与已建立的氧化损伤标志物，如8-OHdG、丙二醛和氧化/还原谷胱甘肽的比率相关联，以查看是否可以识别更敏感和更特异的氧化应激新生物标志物。这些生物标志物将与帕金森病患者的临床改善相关，通过UPDRS评分进行评估。这些研究将确定现有氧化损伤生物标记物的相对效用，并可能导致新生物标记物的开发，这将有助于评估膳食补充剂在体内的抗氧化效果，并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可能影响人类健康的大量饮食干预的有效性。 公共卫生相关性：这项研究建议识别氧化应激的生物标记物，以促进体内研究膳食补充剂辅酶Q10(CoQ10)的抗氧化效果。我们打算全面评估一组已建立的氧化损伤标志物，并利用代谢图谱来识别氧化应激的新标志物。我们将在帕金森病的III期临床试验中检查这些生物标记物的相对敏感度与辅酶Q10临床疗效的关系。开发有用的生物标记物来评估氧化应激与人类健康的关系，可能会对治疗和预防神经退行性疾病的治疗方法的开发产生重大影响。这些生物标记物可能有助于评估对许多其他人类疾病的治疗干预措施，在这些疾病中，氧化应激起重要作用。

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.