Oxidative Stress in First Episode Schizophrenia Assessed in vivo Using NAD+ and NADH Measurement

使用 NAD 和 NADH 测量在体内评估首发精神分裂症中的氧化应激

• 批准号: 9369156
• 负责人: FEI DU
• 金额: $ 24.55万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-18 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9369156
• 关键词: ATP Synthesis Pathway; Address; Adverse effects; Affect; Age; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Antipsychotic Agents; Automobile Driving; Autopsy; Biochemical; Bioenergetics; Biological Assay; Biological Markers; Blood specimen; Brain; Brain Pathology; Cell Culture Techniques; Chemicals; Chronic; Clinic; Clinical; Clinical Trials; Coupled; Creatine Kinase; Cytosol; Data; Data Reporting; Disease; Disease Progression; Dopamine Receptor; Early Intervention; Employee Strikes; Energy Metabolism; Environment; Equilibrium; Free Radical Scavengers; Free Radicals; Functional disorder; Generations; Glutathione; Glutathione Disulfide; Glycolysis; Goals; Homeostasis; Human; Hydrogen Peroxide; Inflammation; Intervention; Knowledge; Lead; Link; Measurement; Measures; Medial; Mediating; Mental disorders; Metabolic; Methods; Mitochondria; Molecular; Monitor; NADH; Organ; Oxidants; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Oxides; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Play; Population; Prefrontal Cortex; Process; Production; Reaction; Reactive Oxygen Species; Recruitment Activity; Role; Scanning; Schizophrenia; Severity of illness; Subgroup; Symptoms; Synaptic plasticity; System; Techniques; Testing; Time; Toxic effect; Work; base; biological research; biological systems; brain cell; cognitive performance; disability; effective therapy; electron donor; first episode schizophrenia; in vivo; insight; intervention effect; neuroinflammation; neuronal survival; new therapeutic target; novel; patient population; screening; secondary analysis; severe psychiatric disorder; sex; synaptic function; therapeutic target

Schizophrenia (SZ) is a severe psychiatric disorder that results in significant disability. All currently approved antipsychotic medications work by primarily blocking D2-type dopamine receptors. Many patients are partially or completely unresponsive to them, and suffer significant side effects. Developing new SZ treatments is a critical need. However, we lack a clear understanding of disease progression mechanisms and have no specific targets for effective treatment and early intervention. Recently several lines of evidence suggest that brain oxidative stress and disturbances in neuroinflammatory system play key roles in SZ. And several antioxidants and anti-inflammatory medications have been tested in some small clinical trials as a supplemental to antipsychotics. However, to date, clinical trials have produced mixed results. The effect of these interventions may greatly depend on the integrity of the antioxidant glutathione (GSH) system and the intrinsic redox status. It is well known that intensive energy demand of brain cells leads to accumulation of toxic reactive oxygen species such as H2O2 and free radicals O2* (i.e. oxidative stress). These are eliminated by GSH, a critical molecule in resisting oxidative stress. These chemical processes also are strongly mediated by the redox state of NAD+/NADH. Dysregulations of the redox state may affect anti-oxidative defense, anti- inflammation and energy homestasis as well as exert downstream effects on synaptic function and plasticity in the brain. Therefore, methods to monitor GSH level and redox state are critically needed. Despite the essential role of redox balance in the human brain, few methods are available to access it in vivo. Most data reported to date have been collected from cell-cultures or postmortem studies. There is a large gap in our knowledge to show how the phenomena observed ex vivo relate to brain function in vivo. The current study aims to develop an in vivo biomarker reflecting oxidative stress in SZ patients. In this proposal, we will utilize in vivo 1H- and 31P-MRS to 1) directly quantify both antioxidant level-GSH and redox state (NAD+/NADH) in 1st episode SZ patients, and healthy controls and 2) validate whether reduced antioxidant GSH level is associated with the reduced redox state in SZ. We will also explore the relationships between clinic measures (negative/positive symptoms and cognitive performance) and experimental measures (redox balance and antioxidant levels indicated by NADH/NAD+ and GSH, respectively). Redox dysregulation would be the upstream molecular mechanism of GSH depletion, oxidative stress and neuroinflammation in SZ. The results would provide new insights into the central “immuno-oxidative” pathway of SZ, a promising therapeutic target. To the best of our knowledge, the current proposal is the first to measure redox state and antioxidant GSH in vivo and link them to the pathophysiology of SZ. The insights obtained from redox state and associated antioxidant GSH levels may help to develop strategies to promote neuronal survival and protection in brain pathologies.

精神分裂症（SZ）是一种严重的精神疾病，会导致严重的残疾。所有目前批准的抗精神病药物主要通过阻断d2型多巴胺受体起作用。许多患者对它们部分或完全没有反应，并遭受明显的副作用。开发新的SZ治疗方法是一项迫切需要。然而，我们缺乏对疾病进展机制的清晰认识，也没有有效治疗和早期干预的具体目标。最近一些证据表明，大脑氧化应激和神经炎症系统紊乱在SZ中起关键作用。一些抗氧化剂和抗炎药物已经在一些小型临床试验中作为抗精神病药物的补充进行了测试。然而，到目前为止，临床试验的结果好坏参半。这些干预措施的效果可能在很大程度上取决于抗氧化剂谷胱甘肽（GSH）系统的完整性和内在氧化还原状态。众所周知，脑细胞对能量的强烈需求导致有毒活性氧如H2O2和自由基O2*的积累（即氧化应激）。GSH是抵抗氧化应激的关键分子。这些化学过程也受到NAD+/NADH氧化还原状态的强烈介导。氧化还原状态的失调可能影响抗氧化防御、抗炎症和能量稳态，并对大脑突触功能和可塑性产生下游影响。因此，迫切需要监测谷胱甘肽水平和氧化还原状态的方法。