Neuroprotection by nNOS inhibitors in perinatal hypoxia-ischemia

nNOS 抑制剂对围产期缺氧缺血的神经保护作用

• 批准号: 10066816
• 负责人: SIDHARTHA TAN
• 金额: $ 64.16万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10066816
• 关键词: Abbreviations; Abruptio Placentae; Acute; Adult; Affect; Animal Model; Antioxidants; Area; Axon; Biochemical; Birth; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Brain region; Cell Culture Techniques; Cell physiology; Cerebral Palsy; Childhood; Cholera Toxin; Clinical; Clinical Trials; Communities; Country; Dancing; Developed Countries; Development; Diffusion; Disease; Dose; Electron Spin Resonance Spectroscopy; Electrophysiology (science); Encephalopathies; Endoplasmic Reticulum; Enzymes; Equation; Estrogen receptor positive; Ethidium; Facilities and Administrative Costs; Family; Fetal Distress; Fetus; Fiber; Financial cost; Free Radicals; Future; Generations; High Pressure Liquid Chromatography; Human; Hypoxia; Injury; Laboratories; Life; Location; Magnetic Resonance Imaging; Measures; Methodology; Modeling; Molecular; Morbidity - disease rate; Mothers; Motor; Muscle Hypertonia; NOS3 gene; Nature; Neuronal Injury; Neurons; Neuroprotective Agents; Nitric Oxide; Nitric Oxide Synthase Type I; Nitric Oxide Synthetase Inhibitor; Nitrogen Oxides; Oryctolagus cuniculus; Outcome; Oxidants; Oxidation-Reduction; Oxidative Stress; Parents; Pathway interactions; Patients; Perinatal; Perinatal Hypoxia; Pharmaceutical Preparations; Phenotype; Placental Insufficiency; Pregnancy; Premature Labor; Prevalence; Prevention; Prevention therapy; Preventive; Problem Solving; Property; Propidium Diiodide; Reactive Nitrogen Species; Reactive Oxygen Species; Reperfusion Therapy; Resources; Rhodamine 123; Rodent Model; Siblings; Societies; Sorting - Cell Movement; Specificity; Speed; Stress; Sum; Superoxide Dismutase; Superoxides; Surrogate Markers; System; Techniques; Testing; Therapeutic; Time; Tissues; Translating; Translations; Western Blotting; antenatal; base; brain cell; burden of illness; cell injury; cost; disability; drug candidate; effective therapy; fetal; gray matter; hydroethidine; in vivo; indexing; inhibitor/antagonist; innovation; interest; magnetic resonance imaging biomarker; mortality; motor deficit; nervous system disorder; neuroprotection; nitrosative stress; novel; novel therapeutics; perinatal period; postnatal; prevent; response; severe injury; white matter; white matter injury

PROJECT SUMMARY/ABSTRACT Cerebral palsy (CP) is a devastating disease usually originating from hypoxia-ischemia (H-I) before birth. It has one of the very highest indices of burden of disease. The costs to society are huge, to the tune of $15 billion. Prevention of a single CP patient would save almost $1.2 million dollars, not factoring indirect costs to parents, siblings, communities and society from life-long commitments. The number of affected CP patients, 800,000 in USA, and burden of disease is higher than many adult neurological diseases affecting the twilight years. Yet, there is a paucity of effective therapies for CP. To solve the problems of finding new neuroprotectants that can be translated to the humans situation, we are proposing to test novel specific inhibitors of neuronal nitric oxide synthase (nNOS) in a rabbit model of cerebral palsy based on human acute placental insufficiency and the clinical paradigm of placental abruption. These new nNOS inhibitors are the most potent neuroprotectants found in our laboratory. We utilize MRI biomarkers that inform us about the immediate fetal brain response to H-I and reliably predict which rabbit fetuses will manifest motor deficits after delivery. We utilize recent advances in detecting oxidative and nitrosative stress (caused by reactive nitrogen species derived from nitric oxide). Instead of a zero-sum way of looking at oxidative stress and antioxidants, we posit the biphasic nature of reactive species in brain cell function and that a dance between various oxidants and antioxidants is necessary for critical brain injury. We hypothesize that the timing and location of nitrosative stress in important in determining which fetuses will develop motor deficits. The proposed studies will lead to the development of a neuroprotective strategy that can also be used in resource-poor countries in addition to developed countries. The first Aim will determine the nature of gray and white matter injury in the fetal brain. The second Aim will determine whether nitric oxide derived from nNOS is responsible for the critical brain injury that results in motor deficits. The third Aim will determine the best candidate drug to take to clinical trials. The new innovations proposed are the systemic integration of MRI as a surrogate marker and high speed sorting into the unique animal model to probe the biochemical basis of specific neuronal injury at a critical time point. The clinical importance of this proposal is that the studies will select the most potent and non-toxic drug in the class of nNOS inhibitors for preventing motor deficits. The proposed studies will thus provide the systematic development of much-needed therapies for CP not only in USA but throughout the world.

项目总结/摘要 脑性瘫痪（CP）是一种严重的疾病，通常起源于出生前的缺氧缺血（H-I）。它 是疾病负担指数最高的国家之一。社会的成本是巨大的，高达15美元 亿预防一名CP患者将节省近120万美元，不考虑间接费用， 父母、兄弟姐妹、社区和社会的终身承诺。受影响的CP患者人数， 800，000在美国，疾病负担高于许多影响黄昏的成人神经系统疾病 年然而，对于CP缺乏有效的治疗方法。为了解决寻找新的 神经保护剂，可以转化为人类的情况下，我们建议测试新的具体 神经元型一氧化氮合酶（nNOS）抑制剂在兔脑性瘫痪模型中的应用 胎盘功能不全和胎盘功能不全的临床模式。这些新的nNOS抑制剂是 最有效的神经保护剂我们利用MRI生物标志物， 胎儿大脑对H-I的即时反应，并可靠地预测哪些兔胎儿将表现出运动缺陷， 交付.我们利用最新的进展，在检测氧化和亚硝化应激（引起活性氮 来源于一氧化氮的物质）。我们不再以零和的方式看待氧化应激和抗氧化剂， 我们研究了脑细胞功能中活性物质的双相性， 氧化剂和抗氧化剂是严重脑损伤所必需的。我们假设， 亚硝化应激在决定哪些胎儿将发展为运动缺陷中起重要作用。拟议的研究 将导致神经保护策略的发展，也可以用于资源贫乏的国家， 除了发达国家。第一个目的将确定灰和白色物质损伤的性质， 胎儿大脑第二个目标将确定是否来自nNOS的一氧化氮是负责关键的 导致运动障碍的脑损伤。第三个目标将确定最佳候选药物，以采取临床 审判提出的新创新是MRI作为替代标记物的系统整合， 快速分类到独特的动物模型，以探索特定神经元损伤的生化基础， 关键时间点。这项建议的临床重要性在于，研究将选择最有效的， 用于预防运动缺陷的nNOS抑制剂类无毒药物。因此，拟议的研究将 不仅在美国，而且在整个美国， 世界