Nrf2-Antioxidant Response Element Neuroprotection in TBI

Nrf2-抗氧化反应元件在 TBI 中的神经保护作用

• 批准号: 9241702
• 负责人: EDWARD D. HALL
• 金额: $ 32.92万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9241702
• 关键词: 3-nitrotyrosine; 4 hydroxynonenal; Acute; Antioxidants; Attention; Attenuated; Biological Preservation; Brain; Brain Injuries; Broccoli - dietary; Buffers; Calcium; Calpain; Cell Culture Techniques; Chronic; Defense Mechanisms; Diffuse; Dose; Drops; Elements; Evaluation; Experimental Designs; Failure; Female; Free Radical Scavengers; Free Radical Scavenging; Free Radicals; Future; Gender; Gene Expression; Genes; Herb; Hippocampus (Brain); Homeostasis; Injury; Lipid Peroxidation; Lipids; Mediating; Membrane Lipids; Messenger RNA; Mitochondria; Modeling; Motor; Mus; Nerve Degeneration; Nervous System Trauma; Neurodegenerative Disorders; Neurologic; Neurons; Nuclear; Oxidoreductase; Pathway interactions; Pharmaceutical Preparations; Proteins; Quinones; Reactive Oxygen Species; Recovery of Function; Respiratory physiology; Response Elements; Rosemary; Severities; Speed; Sulforaphane; Surrogate Endpoint; Surrogate Markers; Testing; Therapeutic; Time; Tissues; Traumatic Brain Injury; Treatment Efficacy; Water; Weight; base; body system; brain tissue; cognitive recovery; cohort; comparative; controlled cortical impact; design; drug discovery; expectation; glutathione peroxidase; heme oxygenase-1; improved; injured; interest; mRNA Expression; male; motor recovery; mouse model; neuroprotection; nitration; novel; object recognition; oxidative damage; prevent; protective effect; prototype; research study; respiratory; response; salvin; therapeutic target; transcription factor; young adult

ABSTRACT Oxygen radical-induced lipid peroxidation and protein oxidative damage constitutes one of our most validated secondary injury mechanisms, and thus remains a highly rational neuroprotective target that continues to inspire a search for improved free radical scavengers and lipid peroxidation inhibiting drugs. In addition to chemically scavenging free radicals, there is increasing interest in the possibility of pharmacologically inducing endogenous enzymatic antioxidant defense mechanisms as a neuroprotective approach. Attention has recently been focused on the transcription factor Nrf2 (Nuclear factor E2-related factor) which interacts with the antioxidant response element (ARE) of various cytoprotective and free radical detoxifying genes as a potential therapeutic target for acute neurological injury. The proposed studies will examine in mouse models of focal controlled cortical impact and diffuse weight drop-induced traumatic brain injury (TBI) the time course of the endogenous induction of specific elements of the Nrf2-ARE pathway compared to the time course of brain oxidative damage in male and female mice. This will be followed by a systematic dose-response evaluation of the comparative potency and efficacy of the prototypical Nrf2-ARE inducing compound carnosic acid in both genders in regards to its ability to speed up and increase the magnitude of post-TBI Nrf2-ARE activation. The most effective dose of carnosic acid will then be examined for its ability to prevent lipid and protein oxidative damage, preserve mitochondrial respiratory and calcium (Ca++) buffering functions and attenuate Ca++-induced, calpain-mediated neuronal cytoskeletal damage, all surrogate markers of secondary brain injury. After completion of those experiments, the ability of repeated administration of the best dose of carnosic acid will be tested for actual neuroprotective effects in terms of short term (7 day) post-traumatic motor and cognitive recovery and brain tissue sparing including the therapeutic efficacy window. These studies will test the hypothesis that pharmacological Nrf2-ARE pathway activation in both focal and diffuse TBI models can be acutely neuroprotective and form the basis for the discovery of more effective and fast- acting Nrf2 inducing compounds for acute and chronic neurodegeneration.

抽象的 氧自由基诱导的脂质过氧化和蛋白质氧化损伤构成了我们最大的 经过验证的二级伤害机制，因此仍然是一个高度理性的神经保护靶标的 继续激发人们寻求改善的自由基清除剂和脂质过氧化抑制药物。 除了化学清除自由基外，人们对 药理学诱导内源性酶抗氧化剂防御机制作为一种 神经保护方法。最近注意到转录因子NRF2（核 因子E2相关因子）与各种抗氧化剂响应元件相互作用的因子） 细胞保护和自由基解毒基因作为急性神经系统的潜在治疗靶点 受伤。拟议的研究将在局灶性控制皮质影响和扩散的小鼠模型中检查 体重下降引起的创伤性脑损伤（TBI）特异性内源性诱导的时间过程 与男性和脑氧化损伤的时间过程相比，NRF2-ARE途径的元素 雌鼠。随后将对比较效力进行系统的剂量反应评估 和典型的NRF2-ARE诱导化合物肉瘤酸在两个性别方面的功效 它的速度和增加TBI NRF2-ARE激活的幅度的能力。最有效的 然后，将检查肉瘤酸的剂量，以防止脂质和蛋白质氧化损伤的能力， 保持线粒体呼吸道和钙（CA ++）缓冲功能，并衰减Ca ++诱导， 钙蛋白酶介导的神经元细胞骨架损伤，所有替代脑损伤的替代标记。后 这些实验的完成，重复给药最佳肉瘤酸的能力 将根据短期（7天）创伤后运动和 认知恢复和脑组织保留，包括治疗功效窗口。这些研究会 检验了局灶性和弥漫性TBI的药理学NRF2-ARE途径激活的假设 模型可以是敏锐的神经保护性，并构成了发现更有效和快速的基础 作用NRF2诱导急性和慢性神经退行性的化合物。