Pro-Electrophilic Drugs PEDs for Alzheimer's Disease

用于治疗阿尔茨海默病的亲电药物 PED

• 批准号: 10230417
• 负责人: STUART A LIPTON
• 金额: $ 88.56万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10230417
• 关键词: AD transgenic mice; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Anti-Inflammatory Agents; Antioxidants; Astrocytes; Back; Behavioral; Binding; Brain; Cell Nucleus; Cells; Cellular Stress; Cerebrum; Clinical; Clinical Trials; Curcumin; Cytoplasm; Data; Elements; Enzymes; Exhibits; Formulation; Fumarates; Genes; Genetic Transcription; Glutathione; Goals; Heart; Herb; Hippocampus (Brain); Histologic; Histology; Human; Injections; J20 mouse; Lead; Learning; Lentivirus Vector; Memory; Modeling; Mus; Mutant Strains Mice; Nervous system structure; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Normal Cell; Nuclear; Organoids; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Prodrugs; Production; Property; Proteins; Publications; Reporting; Rodent; Rosemary; Route; Senile Plaques; Site; Sulfhydryl Compounds; Synapses; Tauopathies; Testing; Therapeutic; Toxic effect; Toxicity Tests; Transcriptional Activation; Transgenic Mice; Transgenic Organisms; Work; age related; cooking; drug candidate; drug discovery; effectiveness testing; frontal lobe; heme oxygenase-1; improved; in vitro Model; in vivo; induced pluripotent stem cell; innovation; lead optimization; mouse model; nervous system disorder; neurobehavior; neuroinflammation; neuroprotection; novel; novel therapeutics; nuclear factor-erythroid 2; oxidation; oxidative damage; prevent; promoter; response; retinal damage; salvin; side effect; stroke model; tau Proteins; transcription factor

We propose a novel target and new drug to treat Alzheimer’s disease (AD) via the Nrf2 transcriptional pathway. Our drug candidates for this target are currently at the stage of active hit-to-lead optimization, as described below. As background, AD is a condition with loss of synapses and neurons in the brain, characterized by the presence of amyloid beta (Aβ) plaques and tau tangles, which cause damage to synapses and neurons at least partially via oxidative stress. Our prior studies have indicated that carnosic acid (CA), a component compound in the herb Rosemary, can protect neurons and synapses from damage caused by oxidative stress by activating the Nrf2 transcriptional pathway. Our Preliminary Data show that CA treatment ameliorates various behavioral and histological deficits in AD transgenic mutant mice, while showing no significant side effects. Activation of the Keap1/Nrf2 (kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2) pathway upregulates transcription of phase II antioxidant and anti-inflammatory proteins. We and others have shown that this can be a valuable therapeutic strategy in several neurodegenerative diseases. Here, we further test this approach in mouse models of AD using carnosic acid (CA), which we have shown in our publications to activate the Keap1/Nrf2 pathway. CA is known to be clinically tolerated because of its presence in herbs like Rosemary. Conversely, in humans with AD, a decreased expression pattern of Nrf2 in hippocampal neurons and astrocytes, as well as a significant decrease in nuclear Nrf2 levels in frontal cortex, have been reported. The Keap1/Nrf2 pathway can be activated by an electrophilic compound when it reacts with a specific thiol on Keap1, releasing Nrf2 in the cytoplasm to enter the nucleus where it binds to the antioxidant responsive element (ARE) on the promoters of phase II genes. An important issue clinically with regard to electrophilic drugs (such as dimethyl fumarate, curcumin, and Bardoloxone) is that they not only react with Keap1 to activate Nrf2, but they also non-specifically react with other thiol groups, which may explain both their actions and side effects. Our alternative, innovative strategy to avoid such side effects is to use pro-electrophilic compounds that are activated by the very oxidation in redox-stressed cells that is injurious. The compound CA represents a starting point for such a pro-electrophilic drug (PED). Accordingly, our Specific Aims/Goals are – Aim/Goal 1. To screen for and characterize the neuroprotective effects of PEDs that activate the Nrf2/ARE transcriptional pathway in an in vitro model of oligomeric Aß-induced oxidative damage and neuroinflammation using hiPSC-derived cortical neurons and cerebral organoids. Aim/Goal 2. To determine the lead PED by assessing neuroprotective effects by neurobehavior and histology in vivo in AD transgenic mouse models (hAPP-J20 and 3x Tg mice) and optimize formulation of the lead. Toxicity testing will also be performed.

我们提出了一种新的靶标和新药物，以通过NRF2转录治疗阿尔茨海默氏病（AD） 路径。我们针对该目标的毒品候选人目前处于主动命中至铅优化的阶段，因为 如下所述。作为背景，AD是一种疾病，大脑中突触和神经元的丧失， 以淀粉样β（Aβ）斑块和tau缠结的存在为特征 突触和神经元至少部分通过氧化应激部分。我们先前的研究表明肉瘤酸 （CA）是草药迷迭香中的成分化合物，可以保护神经元和突触免受损害 通过激活NRF2转录途径通过氧化应激。我们的初步数据表明CA治疗 改善AD转基因突变小鼠的各种行为和组织学缺陷，同时否 重大副作用。 KEAP1/NRF2的激活（Kelch样ECH相关蛋白1/核因子 红细胞2相关因子2）途径上调II期抗氧化剂和抗炎的转录 蛋白质。我们和其他人表明，这可能是几种有价值的治疗策略 神经退行性疾病。在这里，我们在使用肉瘤酸的AD模型中进一步测试了这种方法 （CA），我们在出版物中展示的以激活KEAP1/NRF2途径。 CA是 临床耐受性是因为它在迷迭香等草药中的存在。相反，在与广告的人类中 海马神经元和星形胶质细胞中NRF2表达模式的降低，以及显着降低 据报道，在额叶皮层的核NRF2水平中。 KEAP1/NRF2途径可以通过 当电力化合物与KEAP1上的特定硫醇反应时，在细胞质中释放NRF2进入 它与II期基因启动子上的抗氧化剂响应元件（IS）结合的核。一个 临床上有关亲电药物的重要问题（例如富马酸二甲基，姜黄素和 bardoloxone）是，它们不仅与Keap1反应激活NRF2，而且还与非特异性反应 其他硫醇组，这可以解释其作用和副作用。我们的替代性，创新的策略 避免这种副作用是使用亲电动化合物，这些化合物被氧化激活 有害的氧化还原压力细胞。化合物Ca代表了这种亲电动的起点 药物（PED）。根据以下内容，我们的具体目标/目标是 - 目标/目标1。筛选并表征激活该PED的神经保护作用 NRF2/是寡聚Aß诱导的氧化损伤的体外模型中的转录途径 使用HIPSC衍生的皮质神经元和大脑器官的神经炎症。 AIM/目标2。通过评估神经行为的神经保护作用来确定铅PED AD转基因小鼠模型（HAPP-J20和3X TG小鼠）中的组织学在体内，并优化了公式 带领。还将进行毒性测试。