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: 10256731
• 负责人: STUART A LIPTON
• 金额: $ 87.62万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256731
• 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; Induced pluripotent stem cell derived neurons; 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; 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.

我们提出了一种通过Nrf2转录来治疗阿尔茨海默病(AD)的新靶点和新药 路径。我们针对这一目标的候选药物目前正处于积极的点击到领先优化阶段，因为 如下所述。作为背景，阿尔茨海默病是一种大脑突触和神经元丢失的情况， 以淀粉样β蛋白(Aβ)斑块和tau缠结的存在为特征，这会导致 突触和神经元，至少部分通过氧化应激。我们先前的研究表明，鼠尾草酸 迷迭香中的一种成分(CA)可以保护神经元和突触免受损伤 通过激活Nrf2转录途径的氧化应激。我们的初步数据显示，CA治疗 改善AD转基因突变小鼠的各种行为和组织学缺陷，而没有表现出 严重的副作用。Keap1/Nrf2(海带样ECH相关蛋白1/核因子)的激活 红系相关因子2)途径上调II期抗氧化和抗炎转录 蛋白质。我们和其他人已经证明，这可以在几个方面成为一种有价值的治疗策略 神经退行性疾病。在这里，我们使用鼠尾草酸在AD小鼠模型中进一步测试这种方法 (CA)，我们已经在我们的出版物中展示了它激活Keap1/Nrf2途径。已知CA是 临床上耐受，因为它存在于迷迭香等草药中。相反，在患有阿尔茨海默病的人中， Nrf2在海马神经元和星形胶质细胞中的表达减少，且显著减少 核内Nrf2在额叶皮质中的水平，已有报道。Keap1/Nrf2通路可以被一种 亲电化合物与Keap1上的特定硫醇反应，释放细胞质中的Nrf2进入 与第二阶段基因启动子上的抗氧化反应元件(ARE)结合的细胞核。一个 临床上与亲电药物(如富马酸二甲酯、姜黄素和 Bardoloxone)是它们不仅与Keap1反应以激活Nrf2，而且还与 其他硫醇基团，这可能解释了他们的作用和副作用。我们的替代创新战略 避免这样的副作用是使用亲电化合物，这些化合物是通过在 氧化还原压力过大的细胞是有害的。化合物CA代表了这种亲电性的起点 药物(PED)。因此，我们的具体目标是- 目的/目标1.筛选和表征PEDS的神经保护作用 Nrf2/ARE转录途径在寡聚体Aü诱导的氧化损伤模型中的作用 使用HiPSC来源的皮质神经元和脑器官的神经炎症。 目的/目标2：通过评估神经行为的神经保护作用来确定铅的PED AD转基因小鼠模型(HAPP-J20和3x TG小鼠)体内组织学研究及配方优化 领头。还将进行毒性测试。