Pro-Electrophilic Drugs PEDs for Alzheimer's Disease

用于治疗阿尔茨海默病的亲电药物 PED

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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) 的新靶点和新药我们针对该靶点的候选药物目前正处于积极的先导化合物优化阶段。作为背景，AD 是一种大脑中突触和神经元丧失的疾病，其特征是存在 β 淀粉样蛋白 (Aβ) 斑块和 tau 蛋白缠结，这会导致我们之前的研究表明，鼠尾草酸至少部分通过氧化应激来影响突触和神经元。 (CA) 是迷迭香草本植物中的一种成分化合物，可以保护神经元和突触免受损伤我们的初步数据表明，CA 治疗可通过激活 Nrf2 转录途径来缓解氧化应激。改善 AD 转基因突变小鼠的各种行为和组织学缺陷，同时没有表现出 Keap1/Nrf2（kelch 样 ECH 相关蛋白 1/核因子）的激活红细胞 2 相关因子 2) 通路上调 II 相抗氧化和抗炎转录我们和其他人已经证明，这对于多种疾病来说是一种有价值的治疗策略。在这里，我们使用鼠尾草酸在 AD 小鼠模型中进一步测试了这种方法。 (CA)，我们在出版物中表明它可以激活 Keap1/Nrf2 通路。临床上可以耐受，因为它存在于迷迭香等草药中，在患有阿尔茨海默病的人类中。海马神经元和星形胶质细胞中 Nrf2 的表达模式降低，并且显着降低据报道，Keap1/Nrf2 通路可以被激活。亲电子化合物，当它与Keap1上的特定硫醇反应时，释放细胞质中的Nrf2进入它与 II 相基因启动子上的抗氧化反应元件 (ARE) 结合。临床上关于亲电子药物（如富马酸二甲酯、姜黄素和 Bardoloxone）的优点是它们不仅与 Keap1 反应以激活 Nrf2，而且还与其他硫醇基团，这可以解释它们的作用和副作用。避免此类副作用的方法是使用亲电子化合物，这些化合物通过氧化而被激活化合物 CA 代表了这种亲电亲电的起点。因此，我们的具体目标是 – 目的/目标 1. 筛选并表征 PED 的神经保护作用，该作用可激活寡聚 Aß 诱导的氧化损伤体外模型中的 Nrf2/ARE 转录途径使用 hiPSC 衍生的皮质神经元和大脑类器官研究神经炎症。目的/目标 2. 通过评估神经行为和神经行为的神经保护作用来确定主要 PED AD 转基因小鼠模型（hAPP-J20 和 3x Tg 小鼠）的体内组织学并优化还将进行铅毒性测试。