Improved carnosic acid congener compounds for Alzheimer’s disease

改进的鼠尾草酸同系物化合物可治疗阿尔茨海默病

• 批准号: 10601159
• 负责人: JAMES W LARRICK
• 金额: $ 32.62万
• 依托单位: LARIX BIOSCIENCE, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10601159
• 关键词: ABCC1 gene; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; American; Amyloid beta-Protein; Animal Model; Animals; Anti-Inflammatory Agents; Antioxidants; Behavioral; Binding; Biological Availability; Brain; Carbamates; Catalytic Domain; Catechols; Cell Nucleus; Clinical Trials; Cysteine; Cystine; Cytoplasmic Protein; Data; Dementia; Development; Disease; Diterpenes; Dose; Drug Exposure; Drug Kinetics; Effectiveness; Elements; Enzymes; Esters; Failure; Family; GCLC gene; GCLM gene; Generations; Genes; Genetic Transcription; Glutamates; Glutathione Disulfide; Glutathione S-Transferase; Goals; Half-Life; Herb; Histologic; Human; Impaired cognition; In Vitro; Incidence; Lead; Letters; Ligase; Modeling; Monitor; NADP; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nitrogen; Oral; Oxidative Stress; Oxidoreductase; Oxygen; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phase; Phenols; Prodrugs; Promoter Regions; Proteins; Public Health; Quinones; Reaction; Rosemary; Senile Plaques; Side; Sulfhydryl Compounds; Synapses; TXN gene; Therapeutic; Toxic effect; Transgenic Mice; Work; abeta toxicity; aging population; assay development; burden of illness; care costs; effective therapy; glutathione peroxidase; hydroxyl group; improved; in vitro Assay; mouse model; mutant; neuron loss; nitrosative stress; novel; novel therapeutics; oAβ; peroxiredoxin 2; pre-clinical; salvin; side effect; small molecule therapeutics; synaptic function; tau Proteins; tau aggregation; thioredoxin reductase; transcription factor; transgenic model of alzheimer disease

Improved carnosic acid congener compounds for Alzheimer’s disease Abstract Five million Americans currently suffer the devastating consequences of Alzheimer’s disease (AD), and unfortunately, the numbers are increasing due to our aging population. While some treatments can lower disease burden, there is no cure and all patients inevitably succumb. Cost of care for treatment of AD is expected to reach $1.1 trillion without an effective treatment or a change in the trajectory of AD. Loss of synaptic function is associated with cognitive decline in AD and is a better predictor of cognitive loss in AD than plaques or tangles. Damage to neurons occurs at least partially through generation of oxidative and nitrosative stress, due to excessive generation of reactive oxygen/nitrogen species (ROS/RNS) triggered by oligomeric amyloid beta (Aβ) peptide and downstream hyperphosphorylation and aggregation of tau protein (pTau). Carnosic acid (CA), a phenolic diterpene particularly abundant in the herb rosemary (Rosmarinus officinalis), protects neurons and synapses from damage caused by oxidative stress. In addition to direct antioxidant activity, CA belongs to a class of “pro-electrophiles” that activate the Keap1/Nrf2 pathway, upregulating transcription of a broad range of phase II antioxidant and anti-inflammatory proteins through the antioxidant responsive element (ARE). In vitro, CA protects neurons from Aβ toxicity. CA treatment ameliorates various behavioral and histological deficits in transgenic AD model mice, while showing no significant side effects. During this Phase 1 project, we will develop a novel, proprietary CA-derived therapeutic with improved bioavailability to achieve therapeutic levels with once daily dosing. We will then evaluate this novel compound as a therapeutic small molecule for the treatment of AD.

改良的鼠尾草酸同系物治疗阿尔茨海默病 摘要 目前有500万美国人遭受阿尔茨海默病(AD)的毁灭性后果， 不幸的是，由于我们的人口老龄化，这一数字正在增加。虽然一些治疗方法可以降低疾病 负担，没有治愈的方法，所有的病人都不可避免地屈服。治疗AD的护理费用预计为 在没有有效治疗或AD轨迹没有改变的情况下达到1.1万亿美元。突触功能丧失是 与AD的认知功能下降有关，并且比斑块或缠结更能预测AD的认知功能丧失。 对神经元的损伤至少部分是通过产生氧化和亚硝化应激而发生的，原因是 寡聚体淀粉样β蛋白(Aβ)引发的活性氧/氮物种(ROS/RNS)的过度生成 多肽和下游tau蛋白的过度磷酸化和聚集(Ptau)。鼠尾草酸(CA)，a 迷迭香中特别丰富的酚二萜类化合物，保护神经元和 突触免受氧化应激造成的损害。CA除了具有直接的抗氧化活性外，还属于 一类能激活Keap1/Nrf2途径，上调多种基因转录的亲电体。 第二阶段通过抗氧化反应元件(ARE)的抗氧化和抗炎蛋白。在体外， CA可保护神经元免受A-β毒性。CA治疗改善大鼠各种行为和组织学缺陷 转基因AD模型小鼠，同时没有表现出明显的副作用。在这个第一阶段的项目中，我们将开发 一种新的、专有的CA衍生疗法，具有更高的生物利用度，以达到治疗水平 每天服用一次。然后我们将评估这种新化合物作为一种治疗性小分子药物 治疗阿尔茨海默病。