Development of EP2 receptor antagonists for suppression of Alzheimer's neuropathology

开发用于抑制阿尔茨海默病神经病理学的 EP2 受体拮抗剂

• 批准号: 9645890
• 负责人: Thota Ganesh
• 金额: $ 8.3万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9645890
• 关键词: APP-PS1; Ablation; Acute; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Animal Disease Models; Anti-inflammatory; Biological; Blood - brain barrier anatomy; Brain; CCL2 gene; Cardiovascular system; Caring; Cause of Death; Cell Line; Chronic; Clinical; Clinical Research; Cognitive deficits; Dementia; Development; Dinoprost; Dinoprostone; Disease; Disease Progression; Disease model; Dose; Drug Kinetics; Elderly; Enzyme-Linked Immunosorbent Assay; Epilepsy; Epoprostenol; Event; Formulation; Fracture; Future; G-Protein-Coupled Receptors; Generations; Generic Drugs; Gliosis; Goals; Half-Life; Hippocampus (Brain); Histology; Human; Impaired cognition; In Vitro; Inflammation; Inflammation Mediators; Interleukin-1; Interleukin-1 beta; Interleukin-10; Interleukin-6; Lead; Mediating; Medical; Memory impairment; Microglia; Modeling; Morbidity - disease rate; Mus; Names; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oral; Oxidative Stress; PTGS2 gene; Parkinson Disease; Pathology; Patients; Peptides; Permeability; Persons; Phagocytosis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pilocarpine; Plasma; Plasma Enhancement; Play; Property; Prostaglandin D2; Prostaglandins; Quantitative Reverse Transcriptase PCR; Rodent; Rodent Model; Rofecoxib; Role; Route; Safety; Signal Transduction; Solubility; Stains; Status Epilepticus; TNF gene; Testing; Therapeutic; Up-Regulation; Valdecoxib; WFDC2 gene; Work; aqueous; base; bone; bone healing; bone loss; clinical Diagnosis; cognitive function; cyclooxygenase 2; heart disease risk; high throughput screening; in vivo Model; inhibitor/antagonist; knockout gene; macrophage; morris water maze; mouse model; nervous system disorder; neuroinflammation; neuropathology; neurotoxicity; new therapeutic target; novel; prevent; receptor; salt sensitive hypertension; small molecule; spatial memory

Lay Summary Alzheimer's disease (AD), a neurodegenerative disorder, is a leading cause of dementia in elderly. AD leads to progressive loss of cognitive functions. Currently about 5.4 million Americans (1 in 8 persons 65 or older) are living with AD, and the number is expected to triple by the year 2050. Approximately $200 billion per year is spent on all aspects of caring for AD patients, yet there is no therapy on the horizon that clearly alters the disease progression and inevitable cognitive decline. The small molecule drugs that have been developed based on amyloid cascade hypothesis have not shown a clear clinical benefit so far. Thus it would be very important to focus on identification of novel drug targets and small molecules that work through novel mode of biological action for future AD therapy. COX-2 levels are increased at the early stage of AD, and its levels are correlated with levels of A-peptides. Clinical studies suggest that COX-2 inhibitors may be useful as preventative for AD if they were given at asymptomatic stage of the disease, but they may offer little or no benefit to clinically diagnosed patients with cognitive deficits. However, chronic use of COX-2 drugs (examples, Vioxx and Bextra) resulted in adverse cardiovascular events, which is worrying for the AD patients who already are at increased risk for heart disease. Thus, future use of COX-2 drugs on patients will be limited. COX-2 catalyzes the first-step towards synthesis of five prostaglandins; PGD2, PGE2, PGF2, PGI2, and TxA2, which activate eleven prostanoid receptors, DP1, DP2, EP1, EP2, EP3, EP4, FPα, , IP and TPα,  respectively. We hypothesize that targeting EP2, a specific prostanoid receptor downstream of COX-2, rather than a generic block of the entire COX-2 signaling is a superior therapeutic strategy for AD with an EP2 specific antagonist. In this study, we propose to develop an EP2 selective antagonist, to demonstrate a proof of concept whether EP2 antagonist suppresses inflammation, neurodegeneration and cognitive deficits in 5XFAD model of AD, and to establish a preliminary safety package for using EP2 drugs potentially on AD patients.

条款摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种神经退行性疾病，是老年痴呆的主要病因。AD导致 认知功能逐渐丧失目前约有540万美国人（每8个65岁或以上的人中就有1个）生活在 与AD，这一数字预计到2050年将增加两倍。每年大约有2 000亿美元用于所有 尽管在治疗AD患者的各个方面都存在一些问题，但目前还没有明显改变疾病进展的治疗方法， 不可避免的认知能力下降基于淀粉样蛋白级联假说开发的小分子药物 迄今为止还没有显示出明显的临床益处。因此，重视新药的鉴定工作是十分重要的 靶点和小分子通过新的生物学作用模式发挥作用，用于未来的AD治疗。 考克斯-2水平在AD的早期阶段升高，并且其水平与A β-肽水平相关。临床 研究表明，如果在AD的无症状阶段给予考克斯-2抑制剂， 这些药物可能对这种疾病没有任何益处，但它们对临床诊断的认知缺陷患者可能几乎没有益处。然而，在这方面， 长期使用考克斯-2药物（例如万络和倍他乐）导致不良心血管事件，这是令人担忧的 对于已经有心脏病风险增加的AD患者来说。因此，将来对患者使用考克斯-2药物将 限制。考克斯-2催化合成五种前列腺素的第一步：PGD 2、PGE 2、PGF 2、PGI 2和TxA 2， 其分别激活11种前列腺素受体DP 1、DP 2、EP 1、EP 2、EP 3、EP 4、FPα、FP β、IP和TPα、TP β。我们 假设靶向EP 2，一种考克斯-2下游的特异性前列腺素受体，而不是一般性阻断COX-2， 完整的考克斯-2信号传导是用EP 2特异性拮抗剂治疗AD的上级策略。本研究 我建议开发一种EP 2选择性拮抗剂，以证明EP 2拮抗剂是否抑制 炎症、神经变性和认知缺陷，并建立初步的安全性 用于AD患者的EP 2药物的包装。