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: 9240161
• 负责人: Thota Ganesh
• 金额: $ 75.81万
• 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/9240161
• 关键词: Ablation; Acute; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Biological; Blood - brain barrier anatomy; Brain; CCL2 gene; Cardiovascular system; Caring; Cause of Death; Cells; Chronic; Clinical; Clinical Research; Cognitive deficits; Coxibs; Dementia; Development; Diagnosis; 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; Life; Mediating; Medical; Memory impairment; Microglia; Modeling; Morbidity - disease rate; Mus; Names; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oral; Oxidative Stress; Parkinson Disease; Pathology; Patients; Peptides; Persons; Phagocytosis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pilocarpine; Plasma; Play; Property; Prostaglandin D2; Prostaglandins; Rodent; Rodent Model; Rofecoxib; Role; Route; Safety; Signal Transduction; Solubility; Staging; Staining method; Stains; Status Epilepticus; TNF gene; Testing; Therapeutic; Up-Regulation; Valdecoxib; WFDC2 gene; Work; aqueous; base; bone; bone healing; bone loss; 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; peptide A; 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.

外行总结 阿尔茨海默病（AD）是一种神经退行性疾病，是导致老年人痴呆的主要原因。 AD 导致 认知功能逐渐丧失。目前约有 540 万美国人（65 岁或以上的老年人中每 8 人中就有 1 人）生活在 到 2050 年，这一数字预计将增加两倍。每年大约花费 2000 亿美元用于所有方面 护理 AD 患者的各个方面，但目前还没有任何治疗方法可以明显改变疾病的进展和 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 迄今为止尚未显示出明显的临床益处。因此，关注新药的鉴定非常重要。 通过新的生物作用模式发挥作用的靶标和小分子，用于未来的 AD 治疗。 AD早期COX-2水平升高，其水平与A肽水平相关。临床 研究表明，如果在无症状阶段给予 COX-2 抑制剂，可能有助于预防 AD 疾病，但它们可能对临床诊断的认知缺陷患者几乎没有好处或没有好处。然而， 长期使用 COX-2 药物（例如 Vioxx 和 Bextra）会导致不良心血管事件，这一点令人担忧 对于心脏病风险已经增加的 AD 患者。因此，未来 COX-2 药物对患者的使用将 受到限制。 COX-2 催化五种前列腺素合成的第一步； PGD​​2、PGE2、PGF2、PGI2 和 TxA2， 分别激活 11 个前列腺素受体，DP1、DP2、EP1、EP2、EP3、EP4、FPα、、IP 和 TPα、。我们 假设靶向 EP2（COX-2 下游的一种特定前列腺素受体），而不是 完整的 COX-2 信号传导是使用 EP2 特异性拮抗剂治疗 AD 的优越治疗策略。在这项研究中，我们 提议开发 EP2 选择性拮抗剂，以证明 EP2 拮抗剂是否抑制 AD 5XFAD 模型中的炎症、神经退行性变和认知缺陷，并建立初步安全性 EP2 药物可能用于 AD 患者的包装。