Repurposing of R-etodolac for Alzheimer's disease and related disorders

R-依托度酸的再利用治疗阿尔茨海默病和相关疾病

• 批准号: 10728667
• 负责人: Amal F Khalil Kaddoumi
• 金额: $ 37.04万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10728667
• 关键词: Abeta clearance; Adherens Junction; Adverse effects; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid; Amyloid beta-Protein; Arthritis; Astrocytes; Attenuated; Biochemical; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Brain; Cells; Cerebral Amyloid Angiopathy; Cerebrovascular system; Cerebrum; Characteristics; Chronic; Clinic; Contrast Media; Coxibs; Data; Dementia; Deposition; Development; Disease; Dose; Drug Kinetics; Drug usage; Elderly; Endothelial Cells; Endothelium; Frequencies; Gadolinium; Genetic Transcription; Health; Health Care Costs; Impairment; In Vitro; Laboratories; Learning; Libraries; Magnetic Resonance Imaging; Marketing; Mediating; Memory; Modeling; Mus; Non-Steroidal Anti-Inflammatory Agents; Oral Administration; Outcome; PTGS2 gene; Pain; Pathogenesis; Pathologic; Pathology; Pathway interactions; Permeability; Pharmaceutical Preparations; Phase; Positioning Attribute; Preventive; Prostaglandin-Endoperoxide Synthase; Proteins; Public Health; Publishing; RNA; Reporting; Role; Testing; Therapeutic; Tight Junctions; Time; Toxic effect; Transgenic Mice; Translating; Vascular Diseases; Work; abeta accumulation; abeta deposition; beta amyloid pathology; beta catenin; blood-brain barrier disruption; blood-brain barrier function; blood-brain barrier permeabilization; cerebrovascular; cognitive performance; cognitive task; efficacious treatment; efficacy study; enantiomer; functional improvement; high throughput screening; improved; in vivo; monolayer; mouse model; neuroinflammation; neuroprotection; novel; pharmacologic; prevent; screening; side effect; therapeutic target; transcriptome sequencing

Repurposing of R-Etodolac for Alzheimer’s Disease and Related Disorders Summary The deposition of amyloid-β (Aβ) in cerebrovasculature can result in blood-brain barrier (BBB) dysfunction and the development of cerebral amyloid angiopathy (CAA). CAA is a pathological feature that presents concomitantly with Alzheimer’s disease (AD) at a high frequency, highlighting a potentially important role for vascular Aβ in AD. Currently, no treatment is available to slow or hold the progression of CAA or AD. Recent in vitro and in vivo findings from our laboratory demonstrated that treatment with etodolac, a non-steroidal anti- inflammatory drug (NSAID) used to treat pain and arthritis, restored the BBB function and rectified Aβ toxic effects. However, the long-term use of NSAIDs, especially in the elderly, is not recommended because of toxicities resulting from cyclooxygenase (COX) inhibition. Etodolac is a racemic drug with the S-enantiomer responsible for COX2 inhibition associated with adverse effects. R-etodolac, on the other hand, lacks the COX2-inhibitory effect. Thus, R-etodolac has the potential advantage of avoidance of COX2 inhibitory adverse effects observed with racemic etodolac. Preliminary in vitro data demonstrated that, like racemic etodolac, both enantiomers upregulate tight and adherens junction proteins, which are essential for BBB integrity. However, only R-etodolac upregulates β-catenin, which is required for full cellular control of endothelial permeability and junction stabilization. Based on these findings, this proposal aims to delineate the COX2-independent effect of R-etodolac on endothelium-BBB model integrity and function (R61 phase), and in vivo on BBB function, brain Aβ accumulation and related pathology, and memory function (R33 phase). We hypothesize that R-etodolac attenuates vascular Aβ pathogenesis by restoring the BBB function. In phase 1 (R61, Aim 1), we will investigate and compare the in vitro potency of racemic, R- and S-enantiomers of etodolac to improve the function of a cell- based endothelium-BBB model with Aβ pathology. Concentration-dependent studies will be performed to assess the compounds' effects on the endothelium-BBB model permeability and Aβ clearance, RNA transcriptional changes, and R-etodolac pharmacokinetics and brain disposition. In phase 2 (R33, Aim 2), we will investigate the in vivo efficacy of orally administered R-etodolac to rectify BBB integrity, improve learning and memory and reduce Aβ deposition and related pathology in a transgenic mouse model of CAA/AD. Following treatments, mice will be assessed for cognitive performance using a battery of cognitive tasks, for alterations in BBB permeability using gadolinium contrast agent magnetic resonance imaging (Gd-MRI), and for alterations in biomarkers of Aβ-related pathology. Successful completion of the project will pave the way for the repurposing of R-etodolac as a novel molecule to prevent and/or slow the progression of CAA and AD that can be rapidly translated to the clinic. The results will have a significant positive impact as R-etodolac does not possess COX2- mediated adverse effects making it safe to use for long term by the elderly.

R-依托度酸治疗阿尔茨海默病及相关疾病的再利用 总结 β淀粉样蛋白（Aβ）在脑血管中的沉积可导致血脑屏障（BBB）功能障碍， 脑淀粉样血管病（CAA）的发展。CAA是一种病理特征， 伴随着阿尔茨海默病（AD）的高频率，突出了潜在的重要作用， 血管Aβ在AD中的作用目前，没有治疗方法可以减缓或阻止CAA或AD的进展。中最近 我们实验室的体外和体内研究结果表明，依托度酸，一种非甾体抗- 抗炎药（NSAID）用于治疗疼痛和关节炎，恢复BBB功能并纠正Aβ毒性作用。 然而，由于毒性，不建议长期使用NSAID，尤其是老年人 由环氧合酶（考克斯）抑制引起。依托度酸是一种外消旋药物，S-对映体负责 与不良反应相关的COX 2抑制。另一方面，R-依托度酸缺乏COX 2抑制剂。 效果因此，R-依托度酸具有避免观察到的COX 2抑制性不良反应的潜在优势 外消旋依托度酸初步体外数据表明，与外消旋依托度酸一样，两种对映体 上调紧密连接蛋白和粘附连接蛋白，这是BBB完整性所必需的。然而，只有R-依托度酸 上调β-连环蛋白，这是内皮通透性和连接的完全细胞控制所必需的 稳定化基于这些发现，本提案旨在描述R-依托度酸的COX 2非依赖性作用 对内皮-BBB模型完整性和功能（R61期）以及体内对BBB功能、脑Aβ的影响 积累和相关病理学以及记忆功能（R33期）。我们假设R-依托度酸 通过恢复BBB功能减弱血管Aβ发病机制。在第1阶段（R61，目标1），我们将研究 并比较依托度酸的外消旋体、R-和S-对映体改善细胞功能的体外效力， 建立Aβ病变的内皮-血脑屏障模型。将进行浓度依赖性研究以评估 化合物对内皮-血脑屏障模型通透性和Aβ清除率、RNA转录的影响 变化以及R-依托度酸药代动力学和脑处置。在第2阶段（R33，目标2），我们将研究 口服给药的R-依托度酸纠正BBB完整性、改善学习和记忆以及 减少CAA/AD转基因小鼠模型中的Aβ沉积和相关病理学。治疗后， 将使用一系列认知任务评估小鼠的认知表现、BBB的变化 使用钆对比剂磁共振成像（Gd-MRI）检查渗透性，并检查 Aβ相关病理学的生物标志物。该项目的成功完成将为重新利用铺平道路 R-依托度酸作为一种新的分子来预防和/或减缓CAA和AD的进展， 翻译到诊所结果将具有显著的积极影响，因为R-依托度酸不具有COX 2-。 介导的不良反应，使其安全地长期使用的老年人。