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.

重新利用阿尔茨海默氏病和相关疾病的R-Etodolac重新利用 概括 淀粉样蛋白β（Aβ）在大脑中的沉积会导致血脑屏障（BBB）功能障碍，并且 脑淀粉样血管病（CAA）的发展。 CAA是呈现的病理特征 同时与阿尔茨海默氏病（AD）高频，突出了潜在的重要作用 AD中的血管Aβ。目前，尚无治疗方法可以减慢或保持CAA或AD的进展。最近 从我们实验室的体外和体内发现表明，用非甾体类抗 - 用于治疗疼痛和关节炎的炎症药（NSAID）恢复了BBB功能并纠正了Aβ毒性作用。 但是，不建议长期使用NSAID，尤其是在古老的情况下，因为毒性 由环氧合酶（COX）抑制作用。 Etodolac是一种外消毒药物 对于与不良反应相关的COX2抑制作用。另一方面，R-Etodolac缺乏COX2抑制作用 影响。这是避免观察到的COX2抑制不良反应的潜在优势 带有外星雌激素。初步的体外数据表明，像消极的蚀刻剂一样，两个对映异构体 上调紧密的粘附连接蛋白，这对于BBB完整性至关重要。但是，只有R-依托龙 上调β-catenin，这是对内皮渗透性和连接的全细胞控制所必需的 稳定。基于这些发现，该提案旨在描述R-Etodolac的COX2独立效应 在内皮BBB模型的完整性和功能（R61相）和BBB功能上的体内，脑Aβ 积累和相关病理和记忆功能（R33期）。我们假设R-Etodolac 通过恢复BBB功能来减轻血管Aβ发病机理。在第1阶段（R61，AIM 1）中，我们将调查 并比较了dodolac的外消毒，r-和s-替代物的体外效力，以改善细胞的功能 基于具有Aβ病理的内皮BBB模型。将进行浓度依赖性研究以评估 化合物对内皮BBB模型渗透性和Aβ间隙的影响RNA转录 变化以及R-依托酸药代动力学和大脑处置。在第2阶段（R33，AIM 2）中，我们将调查 口服r-etodolac的体内效率以纠正BBB完整性，改善学习和记忆以及 在CAA/AD的转基因小鼠模型中减少Aβ沉积和相关病理。以下治疗， 将使用一系列认知任务评估小鼠的认知表现，以改变BBB 使用Gadolinium对比剂磁共振成像（GD-MRI）的渗透性，用于改变 与Aβ相关病理的生物标志物。成功完成项目将为重新使用铺平道路 R-Etodolac是一种新的分子，可预防和/或减慢CAA和AD的进展 翻译成诊所。结果将产生重大的积极影响，因为R- Etodolac不具备COX2- 介导的不良影响使得长期使用的安全性是安全的。