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 摘要 淀粉样蛋白-β(A-β)在脑血管系统的沉积可导致血脑屏障功能障碍和 脑淀粉样血管病(CAA)的发展。CAA是一种病理特征，表现为 伴随着阿尔茨海默病(AD)的高发，突显了 阿尔茨海默病中的血管Aβ。目前，还没有可用的治疗方法来减缓或延缓CAA或AD的进展。最近进来的 我们实验室的体外和体内研究结果表明，依托度酸，一种非类固醇抗肿瘤药物，治疗 炎性药物(非甾体类抗炎药)用于治疗疼痛和关节炎，恢复血脑屏障功能，纠正Aβ的毒性作用。 然而，由于毒性，不建议长期使用非类固醇抗炎药，特别是在老年人中。 由环氧合酶(COX)抑制引起。依托度酸是一种与S对映体有关的外消旋药物 用于与不良反应相关的COX2抑制。另一方面，R-依托度酸缺乏COX2抑制作用 效果。因此，R-依托度酸具有避免观察到的COX2抑制不良反应的潜在优势 用外消旋依托度酸。初步的体外数据表明，与外消旋依托度酸一样，这两种对映体都是 上调紧密和黏附连接蛋白，这对血脑屏障的完整性是必不可少的。然而，只有R-依托度酸 上调β-连环蛋白，这是全面细胞控制内皮细胞通透性和连接所必需的 稳定状态。基于这些发现，这项建议旨在描绘R-依托度酸的COX2非依赖性作用 关于内皮-血脑屏障模型的完整性和功能(R61时相)，以及体内对血脑屏障功能的影响，脑Aβ 蓄积和相关病理，以及记忆功能(R33期)。我们假设R-依托度酸 通过恢复血脑屏障功能减轻血管A型血脑屏障的发病。在阶段1(R61，目标1)中，我们将调查 并比较依托度酸的外消旋、R-和S对映体的体外效力，以改善细胞的功能- 基于β病理的内皮-血脑屏障模型。将进行浓度依赖研究，以评估 化合物对内皮-血脑屏障模型通透性及A-β清除和转录的影响 变化，以及R-依托度酸的药代动力学和脑处置。在阶段2(R33，目标2)，我们将调查 口服R-依托度酸纠正血脑屏障完整性、改善学习记忆功能的体内疗效 减少CAA/AD转基因小鼠Aβ沉积及相关病理改变经过治疗后， 将使用一组认知任务来评估小鼠的认知能力，以及血脑屏障的变化 使用Gd造影剂磁共振成像(Gd-MRI)的渗透性，以及 β相关病理的生物标志物。该项目的成功完成将为重新调整用途铺平道路 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 被转送到诊所。这一结果将产生重大的积极影响，因为R-依托度酸不具有COX2- 缓解不良反应，使老年人长期使用安全。