Drug repurposing for Alzheimer’s disease-related inflammation caused by a TBI

药物再利用，治疗 TBI 引起的阿尔茨海默病相关炎症

• 批准号: 10590132
• 负责人: ADAM D BACHSTETTER
• 金额: $ 22.95万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10590132
• 关键词: APP-PS1; Acceleration; Acute; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; American; Antibiotics; Area; Astrocytes; Azithromycin; Behavioral; Behavioral Assay; Biological Products; Brain; Brain Injuries; Clinical Research; Closed head injuries; Cognitive; Cognitive deficits; Data; Dementia; Dose; Drug Targeting; Drug usage; Elderly; Environmental Risk Factor; Evaluation; Evaluation Research; Exploratory/Developmental Grant; FDA approved; Failure; Gliosis; Goals; Histopathology; Immunosuppressive Agents; Incidence; Infection; Inflammation; Inflammatory; Injury; Kentucky; Knock-in Mouse; Microglia; Modeling; Nervous System Trauma; Odds Ratio; Outcome; Pathology; Patient-Focused Outcomes; Pharmaceutical Preparations; Phase; Phenotype; Population; Populations at Risk; Positioning Attribute; Pre-Clinical Model; Predisposition; Property; Prophylactic treatment; Radial; Recovery; Research; Resolution; Risk; Safety; Speed; Spinal cord injury; Synapses; TBI treatment; TNF gene; Testing; Therapeutic; Therapeutic Agents; Time; Traumatic Brain Injury; Universities; Wild Type Mouse; Work; aging brain; amyloid pathology; arm; blood-brain barrier crossing; cost; disorder risk; drug development; drug discovery; drug efficacy; drug repurposing; experience; falls; human old age (65+); immune modulating agents; immunomodulatory therapies; immunoregulation; improved; infection risk; medical attention; mild traumatic brain injury; mouse model; neuroinflammation; neuropathology; neuroprotection; novel therapeutics; pharmacokinetics and pharmacodynamics; pre-clinical; prevent; primary endpoint; research and development; response; tau Proteins; therapeutic development; therapeutic evaluation; treatment duration; water maze

PROJECT SUMMARY/ABSTRACT The CDC estimates that at least 200,000 older Americans (> 65 years) will have a traumatic brain injury (TBI) each year, primarily caused by a closed head injury (CHI) from a fall. The aged brain, with Alzheimer’s disease neuropathological changes, has significant reactive microglia and astrocytes and other markers of neuroinflammation. An acquired brain injury can further exacerbate this state of reactive gliosis and neuroinflammation. Alzheimer’s disease poses a significant therapeutic challenge, given that pathology can develop over decades. However, we believe that it is an obtainable therapeutic goal to prevent the worsening of neuroinflammation caused by an acquired brain injury in those at risk for developing Alzheimer’s disease . Control of neuroinflammation following the TBI in older adults is a promising avenue for improving patient outcomes. However, no drug has earned FDA approval for specific use in mild TBI. There is also limited evidence to guide the repurposing of FDA-approved drugs that target neuroinflammation for this unique population. Broad-spectrum immunosuppressants are not advisable and, while selective biologics (such as anti-TNF) are promising, they also come with the risk of increasing infection, which is problematic in an older adult population at risk for infections. Our goal is to identify targeted immunomodulatory (not, immunosuppressants) with a high benefit-to-risk ratio. We recently identified the commonly prescribed antibiotic, Azithromycin (AZM), as an immunomodulatory agent with neuroprotective effects in spinal cord injury. Because of its safety profile, AZM is frequently prescribed as a prophylactic treatment in several conditions and broadly administered in at-risk disease populations. This proposal aims to provide proof-of- principal data for AZM as a safe and effective neuroinflammatory modulatory drug. We will test the central hypothesis that AZM can alter neuroinflammation and improve cognitive outcomes following a CHI in an APP/PS1 KI mouse model of Alzheimer’s disease-related pathology in the following two specific aims (SA). SA1: Define the immunomodulatory dose-dependent effect of AZM in 8-month-old APP/PS1 KI mouse model following a CHI. SA2: Evaluate the effects of AZM on CHI-induced behavioral and Alzheimer’s disease-related neuropathology in 8-month-old APP/PS1 KI mice. This proof-of-concept study could establish AZM as a safe and well-tolerated FDA-approved drug to reduce damage and speed recovery in the fragile older brain following a CHI. Once the feasibility of AZM treatment has been established, new areas of drug development and clinical research with the potential to more quickly develop a new drug to slow the devastating effects of Alzheimer’s disease can be created.

项目摘要/摘要 疾病预防控制中心估计，至少有200,000名美国人（> 65岁）将遭受创伤性脑损伤（TBI） 每年，主要是由于秋天的闭合头部受伤（CHI）引起的。老年大脑，患有阿尔茨海默氏病 神经病理学的变化，具有明显的反应性小胶质细胞和星形胶质细胞以及其他标记 神经炎症。获得的脑损伤会进一步加剧这种反应性神经胶质的状态和 神经炎症。鉴于病理可以 发展了几十年。但是，我们认为，防止担心是一个可获得的治疗目标 因脑损伤而引起的神经炎症，患有患阿尔茨海默氏病风险的人。 在老年人TBI之后，控制神经炎症是改善患者的有前途的途径 结果。但是，在轻度TBI中，尚无药物获得FDA的批准。也有限 指导FDA批准的药物的重新利用的证据，该药物以神经炎症为目标 人口。广谱免疫抑制剂不建议，而选择性生物制剂（例如 承诺抗TNF），它们还具有增加感染的风险，这在较旧的情况下是有问题的 成人人口有感染风险。我们的目标是确定有针对性的免疫调节性（不是， 免疫抑制剂）具有高益处危比。我们最近确定了通常的规定 抗生素，阿奇霉素（AZM）作为脊髓中神经保护作用的免疫调节剂 受伤。由于其安全性，AZM经常在几种中处方为预防治疗 条件并广泛管理在高危疾病人群中。该建议旨在提供证明 AZM作为安全有效的神经炎症调节药物的主要数据。我们将测试中央 假设AZM可以改变神经炎症并改善CHI之后的认知结果 在以下两个特定目的（SA）中，阿尔茨海默氏病的APP/PS1 Ki小鼠模型。 SA1：定义AZM在8个月大的APP/PS1 Ki小鼠中的免疫调节剂量依赖性效应 CHI后的型号。 SA2：评估AZM对CHI诱导的行为和阿尔茨海默氏病有关的影响 8个月大的APP/PS1 KI小鼠中的神经病理学。 这项概念证明的研究可以将AZM确定为安全且耐受良好的FDA批准药物，以减少 chi后，脆弱的老大脑的损害和速度恢复。一旦AZM治疗的可行性 已经建立了药物开发和临床研究的新领域，有可能更快 开发一种新药可以减慢阿尔茨海默氏病的毁灭性影响。