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 美国疾病控制与预防中心估计，至少有20万美国老年人(65岁)将患有创伤性脑损伤(TBI)。 每年，主要由跌倒造成的闭合性头部损伤(CHI)引起。患有阿尔茨海默病的老年大脑 神经病理改变，具有显著的反应性小胶质细胞和星形胶质细胞等标志物 神经炎。获得性脑损伤会进一步加剧这种反应性胶质细胞增生的状态，并 神经炎。阿尔茨海默病是一个重大的治疗挑战，因为病理可以 经过几十年的发展。然而，我们认为，防止病情恶化是一个可以达到的治疗目标。 阿尔茨海默病高危人群后天脑损伤引起的神经炎症。 控制老年人脑外伤后的神经炎症是改善患者状况的一条有希望的途径 结果。然而，目前还没有一种药物获得FDA批准用于轻度脑外伤。也有有限的 指导FDA批准的针对神经炎症的药物重新用途的证据 人口。广谱免疫抑制剂是不可取的，而选择性生物制品(如 抗肿瘤坏死因子)是有希望的，但它们也伴随着增加感染的风险，这在老年人中是有问题的 处于感染风险的成年人口。我们的目标是识别有针对性的免疫调节(不是， 免疫抑制剂)，具有较高的受益风险比。我们最近确定了常用的处方药 具有脊髓神经保护作用的免疫调节剂阿奇霉素(AZM) 受伤。由于其安全性，阿奇米经常被开作为预防治疗在几个 并在高危疾病人群中广泛使用。这项提案旨在提供以下证据： AZM作为一种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 阿扎姆可以改变神经炎症和改善脑出血后认知结果的假说 APP/PS1Ki小鼠模型对阿尔茨海默病相关病理的研究有以下两个具体目的(SA)。 SA1：确定AZM对8月龄APP/PS1KI小鼠的免疫调节作用 模特儿跟在气后面。 SA2：评估AZM对CHI诱导的行为和阿尔茨海默病相关的影响 8月龄APP/PS1Ki小鼠的神经病理学。 这项概念验证研究可以确定阿奇米是一种安全且耐受性良好的FDA批准的药物，以减少 气过后脆弱的老年大脑的损伤和恢复速度。一旦AZM治疗的可行性 已经建立，新的药物开发和临床研究领域具有更快的潜力 开发一种新药来减缓阿尔茨海默病的破坏性影响可以创造出来。