Antibiotic-mediated improvements in vigilance: mechanisms of action of clarithromycin in hypersomnia syndromes

抗生素介导的警觉性改善：克拉霉素在嗜睡综合征中的作用机制

• 批准号: 9901617
• 负责人: Lynn Marie Trotti
• 金额: $ 42.41万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901617
• 关键词: Accidental Injury; Anatomy; Antibiotics; Biological; Brain; Cerebrospinal Fluid; Clarithromycin; Clinical; Clinical Investigator; Clinical Research; Data; Development; Disease; Disorders of Excessive Somnolence; Drowsiness; Excessive Daytime Sleepiness; Exhibits; Flumazenil; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; Future; GABA Modulators; GABA-A Receptor; Hallucinations; Hypersomnias; Hypersomnolence; Idiopathic Hypersomnolence; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Investigation; Literature; Macrolides; Maintenance; Measures; Mediating; Mediation; Mediator of activation protein; Molecular; Morbidity - disease rate; Multiple Sclerosis; Myotonic Dystrophy; Narcolepsy; Neuraxis; Neurologic; Neurons; Occupational; Parkinson Disease; Pathologic; Patient Self-Report; Patients; Peptides; Performance; Pharmaceutical Preparations; Placebos; Production; Publishing; Quality of life; Refractory; Research Personnel; Rest; Risk; Risk Reduction; Route; Safety; Sleep; Symptoms; Syndrome; TNF gene; Testing; Therapeutic; Translating; Wakefulness; Work; base; conventional therapy; cost; cytokine; design; drug development; dysbiosis; effective therapy; evidence base; experience; gastrointestinal; gut microbiome; gut microbiota; improved; individual patient; innovation; microbiome composition; motor disorder; multimodality; nervous system disorder; neurotransmission; novel; novel therapeutics; patient population; prevent; randomized placebo controlled trial; receptor function; relating to nervous system; standard of care; targeted agent; vigilance

Abstract Excessive daytime sleepiness is a common feature of many neurologic disorders, including Parkinson’s disease, myotonic dystrophy, and multiple sclerosis. In the neurologic disorders of hypersomnolence, excessive daytime sleepiness occurs as the primary disease symptom, often accompanied by other sleep- related phenomena such as long sleep durations, pronounced sleep inertia, sleep-related hallucination, and sleep-related motor dysfunction. For two of these disorders, idiopathic hypersomnia and narcolepsy type 2, clinical features are indistinguishable and underlying pathophysiology is unknown. However, prior work has demonstrated that the macrolide antibiotic clarithromycin is more effective at reducing sleepiness than placebo in these two conditions, although the mechanism or mechanisms by which clarithromycin exerts this effect are unknown. Reduction in GABA-ergic neurotransmission, changes in resting state brain connectivity, suppression of soporific, pro-inflammatory cytokines, and alterations in gastrointestinal microbiome composition are all biologically plausible mechanisms for this effect, but have not been directly tested. In this work, a randomized, placebo-controlled trial of clarithromycin will be performed in patients with idiopathic hypersomnia and narcolepsy type 2 to evaluate for mediators of the beneficial effects of clarithromycin on pathologic sleepiness. The first aim is to identify central nervous system mediators of reduction in sleepiness by clarithromycin, including modulation of GABA-A receptor activity by cerebrospinal fluid in vitro and changes in default mode network connectivity via resting state fMRI. The second aim is to probe extra-neuronal mechanisms by which clarithromycin may reduce sleepiness, including changes in systemic inflammation and changes in gastrointestinal microbiota composition. For all aims, sleepiness will be characterized in a multi- modal fashion, with both self-reported measures of sleepiness, primarily the Epworth Sleepiness Scale, and objective measures of sleepiness, primarily the mean sleep latency measured on the Maintenance of Wakefulness Test. Each of the proposed mechanisms will be evaluated in relation to change in measures of sleepiness via mediation analysis to determine which mechanisms mediate clarithromycin’s reduction in sleepiness. This work leverages the PI and co-investigators’ clinical research expertise in the hypersomnolence disorders, the unique and highly motivated patient population at the Emory Sleep Center, and the complimentary expertise of a team of experienced collaborators. This work will impact the understanding of the central disorders of hypersomnolence and provide a foundation for future drug development for these and other neurologic disorders manifesting with pathologic daytime sleepiness.

摘要 白天过度嗜睡是包括帕金森氏症在内的许多神经系统疾病的共同特征 疾病、强直性肌营养不良和多发性硬化症。在睡眠过多的神经性障碍中， 白天过度嗜睡是主要的疾病症状，通常伴随着其他睡眠- 相关现象，如睡眠时间长，明显的睡眠惰性，与睡眠相关的幻觉，以及 睡眠相关的运动功能障碍。对于其中两种疾病，特发性睡眠症和2型发作性睡病， 临床特征难以区分，潜在的病理生理机制尚不清楚。然而，以前的工作已经完成 证明大环内酯类抗生素克拉霉素在减少嗜睡方面比安慰剂更有效 在这两种情况下，虽然克拉霉素发挥这种作用的一个或多个机制是 未知。GABA能神经传递减少，静息状态脑连接改变， 抑制催眠、促炎细胞因子和胃肠道微生物群的改变 成分都是这种效应的生物学机制，但还没有直接测试过。在这 工作中，克拉霉素的随机、安慰剂对照试验将在特发性患者中进行。 嗜睡和发作性睡病2型用于评估克拉霉素治疗的有益效果的介体 病理性嗜睡。第一个目标是找出减少嗜睡的中枢神经系统媒介。 克拉霉素对GABA-A受体活性的影响及脑脊液对其影响 在默认模式下，通过休眠状态FMRI进行网络连接。第二个目标是探测神经元外 克拉霉素可以减少嗜睡的机制，包括全身炎症和 胃肠道微生物区系组成的变化。对于所有目标来说，嗜睡将表现为一种多方面的 时尚模式，包括自我报告的困倦程度，主要是爱普沃斯困倦程度量表，以及 昏昏欲睡的客观测量，主要是在维持睡眠的过程中测量的平均睡眠潜伏期 觉醒测试。每个拟议的机制都将根据以下措施的变化进行评估 通过中介分析确定哪些机制介导克拉霉素减少嗜睡 困倦。这项工作利用了PI和合作调查员在 睡眠过度障碍，埃默里睡眠中心独特的、高度积极的患者群体， 以及经验丰富的合作者团队提供的免费专业知识。这项工作将对 了解睡眠过多的中枢性障碍，为今后的药物治疗提供基础 这些和其他神经系统疾病的发展，表现为病理性的日间嗜睡。