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: 10475610
• 负责人: Lynn Marie Trotti
• 金额: $ 44.66万
• 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/10475610
• 关键词: Accidental Injury; Anatomy; Antibiotics; 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; 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; antagonist; 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; systemic inflammatory response; 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。在嗜睡的神经系统疾病中， 白天过度嗜睡是主要的疾病症状，通常伴有其他睡眠， 相关的现象，如长睡眠持续时间，明显的睡眠惯性，睡眠相关的幻觉， 睡眠相关的运动功能障碍对于其中两种疾病，特发性嗜睡症和2型发作性睡病， 临床特征难以区分，潜在的病理生理学也未知。然而，先前的工作 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，尽管克拉霉素发挥这种作用的机制是 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组的改变 这些组合物都是这种作用的生物学上合理的机制，但尚未直接测试。在这 这项研究是一项随机、安慰剂对照的克拉霉素试验，将在特发性 2型嗜睡症和发作性睡病，以评价克拉霉素对 病理性嗜睡第一个目的是确定减少嗜睡的中枢神经系统介质 包括体外脑脊液对GABA-A受体活性的调节以及 在默认模式下，通过静息状态fMRI进行网络连接。第二个目标是探测神经元外的 克拉霉素可减少嗜睡的机制，包括全身炎症的变化， 胃肠道微生物群组成的变化。对于所有的目标，嗜睡将在一个多特征- 模态方式，包括自我报告的嗜睡测量，主要是埃普沃思嗜睡量表，以及 嗜睡的客观测量，主要是维持睡眠时测量的平均睡眠潜伏期， 觉醒测试每一个拟议的机制都将根据以下方面的措施变化进行评估： 通过介导分析确定克拉霉素降低嗜睡的机制 困倦这项工作利用了PI和合作研究者在以下方面的临床研究专业知识： 嗜睡症，埃默里睡眠中心独特的和高度积极的患者群体， 以及经验丰富的合作者团队的专业知识。这项工作将影响 了解嗜睡的中枢性障碍，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日间嗜睡。