Adenosine, Hypocretin and Sleep Disorder Comorbidities Associated with Epilepsy

腺苷、下丘脑分泌素和与癫痫相关的睡眠障碍合并症

• 批准号: 8601911
• 负责人: Kristina A Simeone
• 金额: $ 29.91万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8601911
• 关键词: Adenosine; Adenosine A1 Receptor; Adenosine Kinase; Agonist; Animal Model; Anticonvulsants; Arousal; Astrocytes; Attenuated; Benchmarking; Brain; Cell Nucleus; Chemistry; Circadian Rhythms; Clinical; Cognitive; Comorbidity; Data; Diet; Disease; Electrophysiology (science); Epilepsy; Exhibits; Fatty acid glycerol esters; Genetic Models; Goals; Hormonal; Human; Hypothalamic structure; Impaired cognition; In Vitro; Infusion procedures; Injury; Lateral; Left; Mediating; Mental disorders; Metabolic Diseases; Modeling; Molecular Biology; Mus; National Institute of Neurological Disorders and Stroke; Neurons; Pathology; Patient Noncompliance; Patients; Peripheral; Physiological; Physiology; Population; Proteins; Quality of life; Regulation; Reporting; Research; Rest; Seizures; Signal Transduction; Sleep; Sleep Disorders; Sleep Fragmentations; Sleep Wake Cycle; Symptoms; Synapses; Syndrome; System; Techniques; Testing; Up-Regulation; Wakefulness; astrogliosis; base; clinically relevant; experience; hypocretin; improved; in vivo; insight; ketogenic diet; kinase inhibitor; nervous system disorder; new therapeutic target; novel therapeutics; prevent; programs; psychologic; receptor; restoration; treatment strategy

PROJECT SUMMARY/ABSTRACT This proposal focuses on understanding the mechanism responsible for sleep disorder comorbidities associated with epilepsy. Sleep is essential for survival. Lack of appropriate durations and quality of sleep is detrimental to central and peripheral physiological functions that, if left unchecked, can have long-term deleterious consequences ranging from cognitive, immunological, hormonal, metabolic and psychological disorders. In patients with epilepsy, the third most common neurological disorder, lack of sleep can increase seizures, thus exacerbating the core syndrome, and worsen other concomitant disorders such as cognitive impairments and psychological comorbidities. At least one third of epilepsy patients are afflicted with sleep disorder comorbidities, however, because sleep disorders are often overlooked, a realistic estimate may be much higher. Current therapies for epilepsy and its comorbidities are largely symptomatic due to a lack of understanding the underlying disease mechanisms. Therefore, detailed studies elucidating the causes of sleep disorder comorbidities are needed to discover new therapeutic strategies and improve the quality of life of patients with epilepsy. Many of the types of sleep disorders associated with epilepsy are similar to those experienced by people (without epilepsy) which involve a dysregulation of the hypocretin system. Hypocretin neurons are located in the lateral hypothalamus and stimulate arousal nuclei to elicit wakefulness and in sleep disorders, trigger inappropriate awakenings. This proposal is based on the overall premise that pathology exists in the lateral hypothalamus of epileptics that reduces adenosine-inhibition of hypocretin neurons, which ultimately contributes to sleep disorder comorbidities. Using a genetic model of epilepsy with broad clinical relevance, we propose to demonstrate that in LH of epileptic mice (1) there is a pathology that is associated reduced adenosine levels; (2) adenosine A1 receptor-mediated inhibition of hypocretin neurons is diminished; (3) hypocretin protein is elevated and activity of hypocretin neurons is enhanced during periods of rest; and (4) activation of adenosine A1 receptors is necessary for the somnogenic effects of the ketogenic diet. The proposed studies, spanning in vivo and in vitro systems using a combination of techniques in molecular biology, chemistry, electrophysiology and circadian physiology will provide insight into the mechanism of sleep disorder comorbidities associated with epilepsy. The results will have tremendous translational potential by identifying and validating new therapeutic targets for restoring effective sleep to epilepsy patients. Furthermore, effectively treating sleep disorders has the potential to reduce seizures and improve other comorbidities also experienced by a significant portion of the epileptic population. These results will be relevant to other neurological diseases with sleep disorder comordities and astrocytic pathology as a common denominator.

项目摘要/摘要 这项建议的重点是了解睡眠障碍共病的机制。 与癫痫有关。睡眠是生存所必需的。缺乏适当的睡眠时间和质量是 对中枢和外周生理功能有害，如果不加以控制，可能会有长期的 有害后果包括认知、免疫、荷尔蒙、代谢和心理 精神错乱。在癫痫患者中，睡眠不足会增加，这是第三种最常见的神经系统疾病 癫痫发作，从而加剧核心综合征，并恶化其他相伴的障碍，如认知 精神障碍和心理并存。至少三分之一的癫痫患者饱受睡眠的困扰。 然而，由于睡眠障碍经常被忽视，一个现实的估计可能是 高得多。目前治疗癫痫及其合并症的方法大多是有症状的，因为缺乏 了解潜在的疾病机制。因此，关于睡眠原因的详细研究 发现新的治疗策略和提高患者的生活质量需要障碍的并存 癫痫患者。与癫痫有关的许多类型的睡眠障碍与那些 (没有癫痫的)人所经历的涉及下丘脑泌素系统调节失调的症状。下丘脑泌素 神经元位于下丘脑外侧，刺激觉醒核团引起觉醒和睡眠。 紊乱，引发不适当的觉醒。这一建议是基于这样一个总体前提，即病理学 存在于癫痫患者的外侧下丘脑中，它减少了下丘脑下克汀神经元的腺苷抑制，这 最终会导致睡眠障碍的并存。利用癫痫的遗传模型具有广泛的临床意义 与此相关，我们建议证明在癫痫小鼠的黄体生成素(1)中有一种与 腺苷水平降低；(2)腺苷A1受体对下丘脑神经元的抑制作用减弱； (3)静息时下丘脑蛋白升高，下丘脑神经元活性增强； 腺苷A1受体的激活对于生酮饮食的催眠作用是必要的。这个 建议的研究，跨越体内和体外系统，使用分子技术的组合 生物学、化学、电生理学和昼夜生理学将提供对睡眠机制的深入了解 与癫痫相关的疾病合并症。结果将具有巨大的翻译潜力，通过 确定和验证恢复癫痫患者有效睡眠的新治疗目标。此外， 有效地治疗睡眠障碍有可能减少癫痫发作，并改善其他并发症 相当一部分癫痫患者都经历过这种情况。这些结果将与其他 以睡眠障碍、合并症和星形细胞病理为共同特征的神经系统疾病。