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: 8297937
• 负责人: Kristina A Simeone
• 金额: $ 29.27万
• 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/8297937
• 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

DESCRIPTION (provided by applicant): 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 centra 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 effectie 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. PUBLIC HEALTH RELEVANCE: 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. Lack of effective sleep can increase seizures, thus exacerbating the core syndrome, and worsen other concomitant disorders such as cognitive impairments and psychological comorbidities. Therefore, detailed studies elucidating the mechanisms of these sleep disorders are needed to discover new therapeutic strategies and improve the quality of life of patients with epilepsy.

描述（由申请人提供）：该提案侧重于了解与癫痫相关的睡眠障碍合并症的机制。睡眠对生存至关重要。缺乏适当的睡眠持续时间和质量对中枢和外周生理功能是有害的，如果不加以控制，可能会产生长期的有害后果，包括认知、免疫、激素、代谢和心理障碍。癫痫是第三常见的神经系统疾病，在癫痫患者中，睡眠不足会增加癫痫发作，从而加重核心综合征，并使其他伴随疾病（如认知障碍和心理共病）恶化。至少有三分之一的癫痫患者患有睡眠障碍合并症，然而，由于睡眠障碍往往被忽视，现实的估计可能要高得多。由于缺乏对潜在疾病机制的了解，目前癫痫及其合并症的治疗主要是症状性的。因此，需要详细研究阐明睡眠障碍合并症的原因，以发现新的治疗策略，提高癫痫患者的生活质量。与癫痫相关的许多类型的睡眠障碍与人们（没有癫痫）经历的睡眠障碍相似，这些睡眠障碍涉及下丘脑泌素系统的失调。下丘脑泌素神经元位于外侧下丘脑，刺激唤醒核团以引起觉醒，并且在睡眠障碍中，触发不适当的觉醒。这一建议是基于一个总体前提，即病理存在于癫痫患者的下丘脑外侧，降低了下丘脑泌素神经元的腺苷抑制，最终导致睡眠障碍合并症。利用具有广泛临床意义的癫痫遗传模型，我们提出在癫痫小鼠LH中：（1）存在与腺苷水平降低相关的病理学;（2）腺苷A1受体介导的下丘脑泌素神经元抑制减弱;（3）下丘脑泌素蛋白升高，下丘脑泌素神经元活性在休息期间增强;腺苷A1受体的激活是生酮饮食的催眠作用所必需的。拟议的研究，跨越体内和体外系统，使用分子生物学，化学，电生理学和昼夜生理学的技术组合，将提供洞察与癫痫相关的睡眠障碍合并症的机制。通过识别和验证新的治疗靶点来恢复癫痫患者的有效睡眠，这些结果将具有巨大的转化潜力。此外，有效治疗睡眠障碍有可能减少癫痫发作并改善大部分癫痫人群所经历的其他合并症。这些结果将与其他神经系统疾病的睡眠障碍合并症和星形胶质细胞病理学作为一个共同点。 公共卫生关系：至少有三分之一的癫痫患者患有睡眠障碍合并症，然而，由于睡眠障碍往往被忽视，现实的估计可能要高得多。缺乏有效的睡眠会增加癫痫发作，从而加剧核心综合征，并恶化其他伴随疾病，如认知障碍和心理共病。因此，需要详细的研究阐明这些睡眠障碍的机制，以发现新的治疗策略，提高癫痫患者的生活质量。