Sleepiness in Parkinson's Disease

帕金森病的嗜睡

基本信息

批准号：
8385949
负责人：
SEIJI NISHINO
金额：
$ 23.98万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8385949
关键词：
Accidents Affect Agonist Attention Autoreceptors Behavior monitoring Behavioral Bradykinesia Circadian Rhythms Disease model Dopamine Dopamine Agonists Dopamine D2 Receptor Dose Evaluation Excessive Daytime Sleepiness Excision Exhibits Genetic Homeostasis Impairment Intake Life Medial Mediating Microdialysis Midbrain structure Mitochondria Monitor Motor Skills Movement Mus Muscle Rigidity Neurodegenerative Disorders Parkinson Disease Patients Pharmaceutical Preparations Phenotype Play Prefrontal Cortex Quality of life Quinpirole Research Severities Sleep Symptoms Techniques Testing Tissues Tremor Wakefulness disabling disease dopaminergic neuron mitopark mouse mouse model neurotransmission postsynaptic presynaptic prevent receptor receptor sensitivity research study response sleep abnormalities sleep onset transcription factor transmission process

项目摘要

DESCRIPTION (provided by applicant): It is estimated that up to 50% of patients with Parkinson's disease (PD), a chronically progressive neurodegenerative disease that often impairs motor skills (muscle rigidity, tremor and bradykinesia), have suffered from excessive daytime sleepiness (EDS). In addition, sudden onsets of sleep attacks (SA) (sleep episodes without prodroma) appear in PD, with this symptom occurring more often in those patients who intake dopamine D2/3 agonists. Considerable attention has been devoted to the movement impairments in PD, while little attention has been paid to irresistible daytime sleepiness. Although these sleep symptoms also significantly affect patients' quality of life or threaten their lives (i.e., car accidents), current research does not focus on these symptoms, and the pathological mechanism involved in EDS/SA is unknown. Considering that dopaminergic transmission is impaired and D2/3 agonists trigger sleep symptoms in PD patients, combined with the fact that most wake- promoting compounds enhance dopaminergic neurotransmission, the D2/3 autoreceptor-mediated inhibitory dopaminergic neurotransmission likely plays a key role in EDS/SA in PD. In this proposal, we will dissect mechanisms responsible for EDS and dopamine agonist-induced SA in PD patients using the new genetic mouse model of PD (i.e., Mitopark mouse) by systematic evaluations of sleep behavior and monitoring of dopamine release before and after administration of D2/3 agonists in normal and Mitopark PD mice. The results of the study will determine the major factor(s) contributing to the D2/3 agonist induced pathological sleepiness in PD, and prove informative in preventing/treating this life-threatening, disabling disease. PUBLIC HEALTH RELEVANCE: It is estimated that up to 50% of patients with Parkinson's disease (PD) have suffered from excessive daytime sleepiness (EDS). In addition, sudden onsets of sleep attacks (SA), (which are sleep episodes without prodroma) occur in PD, and the PD patients who intake dopamine D2/3 agonists more often exhibit this disabling symptom. Systematic evaluations of sleep behavior and monitoring of dopamine release before and after administration of D2/3 agonists in a normal and a genetic mouse model of PD will be performed in order to evaluate if altered D2/D3 receptor sensitivity contributes to EDS/SA in PD.

描述（由申请人提供）：据估计，帕金森氏病（PD）的患者中，多达50％是一种经常会损害运动技能（肌肉僵硬，颤音和胸肌）的长期渐进性神经退行性疾病，它们患有过度的日常嗜睡（EDS）。此外，在PD中出现了突然的睡眠攻击（SA）（SA）（不含前药的睡眠发作），这种症状发生在那些摄入多巴胺D2/3激动剂的患者中。非常关注PD的运动障碍，而对白天难以抗拒的嗜睡几乎没有关注。尽管这些睡眠症状也显着影响患者的生活质量或威胁他们生命（即汽车事故），当前的研究并不关注这些症状，并且涉及EDS/SA的病理机制尚不清楚。考虑到多巴胺能传播受损，并且D2/3激动剂会引发PD患者的睡眠症状，再加上大多数唤醒化合物增强了多巴胺能神经传递的事实，D2/3自感受器介导的抑制性多发性多发性多巴胺神经疗法可能会扮演EDS/SA中的PD中的抑制作用。在此提案中，我们将使用新的PD遗传小鼠模型（即Mitopark小鼠）进行睡眠行为评估以及在正常和mitopark PD PD小鼠中给药前后释放多巴胺的释放，使用新的PD遗传小鼠模型（即mitopark小鼠）剖析PD患者的ED和多巴胺激动剂诱导的SA的机制。该研究的结果将确定导致D2/3激动剂引起的PD病理嗜睡的主要因素，并在防止/治疗这种威胁生命，致残性疾病方面有用。公共卫生相关性：据估计，多达50％的帕金森氏病（PD）患者的白天嗜睡过多（EDS）。此外，PD突然出现了睡眠攻击（SA）（SA）（没有前药的睡眠发作），而摄入多巴胺D2/3激动剂的PD患者更常见表现出这种残疾症状。在正常情况下对D2/3激动剂的施用前后对多巴胺释放的系统评估将进行PD的遗传小鼠模型，以评估是否改变了D2/D3受体敏感性是否有助于PD中的EDS/SA。