Sleepiness in Parkinson's Disease

帕金森病的嗜睡

• 批准号: 8461545
• 负责人: SEIJI NISHINO
• 金额: $ 19.38万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461545
• 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

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.

描述（由申请人提供）：据估计，多达 50% 的帕金森病 (PD) 患者患有日间过度嗜睡 (EDS)，帕金森病是一种慢性进行性神经退行性疾病，通常会损害运动技能（肌肉僵硬、震颤和运动迟缓）。此外，PD 中还会出现突发性睡眠发作 (SA)（无前驱症状的睡眠发作），这种症状在服用多巴胺 D2/3 激动剂的患者中更常见。人们对帕金森病的运动障碍给予了相当多的关注，而对不可抗拒的白天嗜睡却很少关注。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的健康 生命（即车祸），目前的研究并不关注这些症状，并且 EDS/SA 涉及的病理机制尚不清楚。考虑到多巴胺能传递受损且 D2/3 激动剂会引发 PD 患者的睡眠症状，再加上大多数促醒化合物增强多巴胺能神经传递这一事实，D2/3 自身受体介导的抑制性多巴胺能神经传递可能在 PD 的 EDS/SA 中发挥关键作用。 在本提案中，我们将使用新的 PD 遗传小鼠模型（即 Mitopark 小鼠），通过系统评估正常小鼠和 Mitopark PD 小鼠在给予 D2/3 激动剂前后的睡眠行为和监测多巴胺释放，来剖析 PD 患者中 EDS 和多巴胺激动剂诱导 SA 的机制。 该研究的结果将确定导致 D2/3 激动剂诱发 PD 病理性嗜睡的主要因素，并为预防/治疗这种危及生命、致残的疾病提供信息。