Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice
Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice
复制标题
DOI：
10.1073/pnas.0400590101
复制
发表时间：
2004-03-30
影响因子：
11.1
通讯作者：
Yanagisawa, M
中科院分区：
文献类型：
--
作者：
Mieda, M;Willie, JT;Yanagisawa, M
发作性睡病是一种神经系统疾病，与无法保持清醒和快速眼动睡眠相关现象异常侵入清醒有关，如昏厥。绝大多数发作性睡病-猝倒病个体在脑脊液中具有低水平或不可检测水平的食欲素（下丘脑泌素）神经肽，这可能是由于下丘脑产生食欲素的神经元的特定损失。目前可用于嗜睡症的治疗方法仅为姑息性的、以药物治疗为导向的药物疗法。在这里，我们证明了通过遗传和药理学手段拯救食欲素神经元消融小鼠的发作性睡病-痉挛表型。在没有内源性食欲素神经元的情况下，前原食欲素转基因在大脑中的异位表达完全防止了猝倒性逮捕和其他快速眼动睡眠异常。中枢给予食欲素-A可急性抑制痉挛性行为停止，并增加觉醒3小时。这些结果表明，食欲素神经元消融的小鼠保留了对食欲素神经肽做出反应的能力，并且食欲素的时间调节和空间靶向分泌对于预防发作性睡病症状是不必要的。食欲素受体激动剂对治疗人类嗜睡症具有潜在价值。
Narcolepsy-cataplexy is a neurological disorder associated with the inability to maintain wakefulness and abnormal intrusions of rapid eye movement sleep-related phenomena into wakefulness such as cataplexy. The vast majority of narcoleptic-cataplectic individuals have low or undetectable levels of orexin (hypocretin) neuropeptides in the cerebrospinal fluid, likely due to specific loss of the hypothalamic orexin-producing neurons. Currently available treatments for narcolepsy are only palliative, symptom-oriented pharmacotherapies. Here, we demonstrate rescue of the narcolepsy-cataplexy phenotype of orexin neuron-ablated mice by genetic and pharmacological means. Ectopic expression of a prepro-orexin transgene in the brain completely prevented cataplectic arrests and other abnormalities of rapid eye movement sleep in the absence of endogenous orexin neurons. Central administration of orexin-A acutely suppressed cataplectic behavioral arrests and increased wakefulness for 3 h. These results indicate that orexin neuron-ablated mice retain the ability to respond to orexin neuropeptides and that a temporally regulated and spatially targeted secretion of orexins is not necessary to prevent narcoleptic symptoms. Orexin receptor agonists would be of potential value for treating human narcolepsy.