Narcolepsy: genetic predisposition and neuropharmacological mechanisms. REVIEW ARTICLE.
Narcolepsy: genetic predisposition and neuropharmacological mechanisms. REVIEW ARTICLE.
复制标题
发作性睡病：遗传倾向和神经药理学机制。
作者：
S. Nishino;M. Okura;E. Mignot
发作性睡病是一种致残性睡眠障碍，其特征是白天过度嗜睡（EDS）、cataepsy和REM睡眠相关异常。它是一种经常发生但诊断不足的疾病，影响各国0.02%至0.18%的总人口。虽然大多数病例是零星发生的，但可以观察到家族聚集性;发作性睡病患者的一级亲属发生发作性睡病的风险比一般人群高10-40倍。这种疾病与特定的人类白细胞抗原（HLA）等位基因DQB 1 *0602密切相关[最常与HLA-DR 2（DRB 1 *15）组合]。然而，在大多数情况下，遗传传播可能是多基因的，并且HLA-DQ以外的遗传因素也可能与之有关。此外，环境因素也与疾病易感性有关;文献中报道的大多数同卵双胞胎对发作性睡病的发病率不一致。据报道，在20世纪70年代早期，犬科动物中存在嗜睡症。在该动物种属中也观察到散发性和家族性病例。canarc-1是一个高度外显的单常染色体隐性基因，与杜宾犬和拉布拉多寻回犬发作性睡病的传播有关。该基因的定位克隆正在进行中，该基因的人类同源物或与canarc-1具有功能关系的基因可能涉及某些人类病例。人类嗜睡症目前用中枢神经系统（CNS）兴奋剂治疗EDS，用抗抑郁药治疗紧张症和异常REM睡眠。这些治疗纯粹是症状性的，并引起许多副作用。这些化合物会干扰许多患者的夜间睡眠，持续治疗可能会产生耐受性。犬模型是研究EDS和catabolism的药理学和生理学控制的宝贵资源。使用犬发作性睡病的实验表明，胆碱能传递增加和单胺能传递减少可能是该疾病的病理生理学基础。药理学研究表明，阻断去甲肾上腺素摄取介导目前处方的抗抑郁药的抗惊厥作用，而阻断多巴胺摄取和/或刺激多巴胺释放介导CNS兴奋剂的促醒作用。对犬嗜睡症的研究也表明，触发癫痫发作的机制和大脑部位与调节快速眼动睡眠的机制和大脑部位并不相同。因此，有可能开发新的药理学化合物，专门针对发作性睡病的异常症状，但不干扰生理睡眠/觉醒周期。(See也附言）。
Narcolepsy is a disabling sleep disorder characterized by excessive daytime somnolence (EDS), cataplexy and REM sleep-related abnormalities. It is a frequently-occurring but under-diagnosed condition that affects 0.02 to 0.18% of the general population in various countries. Although most cases occur sporadically, familial clustering may be observed; the risk of a first-degree relative of a narcoleptic developing narcolepsy is 10-40 times higher than in the general population. The disorder is tightly associated with the specific human leukocyte antigen (HLA) allele, DQB1*0602 [most often in combination with HLA-DR2 (DRB1*15)]. Genetic transmission is, however, likely to be polygenic in most cases, and genetic factors other than HLA-DQ are also likely to be implicated. In addition, environmental factors are involved in disease predisposition; most monozygotic twins pairs reported in the literature are discordant for narcolepsy. Narcolepsy was reported to exist in canines in the early 1970s. Both sporadic and familial cases are also observed in this animal species. A highly-penetrant single autosomal recessive gene, canarc-1, is involved in the transmission of narcolepsy in Doberman pinschers and Labrador retrievers. Positional cloning of this gene is in progress, and a human homologue of this gene, or a gene with a functional relationship to canarc-1, might be involved in some human cases. Human narcolepsy is currently treated with central nervous system (CNS) stimulants for EDS and antidepressants for cataplexy and abnormal REM sleep. These treatments are purely symptomatic and induce numerous side effects. These compounds disturb nocturnal sleep in many patients, and tolerance may develop as a result of continuous treatment. The canine model is an invaluable resource for studying the pharmacological and physiological control of EDS and cataplexy. Experiments using canine narcolepsy have demonstrated that increased cholinergic and decreased monoaminergic transmission are likely to be at the basis of the pathophysiology of the disorder. Pharmacological studies have shown that blockade of norepinephrine uptake mediates the anticataplectic effect of currently prescribed antidepressants, while blockade of dopamine uptake and/or stimulation of dopamine release mediates the awake-promoting effect of CNS stimulants. Studies in canine narcolepsy also suggest that mechanisms and brain sites for triggering cataplexy are not identical to those regulating REM sleep. It may thus be possible to develop new pharmacological compounds that specifically target abnormal symptoms in narcolepsy, but do not disturb physiological sleep/wake cycles. (See also postscript remarks).
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血清素摄取抑制剂的去甲基代谢物比其母体化合物更有效地抑制犬猝倒。
影响因子：
5.6
作者：
Nishino,S;Arrigoni,J;Shelton,J;Dement,WC;Mignot,E
通讯作者：
Mignot,E
多巴胺能传递的增加介导中枢神经系统兴奋剂的促醒作用。
DOI：
--
发表时间：
1998
期刊：
Sleep research online : SRO
影响因子：
--
作者：
Nishino,S;Mao,J;Sampathkumaran,R;Shelton,J
通讯作者：
Shelton,J
多巴胺 D3 激动剂进入黑质会加重猝倒，但不会改变睡眠。
影响因子：
1.7
作者：
Honda,K;Riehl,J;Mignot,E;Nishino,S
通讯作者：
Nishino,S
影响因子：
5.6
作者：
S. Nishino;M. Reid;W. Dement;E. Mignot
通讯作者：
S. Nishino;M. Reid;W. Dement;E. Mignot
影响因子：
4.4
作者：
A. Begovich;G. McClure;V. Suraj;R. Helmuth;N. Fildes;T. Bugawan;H. Erlich;W. Klitz
通讯作者：
A. Begovich;G. McClure;V. Suraj;R. Helmuth;N. Fildes;T. Bugawan;H. Erlich;W. Klitz