Effects of IV and ICV hypocretin-1 (Orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin-ligand-deficient narcoleptic dog
Effects of IV and ICV hypocretin-1 (Orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin-ligand-deficient narcoleptic dog
复制标题
DOI：
10.1093/sleep/26.8.953
复制
发表时间：
2003-12-15
期刊：
影响因子：
5.6
通讯作者：
Nishino, S
中科院分区：
文献类型：
--
作者：
Fujiki, N;Yoshida, Y;Nishino, S
研究目的：使用两种不同的发作性睡病犬模型，我们评估了下丘脑分泌素 1 对猝倒和睡眠的治疗效果。测量和结果：侧脑室内给予下丘脑分泌素 1（每只狗 10 和 30 纳摩尔），但静脉内给予（高达 6 微克/千克）不会在对照犬中引起显着的清醒。然而，下丘脑泌素受体 2 基因 (Hcrtr2) 突变的发作性睡病杜宾犬，下丘脑泌素 1 对猝倒或觉醒没有影响，只有非常高的静脉注射剂量的下丘脑泌素 1 (96 - 384 杯/公斤) 穿透大脑，才能在下丘脑泌素配体缺陷的动物中产生短暂的抗惊厥作用。结论：下丘脑泌素 1通过中枢和全身途径给药并不能改善 Hcrtr2 突变杜宾犬的发作性睡病症状。全身性hypocretin-1很难穿过血脑屏障产生治疗作用。为了进一步探索人类的这一治疗途径，需要开发更具中枢渗透性和更持久的下丘脑分泌素类似物。
Study Objectives: Using two different canine models of narcolepsy, we evaluated the therapeutic effects of hypocretin-1 on cataplexy and sleep.Measurements and Results: Intracerebroventricular administration of hypocretin-1 (10 and 30 nmol per dog) but not intravenous administration (up to 6 mug/kg) induced significant wakefulness in control dogs. However, hypocretin-1 had no effect on cataplexy or wakefulness in hypocretin receptor-2 gene (Hcrtr2) mutated narcoleptic Dobermans, Only very high intravenously doses of hypocretin-1 (96 - 384 mug/kg) penetrated the brain, to produce a short-lasting anticataplectic effect in a hypocretin-ligand-deficient animal.Conclusions: Hypocretin-1 administration, by central and systemic routes, does not improve narcoleptic symptoms in Hcrtr2 mutated Dobermans. Systemic hypocretin-1 hardly crosses the blood-brain barrier to produce therapeutic effects. The development of more centrally penetrable and longer lasting hypocretin analogs will be needed to further explore this therapeutic pathway in humans.