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.
OBJECTIVE
Using two different canine models of narcolepsy, we evaluated the therapeutic effects of hypocretin-1 on cataplexy and sleep.


RESULTS
Intracerebroventricular administration of hypocretin-1 (10 and 30 nmol per dog) but not intravenous administration (up to 6 microg/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 microg/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.
Fujiki
Nobuhiro
N
Center for Narcolepsy, Stanford University School of Medicine, Palo Alto, CA 94304-5485, USA.
Yoshida
Yasushi
Y
Ripley
Beth
B
Mignot
Emmanuel
E
Nishino
Seiji
S
D000818:Animals; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000627:therapeutic use; D002385:Cataplexy / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D004569:Electroencephalography; D004576:Electromyography; D004585:Electrooculography; D007275:Injections, Intravenous; D047908:Intracellular Signaling Peptides and Proteins; D009290:Narcolepsy / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D064446:Orexin Receptors; D000068797:Orexins; D017354:Point Mutation / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide / Q000235:genetics* / Q000378:metabolism*
D002352:Carrier Proteins; C000596229:HCRT protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide