Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice

Abstract

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,wedemonstraterescueofthenarcolepsycataplexy 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 neuronablated 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.

Selective loss of GABA B receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture

“…In contrast, transgenic mice with constitutive overexpression of orexin show a fragmented sleep/wake phenotype only during the light (rest) period (35). The activity of orexin neurons is high during the dark period (36); therefore, abnormality of orexin-deficient mice during this period might be expected.…”

“…The activity of orexin neurons is high during the dark period (36); therefore, abnormality of orexin-deficient mice during this period might be expected. On the other hand, because the activity of orexin neurons is low or quiescent during the light period, the sleep/wake abnormality of orexin-overexpressing mice becomes apparent during this period (35). However, oxGKO mice showed severe fragmentation of sleep/wake behavior during both the dark and light periods.…”

Orexin deficiency and narcolepsy

“…This is supported by a study demonstrating that chronic overproduction of orexin from an ectopically expressed transgene effectively prevented the development of narcolepsy symptoms in orexin neuron-ablated (orexin/ataxin-3-transgenic) mice (43). Acute intracerebroventricular (ICV) administration of orexin A also maintained wakefulness, suppressed sleep, and completely inhibited cataplectic attacks in orexin/ataxin-3 mice(43).…”

“…However, chronic overexpression of orexin A in an unregulated fashion results 17 in fragmentation of NREM sleep (44), suggesting it would be beneficial for therapeutically relevant orexin agonists to have a short half-life (<12 hr).…”

Overview of orexin/hypocretin system

“…We demonstrated that orexin neuron-ablated mice, the most accurate pathophysiological murine model of narcolepsy available (Hara et al, 2001), retain the ability to respond to ICV administration of orexin neuropeptides, with stabilization of wake episodes and prevention of cataleptic attacks (Mieda et al, 2004), suggesting that orexin receptor agonists would be of potential value for treating human narcolepsy.…”