The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress

Abstract

Much of the understanding of the hypocretin/orexin (HCRT/OX) system in sleep–wake regulation came from narcolepsy–cataplexy research. The neuropeptides hypocretin-1 and -2/orexin-A and -B (HCRT-1 and -2/OX-A and -B, respectively), as we know, are intimately involved in the regulation wakefulness. The HCRT/OX system regulates sleep–wake control through complex interactions between monoaminergic/cholinergic (wake-promoting) and gamma-aminobutyric acid-ergic (sleep-promoting) neuronal systems. Deficiency of HCRT/OX results in loss of sleep–wake control or stability with consequent unstable transitions between wakefulness to nonrapid eye movement and rapid eye movement sleep. This manifests clinically as abnormal daytime sleepiness with sleep attacks and cataplexy. Research on the development of HCRT/OX agonists and antagonists for the treatment of sleep disorders has dramatically increased with the US Food and Drug Administration approval of the first-in-class dual HCRT/OX receptor antagonist for the treatment of insomnia. This review focuses on the origin, mechanisms of HCRT/OX receptors, clinical progress, and applications for the treatment of sleep disorders.

Hypothalamic neuropeptides and neurocircuitries in Prader Willi syndrome

“…134 Thus, elevated levels of plasma hypocretin in PWS might contribute to the hypertrophy of adipose tissue in PWS, and consequently, promote weight gain. Interestingly, hypocretin has a role in sleep regulation, 135,136 which is also markedly disturbed in PWS. 137 Therefore, the involvement of the hypocretin system in PWS is beyond the regulation of energy metabolism and may play a more complex role in PWS…”

Pituitary Macrotumor Causing Narcolepsy‐Cataplexy in a Dachshund

“…Type 1 primary narcolepsy is caused by selective loss of hypothalamic neurons that produce the neuropeptide hypocretin (also called orexin), resulting in low levels of hypocretin in the CSF 5. These neurons are located in the ventral lateral hypothalamic nucleus in dogs and have extensive connections throughout the central nervous system (CNS) that promote wakefulness and muscle tone in response to the release of hypocretin 6. Humans with primary narcolepsy who suffer from cataplexy as part of their disease are classified as type 1, and the majority have low or undetectable levels of hypocretin in the CSF 7, 8, 9.…”

The Relationship between Plasma Hypocretin Levels and Sleep Disorders in Patients with Parkinson's Disease

“…12,25 Hypocretin deficiency causes a loss of sleep-wake control or stability with the result of an unstable transition between wakefulness to nonREM and REM sleep. 19 In this study it was found that with disease duration. 25 This cannot be proven in this study.…”

“…The HCRT / OX system regulates sleep-wake control through a complex interaction between the monoaminergic / cholinergic (wake-up) nervous system and gamma-aminobutyricergic (sleep-inducing) acid. 19 Hypocretin is specifically a dorsal and lateral hypothalamic neurotransmitter that functions to regulate sleep, appetite and energy use. 20 The final cause of sleep disorders, especially EDS in Parkinson's disease is not known with certainty, but factors such as dopaminergic treatment, motor disability or degenerative disease processes are involved.…”