Orexin supplementation in narcolepsy treatment: A review

Abstract

Narcolepsy is a rare, chronic neurological disease characterized by excessive daytime sleepiness, cataplexy, vivid hallucinations, and sleep paralysis. Narcolepsy occurs in approximately 1 of 3000 people, affecting mainly adolescents aged 15 to 30 years.Recently, people with narcolepsy were shown to exhibit extensive orexin/hypocretin neuronal loss. The orexin system regulates sleep/wake control via complex interactions with monoaminergic, cholinergic and GABA-ergic neuronal systems.Currently, no cure for narcolepsy exists, but some symptoms can be controlled with medication (eg, stimulants, antidepressants, etc). Orexin supplementation represents a more sophisticated way to treat narcolepsy because it addresses the underlying cause of the disease and not just the symptoms.Research on orexin supplementation in the treatment of sleep disorders has strongly increased over the past two decades.This review focuses on a brief description of narcolepsy, the mechanisms by which the orexin system regulates sleep/ wake cycles, and finally, possible therapeutic options based on orexin supplementation in animal models and patients with narcolepsy. K E Y W O R D S cell transplantation, gene therapy, hypocretin, narcolepsy, orexin, orexin agonists Med Res Rev. 2019;39:961-975. wileyonlinelibrary.com/journal/med © 2018 Wiley Periodicals, Inc. | 961 | 971addition, we must keep in mind that the behavioral outcome of orexin signaling is accompanied by parallel signaling via interactions with various brain regions, making the entire situation even more complicated.More studies are needed to elucidate the exact role of the orexin system in narcolepsy and thereby pave the way for developing novel strategies for the treatment of orexin-related disorders.

Orexin Receptor Antagonists as Emerging Treatments for Psychiatric Disorders

“…The number of orexin neurons is selectively reduced in human narcolepsy, and canine narcolepsy is caused by a mutation of the OX2R gene [33,34]. Intranasal administration of orexin peptide, orexin neuron transplants, and orexin gene therapy are promising approaches to the treatment of narcolepsy [35,36]. The selective OX2R agonist YNT-185 has been shown to ameliorate cataplexylike episodes in a mouse model of narcolepsy [37].…”

The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review

“…Orexin A (hypocretin-1) employs a postsynaptic excitatory action on prefrontal cortex neurons by inhibiting potassium currents via the activation of protein kinase C (PKC) and phospholipase C (PLC) signaling pathways (Xia et al, 2005 ). Orexin deficiency is related to narcolepsy according to the reviews (Mahoney et al, 2019 ; Nepovimova et al, 2019 ; Mignot et al, 2021 ). Therefore, high Ih current due to the lack of orexin can play a role in the pathogenesis of narcolepsy.…”

<p>Management Of Excessive Sleepiness In Patients With Narcolepsy And OSA: Current Challenges And Future Prospects</p>

“…Various modalities have been proposed, including orexin agonists, gene therapy, and cell transplantation. Recent experiments in mice showed that central administration of orexin in orexin-cell-ablated mice improved wakefulness and reduced cataplexy 77. Other studies showed amelioration of narcolepsy symptoms with peripherally administered YNT-185 (non-peptide selective orexin type-2 receptor agonist)78 and TAK-925 (orexin 2 receptor selective agonist)79 in mice models, providing further proof of concept.…”