Hypocretins (orexins): The ultimate translational neuropeptides

Abstract

The hypocretins (Hcrts), also known as orexins, are two neuropeptides produced exclusively in the lateral hypothalamus. They act on two specific receptors that are widely distributed across the brain and involved in a myriad of neurophysiological functions that include sleep, arousal, feeding, reward, fear, anxiety and cognition. Hcrt cell loss in humans leads to narcolepsy with cataplexy (narcolepsy type 1), a disorder characterized by intrusions of sleep into wakefulness, demonstrating that the Hcrt system is nonredundant and essential for sleep/wake stability. The causal link between Hcrts and arousal/wakefulness stabilisation has led to the development of a new class of drugs, Hcrt receptor antagonists to treat insomnia, based on the assumption that blocking orexin‐induced arousal will facilitate sleep. This has been clinically validated: currently, two Hcrt receptor antagonists are approved to treat insomnia (suvorexant and lemborexant), with a New Drug Application recently submitted to the US Food and Drug Administration for a third drug (daridorexant). Other therapeutic applications under investigation include reduction of cravings in substance‐use disorders and prevention of neurodegenerative disorders such as Alzheimer's disease, given the apparent bidirectional relationship between poor sleep and worsening of the disease. Circuit neuroscience findings suggest that the Hcrt system is a hub that integrates diverse inputs modulating arousal (e.g., circadian rhythms, metabolic status, positive and negative emotions) and conveys this information to multiple output regions. This neuronal architecture explains the wealth of physiological functions associated with Hcrts and highlights the potential of the Hcrt system as a therapeutic target for a number of disorders. We discuss present and future possible applications of drugs targeting the Hcrt system for the treatment of circuit‐related neuropsychiatric and neurodegenerative conditions.

The Orexin receptors: Structural and anti-tumoral properties

“…As previously described above, studies on pathophysiological roles of orexins and their receptors are focused on CNS ( 7 ) and mainly narcolepsy type I pathology ( 60 ). Moreover, a lot of studies also revealed the impact of orexins on addiction, neuro-inflammation associated to the microglia and neurodegenerative diseases including Alzheimer’s disease ( 11 , 61 , 62 ).…”

“…The major physiological action ( Figure 1 ) in central nervous system (CNS) of the orexins/OXR system, widely studied for over 20 years, was to maintain wakefulness ( 6 , 7 ). The main pathology associated to this action was the narcolepsy type I characterized by excessive daytime sleepiness (EDS) associated to Rapid Eye Movement (REM) symptoms including cataplexy, hallucinations, sleep paralysis and fragmentation of night sleep ( 7 , 8 ). This rare neurological disorder was caused by the loss of orexin neurons leading to the absence of orexins secretion ( 7 ) but in dog, this disorder was related to orexin receptor mutation ( 9 ).…”

“…The main pathology associated to this action was the narcolepsy type I characterized by excessive daytime sleepiness (EDS) associated to Rapid Eye Movement (REM) symptoms including cataplexy, hallucinations, sleep paralysis and fragmentation of night sleep ( 7 , 8 ). This rare neurological disorder was caused by the loss of orexin neurons leading to the absence of orexins secretion ( 7 ) but in dog, this disorder was related to orexin receptor mutation ( 9 ). It should be noted that obesity was more prevalent in patient with narcoleptic type I disorder than in the general population ( 10 ).…”

Orexin/Hypocretin System Dysfunction in ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations)

“… 24–28 , 36–39 For example, manipulations of the Orx-S simultaneously modulate neurotransmitters associated with alertness and wakefulness (ie, dopamine, norepinephrine, acetylcholine, and histamine). 27 …”

Orexin/hypocretin system dysfunction in patients with Takotsubo syndrome: A novel pathophysiological explanation

“…Ox2R mRNA in the adrenal cortex of male rats indicates orexin's involvement in the synthesis and/or release of adrenal steroids ( 17 ). Regarding the development of PTSD, low orexin tone during stressful events has been proposed to be associated with increased risk ( 67 ). Orexin's proposed role in TTS pathophysiology might be similarly understood.…”