Orexin A

Narcolepsy type 1 following immune checkpoint inhibitor therapy for metastatic melanoma.

Aiden Cushnahan, Su Hii, Kirk Kee +2 more

Narcolepsy is a rare disorder of central hypersomnolence which is often under-recognised owing to a variable clinical phenotype. Narcolepsy type 1 (NT1) is caused by loss of hypothalamic hypocretin (orexin) secreting neurons, which function to maintain wakefulness. There is strong evidence that NT1 is an immune-mediated disorder associated with the class II human leucocyte antigen DQB1*06:02 allele. Immune checkpoint inhibitors have revolutionised the treatment of many cancers; however, through their mechanism of action, they are associated with immune-related adverse effects. We describe a complex case of NT1 following ipilimumab and nivolumab exposure for management of metastatic melanoma.

Effects of Traumatic Brain Injury on the Orexin/Hypocretin System.

Rebecca T Somach, Miranda M Lim, Akiva S Cohen

Traumatic Brain Injuries (TBIs) are known to cause a myriad of symptoms in patients. One common symptom after injury is sleep disruptions. One neuropeptide system has been studied repeatedly as a potential cause of sleep disruptions after TBI- the orexin/hypocretin system. Orexin promotes wakefulness and arousal while disrupting the orexin system causes increased sleepiness and narcolepsy. Studies of TBI in human and animal subjects have shown that TBI affects the orexin system. This review serves as an overview of how TBI affects the orexin/hypocretin system, including structural and functional changes to the neurons after injury. This review is the first to include studies that examine how TBI affects orexin/hypocretin receptors. This review also examines how sex is accounted for in the studies of the orexin system after TBI.

Orexin signaling across the female lifespan: developmental, reproductive, and aging perspectives from humans and animal models.

Katarzyna Kirsz, Dorota A Zięba

Orexin-A and orexin-B are hypothalamic neuropeptides that coordinate arousal, metabolic, and reproductive functions through orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R). This review synthesizes evidence from humans, experimental models, and domestic species to examine how orexin signaling modulates female physiology across the lifespan. Perinatally, orexin activation supports neonatal survival by stabilizing respiration, feeding, and sleep-wake organization. During puberty, orexins integrate metabolic and circadian cues to regulate gonadotropin-releasing hormone output and reproductive onset. In pregnancy and lactation, central and peripheral adaptations coordinate maternal metabolism, uteroplacental communication, and prolactin-dependent lactation. In aging, reduced orexin tone contributes to sleep fragmentation, metabolic dysregulation, and cognitive decline. Therapeutically, dual orexin receptor antagonists and intranasal orexin delivery illustrate stage-specific intervention strategies. Evidence across life stages derives from human, rodent, and large-animal models and must be interpreted within species-, sex-, and stage-specific biological constraints. Collectively, orexin signaling represents a conserved integrative network with health relevance.

Secondary narcolepsy and cognitive dysfunction related to craniopharyngioma: a case study.

Amelia Nur Vidyanti, Atika Rahmadini, Rifki Habibi Rahman +3 more

Craniopharyngiomas, benign tumors of the sellar region, frequently disrupt hypothalamic function, leading to endocrine and neurological sequelae, including sleep disorders.

Sleep, wake, and signaling: Functional profiling of orexin agonists and antagonists using newly developed orexin β-arrestin 2 and miniGαq recruitment assays.

Marie H Deventer, Silvia Mori, Marcus Angermann +2 more

The excitatory neuropeptides orexin-A and -B interact with their target G protein-coupled receptors (GPCRs), the orexin 1 and orexin 2 (OX1 and OX2) receptors, which are widely expressed throughout the central nervous system. The orexin system plays a critical role in regulating several physiological processes such as sleep-wake cycles, feeding behaviour, and arousal, and is implicated in a variety of (neurological) disorders. In particular dysregulation of the orexin system is linked to sleep disorders such as narcolepsy (often associated with orexin deficiency) and insomnia (characterized by an overactivity of sleep-wake regulation). This has prompted a growing interest in orexin-targeting therapeutics. This study is the first to report the development of four OX1 and OX2 receptor luminescence bioassays based on functional complementation of a split-nanoluciferase enzyme, capable of monitoring β-arrestin 2 (βarr2) and Gαq recruitment to activated OX1 and OX2 receptors. These assays were successfully applied to evaluate the pharmacological profiles of both agonists and antagonists, including the endogenous ligands orexin-A and -B, the clinically approved small molecule antagonists suvorexant and daridorexant, as well as EMPA (N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulphonyl)-amino]-N-pyridin-3-ylmethyl-acetamide) and four other compounds described in literature to act at orexin receptors. The obtained receptor activation patterns and selectivity profiles were consistent with literature data, indicating the reliability and robustness of the assay systems. Overall, the newly developed assays expand the toolkit for orexin receptor research by allowing the characterization of both agonists and antagonists, thereby contributing to the functional characterization of potential new drug candidates for various pathological conditions.

Orexin Deficiency in Narcolepsy: Molecular Mechanisms, Clinical Phenotypes, and Emerging Therapeutic Frontiers.

Rameesha Rauf, Salwa Asif, Abdallah AlSaafeen +7 more

Narcolepsy Type 1 (NT1) is a chronic neurological disorder characterized by excessive daytime sleepiness (EDS), cataplexy, and REM intrusions, caused by a deficiency of orexin (hypocretin), a hypothalamic neuropeptide essential for arousal, REM sleep regulation, metabolism, and emotional stability. This review synthesizes and critically analyzes the pathophysiological, clinical, and therapeutic dimensions of orexin deficiency in narcolepsy, with particular emphasis on recent advances from 2023 to 2025.

Orexin and Lifestyle Habits: A Meaningful Connection Among Nutrition, Physical Activity, and Sleep Pattern in Health and Diseases.

Ersilia Nigro, Francesca Argentino, Giuseppe Musumeci +1 more

Orexin is a neuropeptide produced in the hypothalamus that plays a key role in regulating slee-wake cycles, energy metabolism, feeding behavior, and physical activity. It exists in two forms, orexin-A and orexin-B, which bind to G protein-coupled receptors OX1R and OX2R with differing affinities. Orexin signaling is widespread in the brain and extends to peripheral tissues, including adipose tissue. Its involvement in hypothalamic and extrahypothalamic circuits suggests a broad role in homeostatic regulation. Dysfunctions in the orexinergic system are implicated in neurodegenerative diseases such as Alzheimer's, Parkinson's, and multiple sclerosis, particularly through mechanisms involving sleep disturbances and neuroinflammation. This study examines how orexin influences neural circuits related to arousal, motivation, and motor control. It also explores how physical activity stimulates orexin release, enhancing neuroplasticity and cognitive resilience. In addition, orexin's role in reward-related feeding, genetic susceptibility to obesity, and brown adipose tissue thermogenesis is discussed. Overall, the orexinergic system represents a vital neurochemical link between physical activity, metabolism, and cognitive health. Although many of its mechanisms remain to be clarified, its central role in integrating energy balance and behavioral responses makes it a promising target for future therapeutic strategies.

Hypocretin: a promising target for the regulation of homeostasis.

Yutong Wang, Su Fu, Jian Mao +2 more

Hypocretin, also known as orexin, is a hypothalamic neuropeptide that regulates essential physiological processes including arousal, energy metabolism, feeding behavior, and emotional states. Through widespread projections and two G-protein-coupled receptors-HCRT-1R and HCRT-2R-the hypocretin system exerts diverse modulatory effects across the central nervous system. The role of hypocretin in maintaining wakefulness is well established, particularly in narcolepsy type 1 (NT1), where loss of hypocretin neurons leads to excessive daytime sleepiness and cataplexy. However, the mechanisms by which hypocretin stabilizes transitions between sleep stages remain incompletely understood. Additionally, while hypocretin integrates metabolic signals such as glucose, leptin, and ghrelin to promote feeding and energy expenditure, NT1 patients paradoxically experience weight gain despite reduced caloric intake-highlighting unresolved questions about hypocretin's role in energy homeostasis. In the affective domain, preclinical studies suggest hypocretin enhances stress resilience and modulates anxiety- and depression-related behaviors. Yet, human data remain inconsistent, in part due to methodological variability and the limited availability of cerebrospinal fluid sampling to accurately assess central hypocretin function. Therapeutically, the hypocretin system is a promising target across several domains. Dual hypocretin receptor antagonists (DORAs), such as suvorexant and daridorexant, are clinically approved for insomnia. Selective HCRT-2R agonists-including TAK-861 and ALKS-2680-are in clinical trials for NT1 and show encouraging results. Additionally, HCRT-2R antagonists like seltorexant are being explored for major depressive disorder. This review will highlight the anatomical distribution, receptor mechanisms, and physiological functions of the hypocretin system. It will also focus to discuss its role in narcolepsy, metabolic regulation, and mood disorders, while addressing key challenges and open questions that must be resolved to fully harness hypocretin's therapeutic potential.

Discovery of natural orexin 2 receptor antagonists from Valeriana species: A potential approach for insomnia treatment.

Aparna G Shenoy, Vishal Ravi, Suhail Subair +3 more

The orexinergic system, comprising orexin-A and orexin-B neuropeptides that bind to OX1R and OX2R receptors, plays a critical role in regulating sleep-wake cycles, appetite, and alertness. OX2R is particularly important for promoting arousal and non-rapid eye movement (NREM) sleep and has been linked to sleep disorders such as insomnia and narcolepsy. Although OX2R antagonists like suvorexant have shown therapeutic promise, they are often associated with side effects including cognitive impairment and dependence, highlighting the need for safer alternatives. This study employed an in-silico approach to identify natural OX2R antagonists from Valeriana species. Phytochemicals were screened based on molecular docking and favourable ADME/T profiles. Molecular dynamics (MD) simulations and post-MD analysis confirmed stable binding of hesperidine and valerosidate to OX2R. Principal component analysis (PCA) revealed minimal conformational variability while gibbs free energy landscape (FEL) analysis and MM-PBSA binding free energy calculations further supported the strong binding of hesperidine and valerosidate to OX2R, comparable to suvorexant. These findings support hesperidine and valerosidate as promising, naturally derived OX2R antagonists, and warrant further invitro and invivo investigations for potential therapeutic application in insomnia treatment.

Orexin effect on physiological pulsations of the human brain.

Matti Järvelä, Janne Kananen, Heta Helakari +10 more

Sleep promotes cerebrospinal fluid (CSF) to interstitial fluid (ISF) exchange in the brain facilitated by brain pulsations. Especially brain vasomotion and arterial pulsations modulated by noradrenaline drive the intracranial fluid dynamics. Narcolepsy type 1 (NT1) entails lessened orexinergic output to wake-promoting systems including the noradrenergic locus coeruleus. As arousal state and noradrenergic signaling affect CSF-ISF clearance, we chose patients with NT1 as a human orexin-targeted model of sleep-related pathology bridging the gap between healthy awake and sleep with respect to CSF flow pulsations. We also investigated the sensitivity of magnetic resonance encephalography to detect flow with a phantom model and sought to replicate earlier pulsation findings in sleep. In this case-control study, we used fast functional MRI to map brain pulsations in groups of healthy sleeping controls (n = 13), healthy awake controls (n = 79), and awake NT1 (n = 21) patients. We measured the very low frequency (0.008 to 0.1) and cardiorespiratory frequencies and calculated in each frequency band the coefficient of variation, spectral power, and full band spectral entropy to obtain brain pulsation maps. We uncovered a brain pulsation profile from healthy waking to sleep to a sleep-related pathology NT1 prominently affected in the vascular-related vasomotor and brain arterial pulsations. Our results established how drivers of brain hydrodynamics are affected by a specific loss of key neurotransmitter governing arousal compared to healthy sleep. We also showed with a phantom model that MREG is sensitive to flow-related signal changes and solidified evidence of brain pulsations in the healthy states of sleep and wakefulness.

Sex effect on disease characteristics in patients with narcolepsy type 1.

Lucie Barateau, Fabio Pizza, Emanuela Postiglione +7 more

Narcolepsy type 1 (NT1) is a rare sleep disorder caused by orexin/hypocretin (Hcrt-1) deficiency, equally prevalent in women and men. Sex differences have been reported in animal models, particularly regarding cataplexy. Whether these differences can be transposed to humans remains unclear. We studied the sex effect on the characteristics of the disease in a large population of patients with NT1 in drug-free conditions.

Unraveling the pathophysiology of narcolepsy type 1 through hypothesis-driven and hypothesis-generating approaches.

Sean A Freeman, Ikram Ayoub, Yves Dauvilliers +1 more

Narcolepsy type 1 (NT1) is a chronic orphan neurological sleep disorder characterized by the loss of hypocretin-producing neurons in the lateral hypothalamus, which play a crucial role in wakefulness. Given the genetic association with the HLA-DQB1 * 06:02 allele and environmental links with the 2009 influenza pandemic, many lines of evidence point towards an immune mechanism, notably autoimmunity, underlying the disease pathophysiology. Autoreactive T cells are found in the blood of NT1 patients, and mouse models demonstrate their migratory capacity and contribution in the selective destruction of hypocretin-producing neurons. However, direct evidence for their role in human NT1 pathophysiology remains elusive. In complementing these findings, hypothesis-generating approaches-including multiparametric immune profiling, transcriptomic sequencing and large-scale proteomic of blood and cerebrospinal fluid-have uncovered promising new avenues into the immune system's involvement in NT1. In this review, we explore the mechanisms driving NT1 pathogenesis, emphasizing both hypothesis-driven and hypothesis-generating approaches, and discuss potential future directions that could pave the way for targeted immunotherapies.

An orexin agonist promotes wakefulness and inhibits cataplexy through distinct brain regions.

Takashi Ishikawa, Emi Kurimoto, Adam A Joyal +3 more

Narcolepsy type 1, caused by selective loss of the orexin-producing neurons, is characterized by poor maintenance of wakefulness and cataplexy. Clinical trials show that orexin receptor 2 (OX2R) agonists substantially improve narcolepsy symptoms, but the key brain regions through which OX2R signaling produces these benefits are only partially understood. To address this question, we produced recombinant mice expressing the human diphtheria toxin receptor driven by the endogenous orexin promoter (orexinDTR mice). After injection with diphtheria toxin, orexinDTR mice had severe and selective loss of the orexin neurons, leading to narcolepsy symptoms, including poor maintenance of wakefulness and cataplexy; these symptoms were substantially improved by an OX2R-selective agonist OX-201. We then crossed orexinDTR mice with OX2R transcription-disrupted (TD) mice to produce a new model lacking orexin neurons and OX2R. We focally restored OX2R expression in specific brain regions of OX2R TD::orexinDTR mice and assessed whether OX-201 improves specific aspects of narcolepsy. In mice expressing OX2R only in the tuberomammillary nucleus (TMN) or basal forebrain (BF) regions, OX-201 improved maintenance of wakefulness but did not suppress cataplexy. In contrast, in mice expressing OX2R in the ventrolateral periaqueductal gray and lateral pontine tegmentum (vlPAG/LPT), OX-201 suppressed cataplexy without improving maintenance of wakefulness. These results suggest that OX2R signaling in the TMN and BF regions can stabilize wakefulness and OX2R signaling in the vlPAG/LPT region can suppress cataplexy, providing key insights into how orexins regulate wakefulness and muscle tone and how OX2R agonists improve the symptoms of narcolepsy. VIDEO ABSTRACT.

The interaction between orexin, sleep deprivation and Alzheimer's disease: Unveiling an Emerging Connection.

Masoumeh Kourosh-Arami, Mahdi Ramezani, Alireza Komaki

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive cognitive decline and memory loss. Sleep-wake disorders are an extremely predominant and often disabling aspect of AD. Ox is vital in maintaining the sleep-wake cycle and promoting wakefulness. Dysfunction of Ox signaling has been associated with sleep disorders such as narcolepsy. In AD patients, the increase in cerebrospinal fluid Ox levels is related to parallel sleep deterioration. The relationship between AD and sleep disturbances has gained increasing attention due to their potential bidirectional influence. Disruptions in sleep patterns are commonly observed in AD patients, leading researchers to investigate the possible involvement of Ox in sleep disturbances characteristic of the disease. This review article explores the role of the Ox system in AD, and the intricate relationship between AD and sleep, highlighting the potential mechanisms, impact on disease pathology, and therapeutic interventions to improve sleep quality in affected individuals.

The Role and Mechanisms of the Hypocretin System in Zebrafish (Danio rerio).

Vyacheslav Dyachuk

Sleep is the most important physiological function of all animals studied to date. Sleep disorders include narcolepsy, which is characterized by excessive daytime sleepiness, disruption of night sleep, and muscle weakness-cataplexy. Narcolepsy is known to be caused by the degeneration of orexin-synthesizing neurons (hypocretin (HCRT) neurons or orexin neurons) in the hypothalamus. In mammals, HCRT neurons primarily regulate the sleep/wake cycle, nutrition, reward seeking, and addiction development. The hypocretin system of the brain is involved in a number of neurological disorders. The distinctive pathologies associated with the disruption of HCRT neurons are narcolepsy and cataplexy, which are caused by the loss of hypocretin neurons that produce HCRT. In Danio, the hypocretin system is also involved in the regulation of sleep and wakefulness. It is represented by a single hcrt gene that encodes the peptides HCRT1 and HCRT2, as well as one HCRT receptor (HCRTR), which is structurally closest to the mammalian HCRTR2. The overexpression of the hcrt gene in Danio rerio larvae causes wakefulness, whereas the physical destruction of HCRT cells or a pharmacological blockade of the type 2 hypocretin receptor leads to fragmentation of sleep in fish larvae, which is also observed in patients with narcolepsy. These data confirm the evolutionary conservatism of the hypocretin system. Thus, Danio rerio is an ideal model for studying the functions of HCRT neural networks and their functions.

The mechanism of different orexin/hypocretin neuronal projections in wakefulness and sleep.

Nanxi Li, Lishan Huang, Bin Zhang +4 more

Since the discovery of orexin/hypocretin, numerous studies have accumulated evidence demonstrating its key role in various aspects of neuromodulation, including addiction, motivation, and arousal. This paper focuses on the projection of orexin neurons to specific target brain regions through distinct neural pathways to regulate sleep and arousal. We provide a detailed discussion of the projection mechanisms of orexin neurons to downstream neurons, particularly emphasizing their activation of monoaminergic and cholinergic neurons associated with arousal. Additionally, we briefly explore the immune response and inflammatory factors linked to the loss of orexin neurons. Our findings underscore the significance of understanding specific neural projections in the generation and maintenance of arousal, which could guide advancements in neuroscience and lead to new therapeutic opportunities for treating insomnia or narcolepsy.

Pharmacological inhibition of histamine N-methyltransferase extends wakefulness and suppresses cataplexy in a mouse model of narcolepsy.

Fumito Naganuma, Birkan Girgin, Anne Bernadette S Agu +7 more

Histamine, a neurotransmitter, plays a predominant role in maintaining wakefulness. Furthermore, our previous studies showed that histamine N-methyltransferase (HNMT), a histamine-metabolizing enzyme, is important for regulating brain histamine concentration. However, the effects of pharmacological HNMT inhibition on mouse behavior, including the sleep-wake cycle and cataplexy, in a mouse model of narcolepsy have not yet been investigated. In the present study, we investigated the effects of metoprine, an HNMT inhibitor with high blood-brain barrier permeability, in wild-type (WT) and orexin-deficient (OxKO) narcoleptic mice. Metoprine increased brain histamine concentration in a time- and dose-dependent manner without affecting peripheral histamine concentrations. Behavioral tests showed that metoprine increased locomotor activity in both novel and familiar environments, but did not alter anxiety-like behavior. Sleep analysis showed that metoprine increased wakefulness and decreased non-rapid eye movement (NREM) sleep through the activation of the histamine H1 receptor (H1R) in WT mice. In contrast, the reduction of rapid eye movement (REM) sleep by metoprine occurred independent of H1R. In OxKO mice, metoprine was found to prolong wakefulness and robustly suppress cataplexy. In addition, metoprine has a greater therapeutic effect on cataplexy than pitolisant, which induces histamine release in the brain and has been approved for patients with narcolepsy. These data demonstrate that HNMT inhibition has a strong effect on wakefulness, demonstrating therapeutic potential against cataplexy in narcolepsy.

Ageing-related modification of sleep and breathing in orexin-knockout narcoleptic mice.

Stefano Bastianini, Sara Alvente, Chiara Berteotti +5 more

Narcolepsy type-1 (NT1) is a lifelong sleep disease, characterised by impairment of the orexinergic system, with a typical onset during adolescence and young adulthood. Since the wake-sleep cycle physiologically changes with ageing, this study aims to compare sleep patterns between orexin-knockout (KO) and wild type (WT) control mice at different ages. Four groups of age-matched female KO and WT mice (16 weeks of age: 8 KO-YO and 9 WT-YO mice; 87 weeks of age: 13 KO-OLD and 12 WT-OLD mice) were implanted with electrodes for discriminating wakefulness, rapid-eye-movement sleep (REMS), and non-REMS (NREMS). Mice were recorded for 48 h in their home cages and for 7 more hours into a plethysmographic chamber to characterise their sleep-breathing pattern. Regardless of orexin deficiency, OLD mice spent less time awake and had fragmentation of this behavioural state showing more bouts of shorter length than YO mice. OLD mice also had more NREMS bouts and less frequent NREMS apneas than YO mice. Regardless of age, KO mice showed cataplexy-like episodes and shorter REMS latency than WT controls and had a faster breathing rate and an increased minute ventilation during REMS. KO mice also had more wakefulness, NREMS and REMS bouts, and a shorter mean length of wakefulness bouts than WT controls. Our experiment indicated that the lack of orexins as well as ageing importantly modulate the sleep and breathing phenotype in mice. The narcoleptic phenotype caused by orexin deficiency in female mice was substantially preserved with ageing.

The beneficial effects of modafinil administration on repeat mild traumatic brain injury (RmTBI) pathology in adolescent male rats are not dependent upon the orexinergic system.

Jennaya Christensen, Elaina Vlassopoulos, Christopher K Barlow +8 more

The sleep-wake cycle plays an influential role in the development and progression of repeat mild traumatic brain injury (RmTBI)-related pathology. Therefore, we first aimed to manipulate the sleep-wake cycle post-RmTBI using modafinil, a wake-promoting substance used for the treatment of narcolepsy. We hypothesized that modafinil would exacerbate RmTBI-induced deficits. Chronic behavioural analyses were completed along with a 27-plex serum cytokine array, metabolomic and proteomic analyses of cerebrospinal fluid (CSF), as well as immunohistochemical staining in structures important for sleep/wake cycles, to examine orexin, melanin-concentrating hormone, tyrosine hydroxylase, and choline acetyltransferase, in the lateral hypothalamus, locus coeruleus, and basal forebrain, respectively. Contrary to expectation, modafinil administration attenuated behavioural deficits, metabolomic changes, and neuropathological modifications. Therefore, the second aim was to determine if the beneficial effects of modafinil treatment were driven by the orexinergic system. The same experimental protocol was used; however, RmTBI rats received chronic orexin-A administration instead of modafinil. Orexin-A administration produced drastically different outcomes, exacerbating anxiety-related and motor deficits, while also significantly disrupting their metabolomic and neuropathological profiles. These results suggest that the beneficial effects of modafinil administration post-RmTBI, work independently of its wake-promoting properties, as activation of the orexinergic wake-promoting system with orexin-A was detrimental. Overall, these findings highlight the complexity of sleep-wake changes in the injured brain and showcase the potential of the arousal and sleep systems in its treatment.

Orexin increases the neuronal excitability of several brain areas associated with maintaining of arousal.

Xin-Yi Chen, Wu Yang, Yan Xue +3 more

Orexin is exclusively produced in neurons localized within the lateral hypothalamic area (LHA) and perifornical area (PFA). Orexin has been identified as a key promotor of arousal. The selective loss of orexinergic neurons results in narcolepsy. It is known that the intrinsic electrophysiological properties are critical for neurons to perform their functions in corresponding brain regions. In addition to hypothalamic orexin, other brain nuclei are involved in the regulation of sleep and wakefulness. Quite a lot of studies focus on elucidating orexin-induced regulation of sleep-wake states and modulation of neuronal electrophysiological properties in several brain regions. Here, we summarize that the orexinergic neurons exhibit spontaneous firing activity which is associated with the states of sleep-wake cycle. Orexin mainly exerts postsynaptic excitatory effects on multiple brain nuclei associated with the process of sleep and wakefulness. This review may provide a background to guide future research about the cellular mechanisms of orexin-induced maintaining of arousal.

[Separation/Conversion Disorders in Functional Coma With Pseudocataplexy: Report of One Case and Literature Review].

Wan-Yu Zhao, Bao-Kun Zhang, Xiao Zhang +3 more

Separation/conversion disorders in functional coma with pseudocataplexy are rare.On December 9,2021,a young female patient with separation/conversion disorders was treated in the Department of Neurology in the First Affiliated Hospital of Shandong First Medical University.The main symptoms were episodic consciousness disorders,sudden fainting,and urinary incontinence.Complete laboratory tests and cranial magnetic resonance imaging showed no obvious abnormalities.Standard multi-channel sleep monitoring and multiple sleep latency tests were performed.The patient was unable to wake up during nap and underwent stimulation tests.There was no response to orbital pressure,loud calls,or tapping,while the α rhythm in all electroencephalogram leads and the increased muscular tone in the mandibular electromyography indicated a period of wakefulness.The results of 24-hour sleep monitoring suggested that the patient had sufficient sleep at night and thus was easy to wake up in the morning.The results of daytime unrestricted sleep and wake-up test showed that the patient took one nap in the morning and one nap in the afternoon.When the lead indicated the transition from N3 to N2 sleep,a wake-up test was performed on the patient.At this time,the patient reacted to the surrounding environment and answered questions correctly.Because the level of orexin in the cerebrospinal fluid was over 110 pg/mL,episodic sleep disorder was excluded and the case was diagnosed as functional coma accompanied by pseudocataplexy.The patient did not present obvious symptom remission after taking oral medication,and thus medication withdrawl was recommended.Meanwhile,the patient was introduced to adjust the daily routine and mood.The follow-up was conducted six months later,and the patient reported that she did not experience similar symptoms after adjusting lifestyle.Up to now,no similar symptoms have appeared in multiple follow-up visits for three years.Functional coma with pseudocataplexy is prone to misdiagnosis and needs to be distinguished from true coma and episodic sleep disorders.

In vivo photocontrol of orexin receptors with a nanomolar light-regulated analogue of orexin-B.

Davia Prischich, Rosalba Sortino, Alexandre Gomila-Juaneda +8 more

Orexinergic neurons are critically involved in regulating arousal, wakefulness, and appetite. Their dysfunction has been associated with sleeping disorders, and non-peptide drugs are currently being developed to treat insomnia and narcolepsy. Yet, no light-regulated agents are available to reversibly control their activity. To meet this need, a photoswitchable peptide analogue of the endogenous neuroexcitatory peptide orexin-B was designed, synthesized, and tested in vitro and in vivo. This compound - photorexin - is the first photo-reversible ligand reported for orexin receptors. It allows dynamic control of activity in vitro (including almost the same efficacy as orexin-B, high nanomolar potency, and subtype selectivity to human OX2 receptors) and in vivo in zebrafish larvae by direct application in water. Photorexin induces dose- and light-dependent changes in locomotion and a reduction in the successive induction reflex that is associated with sleep behavior. Molecular dynamics calculations indicate that trans and cis photorexin adopt similar bent conformations and that the only discriminant between their structures and activities is the positioning of the N-terminus. This, in the case of the more active trans isomer, points towards the OX2 N-terminus and extra-cellular loop 2, a region of the receptor known to be involved in ligand binding and recognition consistent with a "message-address" system. Thus, our approach could be extended to several important families of endogenous peptides, such as endothelins, nociceptin, and dynorphins among others, that bind to their cognate receptors through a similar mechanism: a "message" domain involved in receptor activation and signal transduction, and an "address" sequence for receptor occupation and improved binding affinity.

From past to future: 50 years of pharmacological interventions to treat narcolepsy.

Eric Konofal

The history of narcolepsy research began with the pioneering work of Jean-Baptiste-Édouard Gélineau in the late 19th century. In the 1880s, Gélineau introduced the term "narcolepsy" to describe a condition characterized by sudden and uncontrollable episodes of sleep. His clinical descriptions laid the foundation for our understanding of this complex disorder. Over the last half-century, the pharmacological landscape for narcolepsy treatment has evolved remarkably, shifting from merely managing symptoms to increasingly targeting its underlying pathophysiology. By the 1930s, treatments such as ephedrine and amphetamine were introduced to alleviate excessive daytime sleepiness, marking significant advancements in narcolepsy management. These stimulants provided temporary relief, helping patients maintain wakefulness during the day. As research progressed, the focus shifted towards understanding the disorder's underlying mechanisms. The discovery of orexin (also known as hypocretin) in the late 1990s revolutionized the field. This breakthrough underscored the importance of orexin in regulating sleep-wake cycles and provided new targets for pharmacological intervention. Looking ahead, the future of narcolepsy pharmacotherapy is poised for further innovation. The ongoing exploration of orexin receptor agonists and the potential development of neuroprotective therapeutic targets underscore a promising horizon. Emerging research into the genetic and immunological underpinnings of narcolepsy opens new avenues for personalized medicine approaches and the identification of biomarkers for more precise treatment strategies. Additionally, the refinement of existing treatments through improved delivery systems and the investigation of combination therapies offer opportunities for enhanced efficacy and improved quality of life for patients with narcolepsy.

Inactivation of hypocretin receptor-2 signaling in dopaminergic neurons induces hyperarousal and enhanced cognition but impaired inhibitory control.

Mojtaba Bandarabadi, Sha Li, Lea Aeschlimann +6 more

Hypocretin/Orexin (HCRT/OX) and dopamine (DA) are both key effectors of salience processing, reward and stress-related behaviors and motivational states, yet their respective roles and interactions are poorly delineated. We inactivated HCRT-to-DA connectivity by genetic disruption of Hypocretin receptor-1 (Hcrtr1), Hypocretin receptor-2 (Hcrtr2), or both receptors (Hcrtr1&2) in DA neurons and analyzed the consequences on vigilance states, brain oscillations and cognitive performance in freely behaving mice. Unexpectedly, loss of Hcrtr2, but not Hcrtr1 or Hcrtr1&2, induced a dramatic increase in theta (7-11 Hz) electroencephalographic (EEG) activity in both wakefulness and rapid-eye-movement sleep (REMS). DAHcrtr2-deficient mice spent more time in an active (or theta activity-enriched) substate of wakefulness, and exhibited prolonged REMS. Additionally, both wake and REMS displayed enhanced theta-gamma phase-amplitude coupling. The baseline waking EEG of DAHcrtr2-deficient mice exhibited diminished infra-theta, but increased theta power, two hallmarks of EEG hyperarousal, that were however uncoupled from locomotor activity. Upon exposure to novel, either rewarding or stress-inducing environments, DAHcrtr2-deficient mice featured more pronounced waking theta and fast-gamma (52-80 Hz) EEG activity surges compared to littermate controls, further suggesting increased alertness. Cognitive performance was evaluated in an operant conditioning paradigm, which revealed that DAHcrtr2-ablated mice manifest faster task acquisition and higher choice accuracy under increasingly demanding task contingencies. However, the mice concurrently displayed maladaptive patterns of reward-seeking, with behavioral indices of enhanced impulsivity and compulsivity. None of the EEG changes observed in DAHcrtr2-deficient mice were seen in DAHcrtr1-ablated mice, which tended to show opposite EEG phenotypes. Our findings establish a clear genetically-defined link between monosynaptic HCRT-to-DA neurotransmission and theta oscillations, with a differential and novel role of HCRTR2 in theta-gamma cross-frequency coupling, attentional processes, and executive functions, relevant to disorders including narcolepsy, attention-deficit/hyperactivity disorder, and Parkinson's disease.

Altered reinforcement learning in Narcolepsy type I and other central disorders of hypersomnolence.

Mélanie Strauss, Lucie Griffon, Maxime Elbaz +3 more

Cognitive impairments are described in central disorders of hypersomnolence (CDH), but studies remain very limited and largely focused on narcolepsy type 1 (NT1). The precise nature and origin of these cognitive impairments is poorly understood. Specifically, impaired decision making under ambiguity has been reported in NT1 and suggested to be caused by dysregulation of the direct projections of hypocretin neurons to the dopamine network. However, the decision-making tasks used previously embed different cognitive functions that are difficult to isolate. This study aims to test reinforcement learning in participants with NT1 and with other (non-hypocretin deficient) CDH in a task known to directly depend on the dopamine system. Participants with NT1 (N = 27), other CDH (N = 34, including narcolepsy type 2 and idiopathic hypersomnia, matched with NT1 participants for sleepiness severity), and healthy participants (N = 34) took part in the study. Results showed that all groups had normal and similar positive reinforcement learning, a pattern not suggestive of dopamine deficiency. However, both participants with NT1 and other CDH had decreased learning abilities to avoid losses. This decreased negative reinforcement learning in participants with CDH was associated with the alteration of vigilance. This study provides new insights into the nature of decision making impairment in people with CDH and suggests that these alterations could be minimized by restoring adequate vigilance.

A preliminary study investigating the clinical potential of measuring cerebrospinal-fluid lactate levels in patients with narcolepsy type 1 and 2.

Mariana Fernandes, Matteo Spanetta, Fabio Placidi +6 more

Besides the quantification of orexin-A/hypocretin-1 cerebrospinal fluid (CSF) levels in narcolepsy for diagnostic purposes, several other CSF biomarkers have been evaluated, although with controversial results. Since CSF lactate concentrations fluctuate according to the sleep-wake cycle with higher levels during wakefulness and lower levels during sleep, as documented in animal model studies, the present study aimed at quantifying the CSF lactate levels in patients with narcolepsy type 1 (NT1) and 2 (NT2), which are two sleep disorders featured by excessive daytime sleepiness (EDS).

Deficiency of orexin signaling during sleep is involved in abnormal REM sleep architecture in narcolepsy.

Hiroto Ito, Noriaki Fukatsu, Sheikh Mizanur Rahaman +5 more

Narcolepsy is a sleep disorder caused by deficiency of orexin signaling. However, the neural mechanisms by which deficient orexin signaling causes the abnormal rapid eye movement (REM) sleep characteristics of narcolepsy, such as cataplexy and frequent transitions to REM states, are not fully understood. Here, we determined the activity dynamics of orexin neurons during sleep that suppress the abnormal REM sleep architecture of narcolepsy. Orexin neurons were highly active during wakefulness, showed intermittent synchronous activity during non-REM (NREM) sleep, were quiescent prior to the transition from NREM to REM sleep, and a small subpopulation of these cells was active during REM sleep. Orexin neurons that lacked orexin peptides were less active during REM sleep and were mostly silent during cataplexy. Optogenetic inhibition of orexin neurons established that the activity dynamics of these cells during NREM sleep regulate NREM-REM sleep transitions. Inhibition of orexin neurons during REM sleep increased subsequent REM sleep in "orexin intact" mice and subsequent cataplexy in mice lacking orexin peptides, indicating that the activity of a subpopulation of orexin neurons during the preceding REM sleep suppresses subsequent REM sleep and cataplexy. Thus, these results identify how deficient orexin signaling during sleep results in the abnormal REM sleep architecture characteristic of narcolepsy.

[Multidrug resistant narcolepsy].

A M González-García, M Morán-Sánchez, A R Sánchez-Serrano +3 more

Narcolepsy type 1 is a focal degenerative disease of the hypothalamus that selectively affects orexin (hypocretin)-producing neurons. It presents multiple clinical manifestations, both in wakefulness and in sleep. The symptoms are often so disruptive that they cause enormous suffering and impair patients' quality of life. Although a non-pharmacological approach is sometimes sufficient, the vast majority of patients need medication for adequate clinical management.

Rethinking the Role of Orexin in the Regulation of REM Sleep and Appetite.

Maria P Mogavero, Justyna Godos, Giuseppe Grosso +2 more

Orexin plays a significant role in the modulation of REM sleep, as well as in the regulation of appetite and feeding. This review explores, first, the current evidence on the role of orexin in the modulation of sleep and wakefulness and highlights that orexin should be considered essentially as a neurotransmitter inhibiting REM sleep and, to a much lesser extent, a wake promoting agent. Subsequently, the relationship between orexin, REM sleep, and appetite regulation is examined in detail, shedding light on their interconnected nature in both physiological conditions and diseases (such as narcolepsy, sleep-related eating disorder, idiopathic hypersomnia, and night eating syndrome). Understanding the intricate relationship between orexin, REM sleep, and appetite regulation is vital for unraveling the complex mechanisms underlying sleep-wake patterns and metabolic control. Further research in this field is encouraged in order to pave the way for novel therapeutic approaches to sleep disorders and metabolic conditions associated with orexin dysregulation.

Oral Orexin Receptor 2 Agonist in Narcolepsy Type 1.

Yves Dauvilliers, Emmanuel Mignot, Rafael Del Río Villegas +17 more

Narcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides.