Orexin Receptor Research Articles

Effects of Paradoxical Sleep Deprivation on MCH and Hypocretin Systems

AbstractMelanin-concentrating hormone (MCH) and hypocretins (Hcrt) 1 and 2 are neuropeptides synthesized in the lateral hypothalamic area by neurons that are critical in the regulation of sleep and wakefulness. Their receptors are located in the same cerebral regions, including the frontal cortex and hippocampus. The present study aimed to assess whether 96 hours of paradoxical sleep deprivation alters the functioning of the MCH and hypocretin systems. To do this, in control rats with normal sleep (CTL) and in rats that were deprived of paradoxical sleep (SD), we quantified the following parameters: 1) levels of MCH and hypocretin-1 in the cerebrospinal fluid (CSF); 2) expression of the prepro-MCH (Pmch) and prepro-hypocretin (Hcrt) genes in the hypothalamus; 3) expression of the Mchr1 and Hcrtr1 genes in the frontal cortex and hippocampus; and 4) expression of the Hcrtr2 gene in the hippocampus. These measures were performed at 6 Zeitgeber time (ZT) points of the day (ZTs: 0, 4, 8, 12, 16, and 20). In the SD group, we found higher levels of MCH in the CSF at the beginning of the dark phase. In the frontal cortex, sleep deprivation decreased the expression of Hcrtr1 at ZT0. Moreover, we identified significant differences between the light and dark phases in the expression of Mchr1 and Hcrtr1, but only in the CTL animals. We conclude that there is a day/night modulation in the expression of components of the MCH and hypocretin systems, and this profile is affected by paradoxical sleep deprivation.

Methods of machine learning and big data analysis to establish the molecular mechanisms of the effects of racetams on the metabolism of adipose tissue

Racetams exhibit not only nootropic effects, but also affect the metabolism of fats and carbohydrates. Experimental studies have indicated the possibility of using phenylpiracetam in the treatment of obesity. At the same time, the molecular mechanisms of this pharmacological effect of phenylpiracetam are practically unknown. The paper presents the results of a new artificial intelligence (AI) method for comparative chemoreactome analysis of fonturacetam, piracetam, aniracetam, pramiracetam and levetiracetam. Another AI method, chemoneurocytological analysis, made it possible to compare the neuroprotective effects of molecules on neurons in culture. Despite the similarity of the proteomic interaction profiles of the studied molecules, differential analysis made it possible to establish the molecular mechanisms of the effect of phenylpiracetam on weight loss. Phenylpiracetam can activate β3-adrenoceptors, adenosine, glucagon-like peptide, sphingosine phosphate, and peroxisome proliferator receptors (PPARG); specifically inhibit cannabinoid, opioid, histamine, glutamate, nociceptin, neuropeptide Y and orexin receptors, which is important for normalizing appetite and improving the metabolism of adipose tissue. The synthetic AI method - pharmacoinformatic analysis indicated the advisability of taking phenylpiracetam together with vitamins C, D and group B.

A Simple, Sensitive, and Greener HPLC-DAD Method for the Simultaneous Analysis of Two Novel Orexin Receptor Antagonists.

The orexin receptor antagonist (ORA) is one of the new psychopharmacological agents used in the treatment of insomnia. There are currently no documented greener high-performance liquid chromatography-diode array detector (HPLC-DAD) methods for the analysis of ORA antagonists, lemborexant (LMB) and suvorexant (SUV) simultaneously. Therefore, in this study, a simple, sensitive, and greener HPLC-DAD method has been developed for the simultaneous quantitative analysis of LMB and SUV in bulk and laboratory-prepared mixture. The developed method was validated for numerous validation parameters and evaluated for greenness. The C18 Waters Spherisorb CN (4.6 × 250 mm2; 5 μm) column was used for the chromatographic separation. The mobile phase composition was ethanol: 10 mM KH2PO4 buffer in a ratio of (60:40 v/v). The DAD detection was performed at 253 nm using a Waters DAD detector. The greenness was evaluated using the analytical Eco-Scale (AES), ChlorTox, and analytical GREEnness (AGREE) techniques. The calibration curves showed excellent linearity for LMB and SUV between the concentration range of 125-5000 ng/mL and 250-10,000 ng/mL, respectively. In addition, the proposed HPLC-DAD method was accurate, precise, robust, highly sensitive, and greener. AES, ChlorTox, and AGREE scales were predicted by the HPLC-DAD method to be 91, 1.14 g, and 0.79, respectively, showing an excellent greenness profile. The greener HPLC-DAD method was successfully used to analyze both medicines quantitatively in bulk and laboratory-prepared synthetic mixtures. The findings of this study indicated that the proposed HPLC-DAD method may be consistently applied to evaluate LMB and SUV in bulk and dosage forms.

Cannabinoid and Orexigenic Systems Interplay as a New Focus of Research in Alzheimer’s Disease

Alzheimer’s disease (AD) remains a significant health challenge, with an increasing prevalence globally. Recent research has aimed to deepen the understanding of the disease pathophysiology and to find potential therapeutic interventions. In this regard, G protein-coupled receptors (GPCRs) have emerged as novel potential therapeutic targets to palliate the progression of neurodegenerative diseases such as AD. Orexin and cannabinoid receptors are GPCRs capable of forming heteromeric complexes with a relevant role in the development of this disease. On the one hand, the hyperactivation of the orexins system has been associated with sleep–wake cycle disruption and Aβ peptide accumulation. On the other hand, cannabinoid receptor overexpression takes place in a neuroinflammatory environment, favoring neuroprotective effects. Considering the high number of interactions between cannabinoid and orexin systems that have been described, regulation of this interplay emerges as a new focus of research. In fact, in microglial primary cultures of APPSw/Ind mice model of AD there is an important increase in CB2R–OX1R complex expression, while OX1R antagonism potentiates the neuroprotective effects of CB2R. Specifically, pretreatment with the OX1R antagonist has been shown to strongly potentiate CB2R signaling in the cAMP pathway. Furthermore, the blockade of OX1R can also abolish the detrimental effects of OX1R overactivation in AD. In this sense, CB2R–OX1R becomes a new potential therapeutic target to combat AD.

Transfer of the Dual Orexin Receptor Antagonist Daridorexant into Breast Milk of Healthy Lactating Women.

The novel dual orexin receptor antagonist daridorexant was approved in 2022 for the treatment of adult patients with insomnia. The aim of this post-marketing study was to measure daridorexant and its major metabolites in breast milk and plasma of 10 healthy lactating subjects. This single-center, open-label study evaluated the transfer of the analytes into breast milk. A single dose of 50 mg was orally administered in the morning. Milk and blood samples were collected pre-dose and over a period of 72 h after dosing. The pharmacokinetics of daridorexant in milk and plasma were assessed including the cumulative amount and fraction of dose excreted, daily infant dose, and relative infant dose. Safety and tolerability were also investigated. All subjects completed the study. Daridorexant was rapidly absorbed into and distributed from plasma. Daridorexant and its major metabolites were measurable in breast milk. The cumulative total amount of daridorexant excreted over 72 h was 0.010 mg, which corresponds to 0.02% of the maternal dose. This corresponds to a mean daily infant dose of 0.009 mg/day and a relative infant dose of less than 0.22% over 24 h. The maternal safety profile was similar to that observed in previous studies. Low amounts of daridorexant and its metabolites were detected in the breast milk of healthy lactating women. Since the exposure and potential effects on the breastfed infant are unknown, a risk of somnolence or other depressant effects cannot be excluded.

The potential use of daridorexant in eating disorders: beyond the treatment of insomnia?

A strong interplay exists between sleep and dietary habits, and sleep disturbances have been repeatedly documented in individuals with eating disorders (EDs). The orexin system - implicated in sleep regulation, energy homeostasis, and food reward - may represent a mechanist link between sleep alterations and disordered eating behaviors. Daridorexant is a dual orexin receptor antagonist (DORA) recently approved for the treatment of insomnia, with demonstrated efficacy and tolerability. Owing to its action on orexin neurons, the compound represents an intriguing option for addressing both sleep-related and core symptoms of EDs. By inhibiting motor hyperactivity, daridorexant may reduce excessive physical exercise in individuals with anorexia nervosa (AN) restricting type. Additionally, the compound may exert anti-binge effects, suggesting broad applicability in binge ED, bulimia nervosa, and binge/purging AN. In this framework, daridorexant emerges as a promising therapeutic option, offering a multifaceted approach to improving circadian rhythms, energy balance, and overall quality of life in individuals with diverse ED subtypes.

Structural and Computational Insights into Dynamics and Intermediate States of Orexin 2 Receptor Signaling.

Orexin 2 receptor (OX2R) is a G protein-coupled receptor (GPCR) whose activation is crucial to regulation of the sleep-wake cycle. Recently, inactive and active state structures were determined from X-ray crystallography and cryo-electron microscopy single particle analysis, and the activation mechanisms have been discussed based on these static data. GPCRs have multiscale intermediate states during activation, and insights into these dynamics and intermediate states may aid the precise control of intracellular signaling by ligands in drug discovery. Molecular dynamics (MD) simulations are used to investigate dynamics induced in response to thermal perturbations, such as structural fluctuations of main and side chains. In this study, we proposed collective motions of the TM domain during activation by performing 30 independent microsecond-scale MD simulations for various OX2R systems and applying relaxation mode analysis. The analysis results suggested that TM3 had a vertical structural movement relative to the membrane surface during activation. In addition, we extracted three characteristic amino acid residues on TM3, i.e., Q1343.32, V1423.40, and R1523.50, which exhibited large conformational fluctuations. We quantitatively evaluated the changes in their equilibrium during activation in relation to the movement of TM3. We also discuss the regulation of ligand binding recognition and intracellular signal selectivity by changes in the equilibrium of Q1343.32 and R1523.50, respectively, according to MD simulations and GPCR database. Additionally, the OX2R-Gi signaling complex is stabilized in the conformation resembling a non-canonical (NC) state, which was previously proposed as an intermediate state during activation of neurotensin 1 receptor. Insights into the dynamics and intermediate states during activation gained from this study may be useful for developing biased agonists for OX2R.

Interactions between Lateral Hypothalamic Orexin and Dorsal Raphe Circuitry in Energy Balance.

Orexin/hypocretin terminals innervate the dorsal raphe nucleus (DRN), which projects to motor control areas important for spontaneous physical activity (SPA) and energy expenditure (EE). Orexin receptors are expressed in the DRN, and obesity-resistant (OR) rats show higher expression of these receptors in the DRN and elevated SPA/EE. We hypothesized that orexin-A in the DRN enhances SPA/EE and that DRN-GABA modulates the effect of orexin-A on SPA/EE. We manipulated orexin tone in the DRN either through direct injection of orexin-A or through the chemogenetic activation of lateral-hypothalamic (LH) orexin neurons. In the orexin neuron activation experiment, fifteen minutes prior to the chemogenetic activation of orexin neurons, the mice received either the GABA-agonist muscimol or antagonist bicuculline injected into the DRN, and SPA/EE was monitored for 24 h. In a separate experiment, orexin-A was injected into the DRN to study the direct effect of DRN orexin on SPA/EE. We found that the activation of orexin neurons elevates SPA/EE, and manipulation of GABA in the DRN does not alter the SPA response to orexin neuron activation. Similarly, intra-DRN orexin-A enhanced SPA and EE in the mice. These results suggest that orexin-A in the DRN facilitates negative energy balance by increasing physical activity-induced EE, and that modulation of DRN orexin-A is a potential strategy to promote SPA and EE.

Trigeminal nerve electrical stimulation attenuates early traumatic brain injury through the TLR4/NF-κB/NLRP3 signaling pathway mediated by orexin-A/OX1R system.

Traumatic brain injury (TBI) is a significant contributor to global mortality and disability, and emerging evidence indicates that trigeminal nerve electrical stimulation (TNS) is a promising therapeutic intervention for neurological impairment following TBI. However, the precise mechanisms underlying the neuroprotective effects of TNS in TBI are poorly understood. Thus, the objective of this study was to investigate the potential involvement of the orexin-A (OX-A)/orexin receptor 1 (OX1R) mediated TLR4/NF-κB/NLRP3 signaling pathway in the neuroprotective effects of TNS in rats with TBI. Sprague-Dawley rats were randomly assigned to four groups: sham, TBI, TBI+TNS+SB334867, and TBI+TNS. TBI was induced using a modified Feeney's method, and subsequent behavioral assessments were conducted to evaluate neurological function. The trigeminal nerve trunk was isolated, and TNS was administered following the establishment of the TBI model. The levels of neuroinflammation, brain tissue damage, and proteins associated with the OX1R/TLR4/NF-κB/NLRP3 signaling pathway were assessed using hematoxylin-eosin staining, Nissl staining, western blot analysis, quantitative real-time polymerase chain reaction, and immunofluorescence techniques. The findings of our study indicate that TNS effectively mitigated tissue damage, reduced brain edema, and alleviated neurological deficits in rats with TBI. Furthermore, TNS demonstrated the ability to attenuate neuroinflammation levels and inhibit the expression of proteins associated with the TLR4/NF-κB/NLRP3 signaling pathway. However, it is important to note that the aforementioned effects of TNS were reversible upon intracerebroventricular injection of an OX1R antagonist. TNS may prevent brain damage and relieve neurological deficits after a TBI by inhibiting inflammation, possibly via the TLR4/NF-κB/NLRP3 signaling pathway mediated by OX-A/OX1R.

The Role of Orexin Receptor Antagonists in Inhibiting Drug Addiction: A Review Article.

The orexinergic system and its receptors are involved in many physiological processes. Their functions in energy homeostasis, arousal, cognition, stress processing, endocrine functions, and pain modulation have been investigated. Many studies have shown that the orexinergic system cooperates with the dopaminergic system in the addiction process. Emerging evidence suggests that the orexinergic system can be effective in the induction of drug dependence and tolerance. Therefore, several researches have been conducted on the effect of orexin receptor (OXR) antagonists on reducing tolerance and dependence caused by drug abuse. Due to the significant growth of the studies on the orexinergic system, the current literature was conducted to collect the findings of previous studies on orexin and its receptors in the induction of drug addiction. In addition, cellular and molecular mechanisms of the possible role of orexin in drug tolerance and dependence are discussed. The findings indicate that the administration of OXR antagonists reduces drug dependence. OXR blockers seem to counteract the addictive effects of drugs through multiple mechanisms, such as preventing neuronal adaptation. This review proposes the potential clinical use of OXR antagonists in the treatment of drug dependence.

Selective Orexin 2 Receptor Blockade Alleviates Cognitive Impairments and the Pathological Progression of Alzheimer's Disease in 3xTg-AD Mice.

The orexin system is closely related to the pathogenesis of Alzheimer's disease (AD). Orexin-A aggravates cognitive dysfunction and increases amyloid β (Aβ) deposition in AD model mice, but studies of different dual orexin receptor (OXR) antagonists in AD have shown inconsistent results. Our previous study revealed that OX1R blockade aggravates cognitive deficits and pathological progression in 3xTg-AD mice, but the effects of OX2R and its potential mechanism in AD have not been reported. In the present study, OX2R was blocked by oral administration of the selective OX2R antagonist MK-1064, and the effects of OX2R blockade on cognitive dysfunction and neuropsychiatric symptoms in 3xTg-AD mice were evaluated via behavioral tests. Then, immunohistochemistry, western blotting, and ELISA were used to detect Aβ deposition, tau phosphorylation, and neuroinflammation, and electrophysiological and wheel-running activity recording were recorded to observe hippocampal synaptic plasticity and circadian rhythm. The results showed that OX2R blockade ameliorated cognitive dysfunction, improved LTP depression, increased the expression of PSD-95, alleviated anxiety- and depression-like behaviors and circadian rhythm disturbances in 3xTg-AD mice, and reduced Aβ pathology, tau phosphorylation, and neuroinflammation in the brains of 3xTg-AD mice. These results indicated that chronic OX2R blockade exerts neuroprotective effects in 3xTg-AD mice by reducing AD pathology at least partly through improving circadian rhythm disturbance and the sleep-wake cycle and that OX2R might be a potential target for the prevention and treatment of AD; however, the potential mechanism by which OX2R exerts neuroprotective effects on AD needs to be further investigated.

Effect of antorex, a new antagonist of orexin receptors, on binge eating in rats caused by weaning from the mother in early ontogenesis

BACKGROUND: Research on the elements of food addiction in animal models shows that its manifestations are attributed to intermittent consumption of high-calorie foods. Chronic stress in ontogenesis can cause episodes of binge eating or dietary restrictions such as anorexia. AIM: This study aimed to investigate the effect of a new orexin receptor antagonist antorex on binge eating in a rat model of maternal neglect. MATERIALS AND METHODS: Mature male rats weaned from their mothers for 3 h after birth from days 2 to 12 received a high-carbohydrate diet every third day for 1 h for 45 days. Moreover, high-calorie food was placed within 5 cm of visual contact 15 min before feeding. Antorex, an orexin receptor antagonist, was administered intranasally at a dose of 1 µg/1µL for a total of 20 µL for 7 days. RESULTS: Intermittent consumption of high-calorie food products induced binge eating in rats. The frequency of the signs of binge eating increased after chronic weaning stress. The consumption of standard briquette feed was not altered. Intranasal administration of both the orexin receptor antagonist antorex reduced the manifestations of food addiction in rats after maternal deprivation under conditions of intermittent consumption of high-calorie food compared with controls. Standard food intake did not differ relative to the control group both before and after аntorex administration. CONCLUSIONS: The results suggest new ways to study and synthesize peptide drugs based on orexin and its antagonists for the correction of food addiction caused by chronic stress in ontogenesis.

Novel Strategies for Acute Relief and Prevention of Migraine

Migraine is a debilitated disorder that is often under diagnosed in clinical practice. Early detection of migraine leads to outstanding improvements in patients’ quality of life. New researchers had developed the central sensitization and cutaneous allodina in chronic migraine which is helpful in early treatment approach with triptans and other agents in acute migraine episodes. Right now, five agents are accepted by US food and drug administration (FDA) for migraine prevention. They are namely Divalporex sodium, Propranolol, Timolol maleate, Topiramate and Methysergide. For so many years, other medications have been used to prevent migraine with not much more success rate. They are Tricyclic anti depressants, anti epileptic agents, Nonsteroidal anti-inflammatory drugs (NSAIDs), Selective serotonin reuptake inhibitors (SSRIS), Calcium channel blockers and muscle relaxants. Calcitonin gene related peptide antagonist, Ditans, Botulinum toxin type A, Orexin receptor antagonists etc were the recent novel agents in the treatment and management of migraine. These novel agents showed more affect than other medications in the acute and prophylactic management of migraines. They play a pivotal role in the standard care for migraine treatment that will improve the patient quality of life with better outcomes.

0049 Sleep and Electroencephalogram Effects from a Dual Orexin Receptor Antagonist in Mice with Traumatic Brain Injury

0049 Sleep and Electroencephalogram Effects from a Dual Orexin Receptor Antagonist in Mice with Traumatic Brain Injury

0087 Effects of a Dual Orexin Receptor Antagonist on Anxiety-like Behavior and Cognition in a Mouse Model of TBI

0087 Effects of a Dual Orexin Receptor Antagonist on Anxiety-like Behavior and Cognition in a Mouse Model of TBI

Bioactive compounds from Ocimum tenuiflorum and Poria cocos: A novel natural Compound for insomnia treatment based on A computational approach

Insomnia, a widespread public health issue, is associated with substantial distress and daytime functionality impairments and can predispose to depression and cardiovascular disease. Cognitive Behavioral Anti-insomnia therapies including benzodiazepines often face limitations due to patient adherence or potential adverse effects. This study focused on identifying novel bioactive compounds from medicinal plants, aiming to discover and develop new therapeutic agents with low risk-to-benefit ratios using computational drug discovery methods. Through a systematic framework involving compound library preparation, evaluation of drug-likeness and pharmacokinetics, toxicity prediction, molecular docking, and molecular dynamic simulations, two natural compounds such as 2-(4-hydroxy-3-methoxyphenyl)-8-methoxy-6-prop-2-enyl-3,4-dihydro-2H-chromen-3-ol from Ocimum tenuiflorum and 7-(2-hydroxypropan-2-yl)-1,4a-dimethyl-9-oxo-3,4,10,10a-tetrahydro-2H-phenanthrene-1-carboxylic acid from Poria cocos exhibited high binding affinity with orexin receptor type 1 (OX1R) and type 2 (OX2R), surpassing commercial drugs used in insomnia treatment. Additionally, they showed interactions with critical amino acid residues within the receptors that play crucial roles in competitive inhibitor activity, like commercial drugs such as Suvorexant, Lemborexant, and Daridorexant. Further, molecular dynamics simulations of the protein-ligand complexes under conditions that mimic the in vivo environment revealed both compounds' sustained and robust interactions with the OX1R and OX2R, reinforcing their potential as effective therapeutic candidates. Furthermore, upon evaluating both compounds' drug-likeness, pharmacokinetics, and toxicity profiles, it was discerned that they displayed considerable drug-like properties and favorable pharmacokinetics, along with diminished toxicity. The research provides a solid foundation for further exploring and validating these compounds as potential anti-insomnia therapeutics.

A Review of Recent Advances in the Management of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative condition and a form of dementia encountered in medical practice. Despite many proposed and attempted treatments, this disease remains a major puzzle in the public health systems worldwide. The initial part of this article provides an overview and illustration of the primary mechanisms responsible for neuronal damage in AD. Subsequently, it offers a critical evaluation of the most noteworthy studies on pharmacological therapy for AD and outlines recent advancements and novel approaches to managing this condition. Main properties, categorization, Food and Drug Administration (FDA) status, mechanisms of action, benefits, and common side effects of the classical and the most recently proposed pharmacological treatments for AD are described. The conventional pharmacological agents revised comprise cholinesterase inhibitors, monoclonal antibodies, and other therapies, such as memantine, valproic acid, and rosiglitazone. The innovative reviewed pharmacological agents comprise the monoclonal antibodies: donanemab, gantenerumab, solanezumab, bapineuzumab, crenezumab, and semorinemab. Nutritional supplements such as alpha-tocopherol (vitamin E) and caprylidene are also revised. Tau and amyloid-targeting treatments include methylthioninium moiety (MT), leuco-methylthioninium bis (LMTM), an oxidized form of MT, and tramiprosate, which inhibits the beta-amyloid (Aβ) monomer aggregation into toxic oligomers. Antidiabetic and anti-neuroinflammation drugs recently proposed for AD treatment are discussed. The antidiabetic drugs include NE3107, an anti-inflammatory and insulin sensitizer, and the diabetes mainstream drug metformin. The anti-neuroinflammatory AD therapies include the use of sodium oligomannate (GV-971), infusions with intravenous immunoglobulin aiming to decrease plasma levels of the constituents of Aβ plaques, and masitinib, a tyrosine kinase inhibitor that impacts mast and microglia cells. Additional anti-inflammatory agents being currently tested in phase-2 clinical trials, such as atomoxetine (selective norepinephrine reuptake inhibitor), losartan (angiotensin 2 receptor agonist), genistein (anti-inflammatory isoflavone neuroprotective agent), trans-resveratrol (polyphenol antioxidant plant estrogen), and benfotiamine (synthetic thiamine precursor), were reviewed. Lastly, drugs targeting Alzheimer's-associated symptoms, such as brexpiprazole (serotonin dopamine activity modulator) and suvorexant (orexin receptor antagonist), respectively, used for agitation and insomnia in AD patients, are reviewed.As experimental investigations and clinical research progress, there is a possibility that a combination of newly tested medications and traditional ones may emerge as a promising treatment option for AD in the future.

Current status, mechanism and research progress of major sedative-hypnotic drugs for the treatment of insomnia

Insomnia, a widespread condition in modern society, has seen a rise in its affected population in recent years. Prolonged insomnia not only causes anxiety and depression but also impairs individuals’ work and study efficiency while posing a threat to their physical health. Drug therapy is the predominant treatment for insomnia, encompassing drugs such as barbiturates, benzodiazepines, novel non-benzodiazepines, melatonin receptor agonists, melatonin, and orexin receptor antagonists. However, concerns arise due to the significant side effects, ease of tolerance development, dependency issues, and rebound phenomena upon drug discontinuation for some of these medications. Hence, there’s an urgent need for the research and development of novel hypnotic-sedative drugs that offer minimal toxic side effects, excellent tolerance, and reduced dependency. This paper presents a review of the mechanisms and research advancements of key sedative-hypnotic drugs in recent years. Furthermore, based on conformational relationships, we aim to predict the structure of these novel drugs, providing a valuable reference for drug research and development, while offering diverse drug options tailored to different patient needs.

Orexins in apoptosis: a dual regulatory role.

The orexins, also referred to as hypocretins, are neuropeptides that originate from the lateral hypothalamus (LH) region of the brain. They are composed of two small peptides, orexin-A, and orexin-B, which are broadly distributed throughout the central and peripheral nervous systems. Orexins are recognized to regulate diverse functions, involving energy homeostasis, the sleep-wake cycle, stress responses, and reward-seeking behaviors. Additionally, it is suggested that orexin-A deficiency is linked to sleepiness and narcolepsy. The orexins bind to their respective receptors, the orexin receptor type 1 (OX1R) and type 2 (OX2R), and activate different signaling pathways, which results in the mediation of various physiological functions. Orexin receptors are widely expressed in different parts of the body, including the skin, muscles, lungs, and bone marrow. The expression levels of orexins and their receptors play a crucial role in apoptosis, which makes them a potential target for clinical treatment of various disorders. This article delves into the significance of orexins and orexin receptors in the process of apoptosis, highlighting their expression levels and their potential contributions to different diseases. The article offers an overview of the existing understanding of the orexin/receptor system and how it influences the regulation of apoptosis.

Impact of the Oral Orexin Receptor 2 Agonist TAK-994 on Sustained Attention in Patients with Narcolepsy Type 1: Exploratory Results from a Phase 2 Study (P11-9.012)

Impact of the Oral Orexin Receptor 2 Agonist TAK-994 on Sustained Attention in Patients with Narcolepsy Type 1: Exploratory Results from a Phase 2 Study (P11-9.012)