Orexin Receptor Research Articles

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.

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)

Effects of methamphetamine on actigraphy-based sleep parameters in female rhesus monkeys: Orexin receptor mechanisms

BackgroundThe orexin system has been implicated as a mechanism underlying insomnia and methamphetamine-induced sleep disruptions, with a potential role for OX2 receptors in the sleep-modulating effects of orexin. The aim of the present study was to investigate the extent to which orexin receptors mediate the effects of acute methamphetamine administration on actigraphy-based sleep in female rhesus monkeys. MethodsActigraphy-based sleep measures were obtained in female rhesus monkeys (n=5) under baseline and acute test conditions. First, morning (10h) i.m. injections of methamphetamine (0.03 – 0.56mg/kg) were administered to determine the effects of methamphetamine alone. Then, saline or methamphetamine (0.3mg/kg) were administered at 10h, and evening (17h30) oral treatments with vehicle, the non-selective orexin receptor antagonist suvorexant (1 – 10mg/kg, p.o.), or the OX2-selective orexin receptor antagonist MK-1064 (1 – 10mg/kg, p.o.) were given. The ability of suvorexant and MK-1064 (10mg/kg, p.o.) to improve actigraphy-based sleep was also assessed in a group of female monkeys quantitatively identified with “short-duration sleep” (n=4). ResultsMethamphetamine dose-dependently disrupted actigraphy-based sleep parameters. Treatment with either suvorexant or MK-1064 dose-dependently improved actigraphy-based sleep in monkeys treated with methamphetamine. Additionally, both suvorexant and MK-1064 promoted actigraphy-based sleep in a group of monkeys with baseline short actigraphy-based sleep. ConclusionsThese findings suggest that orexin-mediated mechanisms play a role in the effects of methamphetamine on actigraphy-based sleep in female monkeys. Targeting the orexin system, in particular OX2 receptors, could be an effective option for treating sleep disruptions observed in individuals with methamphetamine use disorder.

Orexinergic Receptor Antagonists as a New Therapeutic Target to Overcome Limitations of Current Pharmacological Treatment of Insomnia Disorder.

Insomnia disorder is a common condition that is considered a risk factor for multiple physical and mental disorders, contributing to reduced quality of life and increased healthcare expenditures. Although cognitive behavioral therapy (CBT) is typically recommended as the primary intervention, its accessibility is hindered by limited resources, prompting the prevalent use of pharmacological interventions as the primary treatment in clinical settings. This study reviews the benefits and risks of current pharmacological treatments for insomnia, with special reference to the orexinergic system as a novel therapeutic target for treatment. The prescription of GABAergic mechanism enhancers (benzodiazepine (BZD) and "Z drugs") has shown efficacy in short-term insomnia treatment (less than 4 weeks), however, concerns arise regarding their long-term effectiveness, unfavorable tolerability and safety profiles, including the potential for dependency. Drugs with antihistamine properties, including certain antidepressants and antipsychotics, exhibit short-term efficacy but have documented tolerability limitations, especially in the elderly. The use of melatonin, available in various formulations, lacks comprehensive long-term data. Dual orexin receptor antagonists (DORAs) such as daridorexant, lemborexant, and suvorexant, represent a novel approach to insomnia treatment by inhibiting wakefulness rather than enhancing sedation. As the only DORA approved for insomnia treatment by the European Medicines Agency (EMA) and Food and Drug Administration (FDA), daridorexant has demonstrated sustained efficacy over a 12-month period, improving nocturnal sleep parameters and daytime functionality, with a favorable safety and tolerability profile.

Sleep Disorder and its Treatment: From Nature to Laboratory

Sleep is the natural cellular repair mechanism to improve and restore central neural mechanism, memory, hormonal imbalance, and finally, cell rejuvenation. Sleep disorder is characterized by insomnia, circadian rhythm disorder (CRD), sleep apnea, narcolepsy, parasomnia, and restless leg syndrome (RLS) or periodic limb movement disorder (PLMD). Both oversleeping and less sleeping are associated with sleep disorders (SD). Anxiety, schizophrenia, weight loss/gain, hypothyroidism, and oxidative stress are the most common outcomes of SD. There is also a genetic explanation behind circadian rhythmicity, circadian disorder, narcolepsy-cataplexy syndrome, fatal familial insomnia, and somnambulism. Excessive work pressure, stress, and consumption of caffeine and alcohol collectively push a person toward sleep deprivation. Anxiety, schizophrenia, weight loss/gain, hypothyroidism, and oxidative stress are the most common outcomes of SD. Adenosine, melatonin, dopamine, serotonin, gamma amino butyric acid (GABA), orexin, and histamine regulate SDs by various pathways. Among natural sources, Centella asiatica, Bacopa monnieri, Acorus calamus, Withania somnifera, Nardostachys jatamansi, Poria cocos is, Valeriana officinalis, Matricaria chamomilla, Lavandula angustifolia, Nelumbo nucifera, Melissa officinalis, Convolvulus pluricaulis, Camellia sinensis, Ziziphus jujube, Datura stramonium, Zhizhipus jujube, Passiflora incarnata, and Moringa oleifera showed remarkable effects on different forms of SDs through GABAA, serotonin, and melatonin receptors. Pramipexole, ropinirole, rotigotine, clonazepam, lorazepam, estazolam, zolpidem, lemborexant, daridorexant, and suvorexant showed its activity in the treatment of SDs as a dopamine agonist, inhibitor of GABAA receptor, dual orexin receptor antagonist, respectively. This article focused on the types of SDs, the effects of SDs on mental health, receptors involved in the sleep cycle, and the impact of natural molecules and synthetic molecules in the management of SDs.

Effects of Orexin Receptor Antagonist on Cognitive Function in Adults: A Systematic Review

Background:: Orexin receptor antagonists (ORAs) are the emerging class of hypnotics used for the treatment of insomnia. However, from the available literature, the effect of ORA on cognitive functions is not clear yet. Therefore, the current study aimed to systematically evaluate the effect of ORA on cognitive function from available clinical studies. Methods:: The extensive literature search was conducted in various databases, including Pubmed, Embase, Cochrane Library, and clinicaltrials.gov, using suitable keywords. The quality of the included studies was evaluated using the Cochrane risk of bias tool (ROB2). Results:: We obtained a total of 450 articles from different databases. Finally, 07 articles met the inclusion criteria and were included in the current systematic review for qualitative analysis. Available literature showed conflicting results, with few studies showing no impact of ORA on cognitive function, while others reported dose-dependent adverse effects of ORA on cognitive function. The risk of bias in included studies was found to be low. Conclusion:: In conclusion, ORA is generally safe in clinical doses. However, it is important to note that there is a dose-dependent decline in cognitive function after the administration of ORA. Therefore, clinicians must be careful while prescribing ORA and adjust the dose as per the needs of the individual patients and the potential risk factors.

The Role of the Orexin System in Craniocerebral Trauma-Induced Epilepsy in Mice.

Following traumatic brain injury (TBI), an imbalance arises in the central nervous system within the hippocampus region, resulting in the proliferation of mossy cell fibers, causing abnormal membrane discharge. Moreover, disruptions in cellular neurotransmitter secretion induce post-traumatic epilepsy. Extensive experimental and clinical data indicate that the orexin system plays a regulatory role in the hippocampal central nervous system, but the specific regulatory effects are unclear. Therefore, further experimental evaluation of its relevance is needed. This study aims to investigate the effects of orexin receptor agonists (OXA) on the seizure threshold and intensity in controlled cortical impact (CCI) mice, and to understand the role of the orexin system in post-traumatic epilepsy (PTE). Male C57BL/6 mice weighing 18-22 g were randomly divided into three groups: Sham, CCI, and CCI+OXA. The three groups of mice were sequentially constructed with models, implanted with electrodes, and established drug-delivery cannulas. After a 30-day recovery, the Sham and CCI groups were injected with physiological saline through the administration cannulas, while the CCI+OXA group was injected with OXA. Subsequently, all mice underwent electrical stimulation every 30 minutes for a total of 15 times. Epileptic susceptibility, duration, intensity, and cognitive changes were observed. Concurrently, the expression levels and changes of GABAergic neurons in the hippocampus of each group were examined by immunofluorescence. Injecting OXA into hippocampal CA1 reduces the threshold of post-traumatic seizures, prolongs the post-discharge duration, prolongs seizure duration, reduces cognitive ability, and exacerbates the loss of GABAergic neurons in the hippocampal region. Based on the results, we can find that injecting OXA antagonists into the CA1 region of the hippocampus can treat or prevent the occurrence and progression of post-traumatic epilepsy.

Control of breathing by orexinergic signaling in the nucleus tractus solitarii

Orexin signaling plays a facilitatory role in respiration. Abnormalities in orexin levels correlate with disordered breathing patterns and impaired central respiratory chemoreception. Nucleus tractus solitarii (NTS) neurons expressing the transcription factor Phox2b contribute to the chemoreceptive regulation of respiration. However, the extent to which orexinergic signaling modulates respiratory activity in these Phox2b-expressing NTS neurons remains unclear. In the present study, the injection of orexin A into the NTS significantly increased the firing rate of the phrenic nerve. Further analysis using fluorescence in situ hybridization and immunohistochemistry revealed that orexin 1 receptors (OX1Rs) were primarily located in the ventrolateral subdivision of the NTS and expressed in 25% of Phox2b-expressing neurons. Additionally, electrophysiological recordings showed that exposure to orexin A increased the spontaneous firing rate of Phox2b-expressing neurons. Immunostaining experiments with cFos revealed that the OX1R-residing Phox2b-expressing neurons were activated by an 8% CO2 stimulus. Crucially, OX1R knockdown in these NTS neurons notably blunted the ventilatory response to 8% CO2, alongside an increase in sigh-related apneas. In conclusion, orexinergic signaling in the NTS facilitates breathing through the activation of OX1Rs, which induces the depolarization of Phox2b-expressing neurons. OX1Rs are essential for the involvement of Phox2b-expressing NTS neurons in the hypercapnic ventilatory response.

Molecular mechanisms underlying the therapeutic effects of Linggui Zhugan decoction in stroke: Insights from network pharmacology and single-cell transcriptomics analysis.

Linggui Zhugan decoction (LZD), a traditional Chinese medicine formula, has demonstrated significant therapeutic effects in managing poststroke cognitive impairment and hemiplegia. However, the precise molecular mechanisms underlying its efficacy remain incompletely elucidated. The active ingredients and target proteins of LZD were retrieved from the traditional Chinese medicine systems pharmacology database and analysis platform database, which is specifically designed for traditional Chinese medicine research. The stroke-related genes were obtained from publicly available databases. Protein-protein interaction, enrichment analysis, and single-cell data analysis were conducted to identify key cells, targets, and pathways. Molecular docking was employed to assess the binding affinity between key components and targets. Network pharmacology analysis identified 190 active ingredients and 248 targets in LZD. These targets were significantly enriched in processes and pathways such as cellular response to lipid, orexin receptor pathway, and were significantly associated with Cerebral infarction and Middle Cerebral Artery Occlusion. Intersection analysis with 2035 stroke-related genes revealed 144 potential targets, which exhibited 2870 interactions and were significantly enriched in signaling pathways such as PI3K-AKT single pathway, MAPK single pathway, and tumor necrosis factor single pathway. Gene set variation analysis showed that the targets of LZD exhibited higher enrichment scores in microglia, M2 macrophages, endothelial cells, and neutrophils, while lower enrichment scores were observed in oligodendrocytes. Furthermore, molecular docking demonstrated a strong binding affinity between key active ingredients and targets. Network pharmacology and single-cell sequencing analysis elucidated the key cells, pathways, targets, and components involved in the therapeutic mechanism of LZD for the treatment of stroke.

Early experience with the new DORA daridorexant in patients with insomnia disorder and comorbid mental disturbances: Results of a naturalistic study with 3 months follow-up.

Insomnia disorder may affect mental health, increasing suicidal risk. Targeting insomnia is crucial in the clinical practice. Sixty-six consecutive patients with insomnia disorder according with the DSM-5-TR criteria were treated with the dual orexin receptor antagonist, daridorexant 50 mg. Baseline (T0), 1 month (T1) and 3 month (T2) evaluations were performed. Insomnia severity (Insomnia Severity Index), mood, anxiety symptoms and suicidal risk (Beck Depression Inventory-II, Young Mania Rating Scale, Self-Reported Anxiety Scale, Suicidal Ideation Scale), dysfunctional insomnia-cognitive factors and pre-sleep arousal (Dysfunctional Beliefs About Sleep, Pre-Sleep Arousal Scale) were evaluated. The final sample included 66 patients (n = 36, 54% females, mean age 60 ± 13.6 years). Most of them, 64%, suffered from insomnia disorder comorbid with unipolar/bipolar depression, anxiety disorders and substance use disorders. Repeated ANOVA analyses showed that Insomnia Severity Index, Dysfunctional Beliefs About Sleep and Pre-Sleep Arousal Scale total score decreased across time (F = 68.818, p < 0.001; F = 47.561, p < 0.001; F = 28.142, p < 0.001, respectively). Similarly, Beck Depression Inventory-II, Self-Reported Anxiety Scale, Young Mania Rating Scale, and Suicidal Ideation Scale significantly decreased over time (p < 0.001). Predictors of insomnia remission (Insomnia Severity Index < 8) at T1 were improvement of Insomnia Severity Index at T1 (F = 60.205, p < 0.001), and improvement of Dysfunctional Beliefs About Sleep at T1 (F = 4.432, p = 0.041). Insomnia remission at T2 was best predicted by improvement of Dysfunctional Beliefs About Sleep at T2 (F = 3.993, p = 0.023). Multiple-regression models showed that clinical improvement of Beck Depression Inventory-II was best predicted by improvement in Dysfunctional Beliefs About Sleep at T1 and T2, manic symptoms by Insomnia Severity Index at T2, anxiety symptoms by Dysfunctional Beliefs About Sleep, Insomnia Severity Index and somatic Pre-Sleep Arousal Scale at T1 and T2. With the caution of a naturalistic design, early experience with daridorexant showed that by targeting insomnia it may be possible to improve not only insomnia symptoms but also comorbid symptoms.