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Frontiers in Cellular Neuroscience 2024The 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... (Review)
Review
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.
PubMed: 38699177
DOI: 10.3389/fncel.2024.1336145 -
Cureus Apr 2024Alzheimer's disease (AD) is the most common neurodegenerative condition and a form of dementia encountered in medical practice. Despite many proposed and attempted... (Review)
Review
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.
PubMed: 38756263
DOI: 10.7759/cureus.58416 -
Nature and Science of Sleep 2023Pain disrupts sleep, and sleep deprivation or interference can alter pain perception in animals and humans, for example by increasing sensitivity to pain. However, the... (Review)
Review
Pain disrupts sleep, and sleep deprivation or interference can alter pain perception in animals and humans, for example by increasing sensitivity to pain. However, the mechanism by which sleep affects neuropathic pain remains unclear. In this review, we discuss the available evidence from the epidemiologic, clinical, and human, as well as laboratory studies. In previous studies, we have found that sleep deprivation affects various injurious systems, including opioids, dopaminergic, immune, orexins, hypothalamic-pituitary-adrenal axis, and adenosine. At the same time, these systems play a crucial role in neuropathic pain regulation. In the complex interactions between these neurobiological systems, there may be potential regulatory pathways through which sleep deprivation amplifies neuropathic pain. Because of the impact sleep problems and neuropathic pain can have on the patients' quality of life, studying the link between sleep and neuropathic pain is important for neuropathic pain prevention and public health.
PubMed: 37533626
DOI: 10.2147/NSS.S414174 -
Sleep Science (Sao Paulo, Brazil) Jun 2023Insomnia is one of the major challenges in medical science nowadays as it leads to great socio-economic burden by impairing daytime function as well as the development...
Insomnia is one of the major challenges in medical science nowadays as it leads to great socio-economic burden by impairing daytime function as well as the development of exhaustion, depression, and memory disturbance in affected individuals. Several important classes of drugs have been tried, including the BZDs and non-BZD hypnotics. Available drugs to combat this disease have the limitations of abuse potential, tolerance, and cognitive impairment. In some instances, withdrawal symptoms have been observed upon the abrupt cessation of those drugs. The Orexin system has been very recently targeted as a therapeutic option to overcome those limitations. Treatment of insomnia with Daridorexant as a Dual Orexin Receptor Antagonist (DORA) has been evaluated in several preclinical and clinical studies. Available information obtained from those studies has shown a promising future for this drug in the management of insomnia. Beyond its effectiveness in insomnia, it has been successfully used in patients suffering from obstructive sleep apnoea, chronic obstructed airway disease (COAD), Alzheimer's disease (AD), hypertension, and cardiovascular disorders. Larger studies need to address the safety issues as well as obtain robust pharmacovigilance information to safeguard the risk-benefit aspect of this drug in insomniac adults.
PubMed: 37425970
DOI: 10.1055/s-0043-1770805 -
Sleep Apr 2024
Topics: Animals; Mice; Orexins; Influenza A Virus, H1N1 Subtype; Down-Regulation; Vaccination; Influenza Vaccines
PubMed: 38289980
DOI: 10.1093/sleep/zsae029 -
Tzu Chi Medical Journal 2024Sleep is an essential activity for the survival of mammals. Good sleep quality helps promote the performance of daily functions. In contrast, insufficient sleep reduces... (Review)
Review
Sleep is an essential activity for the survival of mammals. Good sleep quality helps promote the performance of daily functions. In contrast, insufficient sleep reduces the efficiency of daily activities, causes various chronic diseases like Alzheimer's disease, and increases the risk of having accidents. The GABAergic system is the primary inhibitory neurotransmitter system in the central nervous system. It transits the gamma-aminobutyric acid (GABA) neurotransmitter via GABA and GABA receptors to counterbalance excitatory neurotransmitters, such as glutamate, noradrenaline, serotonin, acetylcholine, orexin, and dopamine, which release and increase arousal activities during sleep. Several studies emphasized that dysfunction of the GABAergic system is related to insomnia, the most prevalent sleep-related disorder. The GABAergic system comprises the GABA neurotransmitter, GABA receptors, GABA synthesis, and degradation. Many studies have demonstrated that GABA levels correlate with sleep quality, suggesting that modulating the GABAergic system may be a promising therapeutic approach for insomnia. In this article, we highlight the significance of sleep, the classification and pathology of insomnia, and the impact of the GABAergic system changes on sleep. In addition, we also review the medications that target the GABAergic systems for insomnia, including benzodiazepines (BZDs), non-BZDs, barbiturates, GABA supplements, and Chinese herbal medicines.
PubMed: 38645778
DOI: 10.4103/tcmj.tcmj_243_23 -
Journal of Sleep Research Jul 2024Since the first description of narcolepsy at the end of the 19th Century, great progress has been made. The disease is nowadays distinguished as narcolepsy type 1 and... (Review)
Review
Since the first description of narcolepsy at the end of the 19th Century, great progress has been made. The disease is nowadays distinguished as narcolepsy type 1 and type 2. In the 1960s, the discovery of rapid eye movement sleep at sleep onset led to improved understanding of core sleep-related disease symptoms of the disease (excessive daytime sleepiness with early occurrence of rapid eye movement sleep, sleep-related hallucinations, sleep paralysis, rapid eye movement parasomnia), as possible dysregulation of rapid eye movement sleep, and cataplexy resembling an intrusion of rapid eye movement atonia during wake. The relevance of non-sleep-related symptoms, such as obesity, precocious puberty, psychiatric and cardiovascular morbidities, has subsequently been recognized. The diagnostic tools have been improved, but sleep-onset rapid eye movement periods on polysomnography and Multiple Sleep Latency Test remain key criteria. The pathogenic mechanisms of narcolepsy type 1 have been partly elucidated after the discovery of strong HLA class II association and orexin/hypocretin deficiency, a neurotransmitter that is involved in altered rapid eye movement sleep regulation. Conversely, the causes of narcolepsy type 2, where cataplexy and orexin deficiency are absent, remain unknown. Symptomatic medications to treat patients with narcolepsy have been developed, and management has been codified with guidelines, until the recent promising orexin-receptor agonists. The present review retraces the steps of the research on narcolepsy that linked the features of the disease with rapid eye movement sleep abnormality, and those that do not appear associated with rapid eye movement sleep.
PubMed: 38955433
DOI: 10.1111/jsr.14277 -
International Immunopharmacology Nov 2023Crosstalk between the central nervous system and immune system by the neuroendocrine and autonomic nervous systems is critical during the inflammatory response. Exposure...
Crosstalk between the central nervous system and immune system by the neuroendocrine and autonomic nervous systems is critical during the inflammatory response. Exposure to endotoxin alters the activity of hypothalamic homeostatic systems, resulting in changed transmitter release within the brain. This study investigated the effects and cellular molecular mechanisms of neurogenic and exogenous orexin-A (OXA) in LPS-induced acute lung injury (ALI). We found the production of OXA in the hypothalamus and lungs was both decreased following LPS infection. LPS-induced lung injury including the destruction of the structure, inflammatory cell infiltration, and pro-inflammatory cytokines generation was aggravated in mice in which orexin neurons were lesioned with the neurotoxin orexin-saporin (orexin-SAP). Administration of exogenous OXA greatly improved lung pathology and reduced inflammatory response. Orexin receptors were found in cultured mouse bone marrow-derived macrophages (BMDMs) and lung macrophages (LMs), adoptive transfer of OXA-treated macrophages showed alleviative lung injury compared to adoptive transfer of macrophages without OXA treatment. Mechanistically, it is the induction of autophagy via JNK activation that is responsible for OXA to suppress macrophage-derived pro-inflammatory cytokine production. These findings highlight the importance of neuro-immune crosstalk and indicate that OXA may be a potential therapeutic agent in the treatment of ALI.
Topics: Animals; Mice; Acute Lung Injury; Autophagy; Cytokines; Lipopolysaccharides; Lung; Macrophage Activation; Mice, Inbred C57BL; Orexins
PubMed: 37801969
DOI: 10.1016/j.intimp.2023.111018 -
Medicinal Research Reviews Sep 2023Orexin-A and orexin-B, also named hypocretin-1 and hypocretin-2, are two hypothalamic neuropeptides highly conserved across mammalian species. Their effects are mediated... (Review)
Review
Orexin-A and orexin-B, also named hypocretin-1 and hypocretin-2, are two hypothalamic neuropeptides highly conserved across mammalian species. Their effects are mediated by two distinct G protein-coupled receptors, namely orexin receptor type 1 (OX1-R) and type 2 (OX2-R), which share 64% amino acid identity. Given the wide expression of OX-Rs in different central nervous system and peripheral areas and the several pathophysiological functions in which they are involved, including sleep-wake cycle regulation (mainly mediated by OX2-R), emotion, panic-like behaviors, anxiety/stress, food intake, and energy homeostasis (mainly mediated by OX1-R), both subtypes represent targets of interest for many structure-activity relationship (SAR) campaigns carried out by pharmaceutical companies and academies. However, before 2017 the research was predominantly directed towards dual-orexin ligands, and limited chemotypes were investigated. Analytical characterizations, including resolved structures for both OX1-R and OX2-R in complex with agonists and antagonists, have improved the understanding of the molecular basis of receptor recognition and are assets for medicinal chemists in the design of subtype-selective ligands. This review is focused on the medicinal chemistry aspects of small molecules acting as dual or subtype selective OX1-R/OX2-R agonists and antagonists belonging to different chemotypes and developed in the last years, including radiolabeled OX-R ligands for molecular imaging. Moreover, the pharmacological effects of the most studied ligands in different neuropsychiatric diseases, such as sleep, mood, substance use, and eating disorders, as well as pain, have been discussed. Poly-pharmacology applications and multitarget ligands have also been considered.
Topics: Humans; Animals; Orexin Receptors; Ligands; Orexins; Neuropeptides; Receptors, G-Protein-Coupled; Central Nervous System; Receptors, Neuropeptide; Mammals
PubMed: 37036052
DOI: 10.1002/med.21959 -
Journal of Clinical Sleep Medicine :... Oct 2023We conducted a retrospective study to investigate the efficacy and safety of switching from other hypnotics, including benzodiazepines and Z-drugs, suvorexant,...
STUDY OBJECTIVES
We conducted a retrospective study to investigate the efficacy and safety of switching from other hypnotics, including benzodiazepines and Z-drugs, suvorexant, ramelteon, mirtazapine, trazodone, and antipsychotics, to lemborexant, a dual orexin receptor antagonist, for 3 months.
METHODS
Clinical data obtained from the medical records of 61 patients treated at the Horikoshi Psychosomatic Clinic between December 2020 and February 2022 were analyzed, including the Athens Insomnia Scale, Epworth Sleepiness Scale, and Perceived Deficits Questionnaire-5. The primary outcome was the mean change in Athens Insomnia Scale score after 3 months. Secondary outcomes were the mean changes in the Epworth Sleepiness Scale and Perceived Deficits Questionnaire-5 scores over 3 months. We also compared pre- and post-diazepam equivalents.
RESULTS
The mean Athens Insomnia Scale score decreased over 3 months after switching to lemborexant (1 mo: -2.98 ± 5.19, < .001; 2 mo: -3.20 ± 5.64, < .001; 3 mo: -3.38 ± 5.61, < .001). Mean Epworth Sleepiness Scale score did not change from baseline to 1 month (-0.49 ± 3.41, = 0.27), 2 months (0.082 ± 4.62, = .89), or 3 months (-0.64 ± 4.80, = .30). Mean Perceived Deficits Questionnaire-5 score did improve from baseline to 1 month (-1.17 ± 2.47, = .004), 2 months (-1.05 ± 2.97, = .029), and 3 months (-1.24 ± 3.06, = .013). There was also a reduction in the total diazepam equivalent (baseline vs 3 mo: 14.0 ± 20.2 vs 11.3 ± 20.6, < .001).
CONCLUSIONS
Our study showed that, by switching to lemborexant from other hypnotics, the risks associated with benzodiazepines and Z-drugs may be reduced.
CITATION
Horikoshi S, Miura I, Suzuki Y, et al. Switching to lemborexant for the management of insomnia in mental disorders: the SLIM study. . 2023;19(10):1753-1758.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Retrospective Studies; Sleepiness; Hypnotics and Sedatives; Orexin Receptor Antagonists; Benzodiazepines; Diazepam
PubMed: 37243798
DOI: 10.5664/jcsm.10668