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Biomedicine & Pharmacotherapy =... Nov 2021Modified Suanzaoren Decoction (MSZRD) is obtained by improving Suanzaoren Decoction (SZRT), a traditional Chinese herbal prescription that has been used to treat...
AIM
Modified Suanzaoren Decoction (MSZRD) is obtained by improving Suanzaoren Decoction (SZRT), a traditional Chinese herbal prescription that has been used to treat insomnia for more than thousands of years. Our previous study showed that MSZRD can improve the gastrointestinal discomfort related insomnia by regulating Orexin-A. This study is the first study to evaluate the effects and possible mechanisms of MSZRD in mice with insomnia caused by p-chlorophenylalanine (PCPA) combined with multifactor random stimulation.
METHODS
After 14 days of multifactor stimulation to ICR mice, a PCPA suspension (30 mg/mL) was injected intraperitoneally for two consecutive days to establish an insomnia model. Three different doses of MSZRD (3.6, 7.2, and 14.4 g/kg/day) were given to ICR mice for 24 days. The food intake and back temperature were measured, and behavioral tests and pentobarbital sodium-induced sleep tests were conducted. The levels of Orexin-A, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and adrenocortical hormones (CORT) in the serum and 5-hydroxytryptamine (5-HT), dopamine (DA), and norepinephrine (NE) in hypothalamus were measured using enzyme-linked immunosorbent assay (ELISA) kits. The levels of γ-aminobutyric acid (GABA) and glutamic acid (Glu) were measured by high-performance liquid chromatography (HPLC). The expression of 5HT1A receptor (5-HTRIA) and orexin receptor 2 antibody (OX2R) was measured by Western blot (WB) and immunohistochemical staining (ICH). Hematoxylin and eosin (H&E) staining and Nissl staining were used to assess the histological changes in hypothalamus tissue.
RESULTS
Of note, MSZRD can shorten the sleep latency of insomnia mice (P < 0.05, 0.01), prolonged the sleep duration of mice (P < 0.05, 0.01), and improve the circadian rhythm disorder relative to placebo-treated animals. Furthermore, MSZRD effectively increased the content of 5-HT and 5-HTR1A protein in the hypothalamus of insomnia mice (P < 0.05, 0.01), while downregulated the content of DA and NE (P < 0.05, 0.01). Importantly, serum GABA concentration was increased by treatment with MSZRD (P < 0.05), as reflected by a decreased Glu/GABA ratio (P < 0.05). Moreover, MSZRD decreased the levels of CORT, ACTH, and CRH related hormones in HPA axis (P < 0.05, 0.01). At the same time, MSZRD significantly downregulated the serum Orexin-A content in insomnia mice (P < 0.05), as well as hypothalamic OX2R expression (P < 0.05). In addition, MSZRD also improved the histopathological changes in hypothalamus in insomnia mice.
CONCLUSION
MSZRD has sleep-improvement effect in mice model of insomnia. The mechanism may be that regulating the expression of Orexin-A affects the homeostasis of HPA axis and the release of related neurotransmitters in mice with insomnia.
Topics: Adrenal Glands; Animals; Behavior, Animal; Disease Models, Animal; Drugs, Chinese Herbal; Hypothalamo-Hypophyseal System; Male; Mice, Inbred ICR; Neurotransmitter Agents; Orexin Receptors; Orexins; Signal Transduction; Sleep; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Mice
PubMed: 34509822
DOI: 10.1016/j.biopha.2021.112141 -
Frontiers of Neurology and Neuroscience 2021
Topics: Humans; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Sleep; Sleep Initiation and Maintenance Disorders
PubMed: 34052818
DOI: 10.1159/000514968 -
Frontiers in Aging Neuroscience 2021Orexinergic system consisting of orexins and orexin receptors plays an essential role in regulating sleep-wake states, whereas sleep disruption is a common symptom of a... (Review)
Review
Orexinergic system consisting of orexins and orexin receptors plays an essential role in regulating sleep-wake states, whereas sleep disruption is a common symptom of a number of neurodegenerative diseases. Emerging evidence reveals that the orexinergic system is disturbed in various neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS), whereas the dysregulation of orexins and/or orexin receptors contributes to the pathogenesis of these diseases. In this review, we summarized advanced knowledge of the orexinergic system and its role in sleep, and reviewed the dysregulation of the orexinergic system and its role in the pathogenesis of AD, PD, HD, and MS. Moreover, the therapeutic potential of targeting the orexinergic system for the treatment of these diseases was discussed.
PubMed: 34483883
DOI: 10.3389/fnagi.2021.713201 -
WIREs Mechanisms of Disease Jan 2022The lateral hypothalamus is critical for the control of ingestive behavior and spontaneous physical activity (SPA), as lesion or stimulation of this region alters these... (Review)
Review
The lateral hypothalamus is critical for the control of ingestive behavior and spontaneous physical activity (SPA), as lesion or stimulation of this region alters these behaviors. Evidence points to lateral hypothalamic orexin neurons as modulators of feeding and SPA. These neurons affect a broad range of systems, and project to multiple brain regions such as the dorsal raphe nucleus, which contains serotoninergic neurons (DRN) important to energy homeostasis. Physical activity is comprised of intentional exercise and SPA. These are opposite ends of a continuum of physical activity intensity and structure. Non-goal-oriented behaviors, such as fidgeting, standing, and ambulating, constitute SPA in humans, and reflect a propensity for activity separate from intentional activity, such as high-intensity voluntary exercise. In animals, SPA is activity not influenced by rewards such as food or a running wheel. Spontaneous physical activity in humans and animals burns calories and could theoretically be manipulated pharmacologically to expend calories and protect against obesity. The DRN neurons receive orexin inputs, and project heavily onto cortical and subcortical areas involved in movement, feeding and energy expenditure (EE). This review discusses the function of hypothalamic orexin in energy-homeostasis, the interaction with DRN serotonin neurons, and the role of this orexin-serotonin axis in regulating food intake, SPA, and EE. In addition, we discuss possible brain areas involved in orexin-serotonin cross-talk; the role of serotonin receptors, transporters and uptake-inhibitors in the pathogenesis and treatment of obesity; animal models of obesity with impaired serotonin-function; single-nucleotide polymorphisms in the serotonin system and obesity; and future directions in the orexin-serotonin field. This article is categorized under: Metabolic Diseases > Molecular and Cellular Physiology.
Topics: Animals; Energy Metabolism; Humans; Hypothalamic Area, Lateral; Hypothalamus; Orexins; Serotonin
PubMed: 35023323
DOI: 10.1002/wsbm.1536 -
Trends in Neurosciences Nov 2021Although originally implicated in appetite and sleep/wakefulness, the hypothalamic orexin (hypocretin) system has now been demonstrably linked with motivated behavior....
Although originally implicated in appetite and sleep/wakefulness, the hypothalamic orexin (hypocretin) system has now been demonstrably linked with motivated behavior. This highly plastic system responds to reward-associated environmental stimuli and becomes pathologically overactive in addicted states. Here, we provide a brief overview of the roles of the orexin system in reward-seeking and addiction, as well as potential therapeutic opportunities for substance use disorders based on normalizing orexin function.
Topics: Humans; Hypothalamus; Intracellular Signaling Peptides and Proteins; Neuropeptides; Orexins; Wakefulness
PubMed: 34642086
DOI: 10.1016/j.tins.2021.09.002 -
Frontiers in Cellular Neuroscience 2022The orexin system comprises two G protein-coupled receptors, OX and OX receptors (OXR and OXR, respectively), along with two endogenous agonists cleaved from a common... (Review)
Review
The orexin system comprises two G protein-coupled receptors, OX and OX receptors (OXR and OXR, respectively), along with two endogenous agonists cleaved from a common precursor (prepro-orexin), orexin-A (OX-A) and orexin-B (OX-B). For the receptors, a complex array of signaling behaviors has been reported. In particular, it becomes obvious that orexin receptor coupling is very diverse and can be tissue-, cell- and context-dependent. Here, the early signal transduction interactions of the orexin receptors will be discussed in depth, with particular emphasis on the direct G protein interactions of each receptor. In doing so, it is evident that ligands, additional receptor-protein interactions and cellular environment all play important roles in the G protein coupling profiles of the orexin receptors. This has potential implications for our understanding of the orexin system's function in both central and peripheral environments, as well as the development of novel agonists, antagonists and possibly allosteric modulators targeting the orexin system.
PubMed: 35496914
DOI: 10.3389/fncel.2022.812359 -
International Journal of Molecular... Apr 2022Sleep and wakefulness are basic behavioral states that require coordination between several brain regions, and they involve multiple neurochemical systems, including... (Review)
Review
Sleep and wakefulness are basic behavioral states that require coordination between several brain regions, and they involve multiple neurochemical systems, including neuropeptides. Neuropeptides are a group of peptides produced by neurons and neuroendocrine cells of the central nervous system. Like traditional neurotransmitters, neuropeptides can bind to specific surface receptors and subsequently regulate neuronal activities. For example, orexin is a crucial component for the maintenance of wakefulness and the suppression of rapid eye movement (REM) sleep. In addition to orexin, melanin-concentrating hormone, and galanin may promote REM sleep. These results suggest that neuropeptides play an important role in sleep-wake regulation. These neuropeptides can be divided into three categories according to their effects on sleep-wake behaviors in rodents and humans. (i) Galanin, melanin-concentrating hormone, and vasoactive intestinal polypeptide are sleep-promoting peptides. It is also noticeable that vasoactive intestinal polypeptide particularly increases REM sleep. (ii) Orexin and neuropeptide S have been shown to induce wakefulness. (iii) Neuropeptide Y and substance P may have a bidirectional function as they can produce both arousal and sleep-inducing effects. This review will introduce the distribution of various neuropeptides in the brain and summarize the roles of different neuropeptides in sleep-wake regulation. We aim to lay the foundation for future studies to uncover the mechanisms that underlie the initiation, maintenance, and end of sleep-wake states.
Topics: Galanin; Intracellular Signaling Peptides and Proteins; Neuropeptides; Orexins; Sleep; Vasoactive Intestinal Peptide
PubMed: 35562990
DOI: 10.3390/ijms23094599 -
Frontiers of Neurology and Neuroscience 2021Advances in translational research provide key opportunities to explore the physiological and pathological effects of sleep in different neurodegenerative diseases.... (Review)
Review
Advances in translational research provide key opportunities to explore the physiological and pathological effects of sleep in different neurodegenerative diseases. Recent findings suggest that sleep-wakefulness dysfunctions may predispose to neurodegenerative disorders such as Alzheimer's disease (AD), and vice versa. New theories on the link between sleep and β-amyloid and tau secretion, accumulation and clearance, and its interaction with hypocretins/orexins (key neuropeptides regulating wakefulness) suggest mechanistic ways to better understand the impact of sleep alterations in the pathogenesis of AD. Further studies should validate whether changes in circadian rhythm and sleep-wakefulness patterns could be used for early AD diagnosis and as prognostic markers for cognitive decline. Longitudinal studies are needed, not only to validate these biomarker interactions and to determine the cause-effect relationship and the role of sleep-wakefulness behavior in the regulation of amyloid plaque and neurofibrillary tangle formation, but also to identify the best sleep therapies and related preventive strategies for AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Glymphatic System; Humans; Narcolepsy; Orexins; Sleep Wake Disorders; tau Proteins
PubMed: 34052817
DOI: 10.1159/000514967 -
Journal of Internal Medicine May 2022The hypocretins (Hcrts), also known as orexins, are two neuropeptides produced exclusively in the lateral hypothalamus. They act on two specific receptors that are... (Review)
Review
The hypocretins (Hcrts), also known as orexins, are two neuropeptides produced exclusively in the lateral hypothalamus. They act on two specific receptors that are widely distributed across the brain and involved in a myriad of neurophysiological functions that include sleep, arousal, feeding, reward, fear, anxiety and cognition. Hcrt cell loss in humans leads to narcolepsy with cataplexy (narcolepsy type 1), a disorder characterized by intrusions of sleep into wakefulness, demonstrating that the Hcrt system is nonredundant and essential for sleep/wake stability. The causal link between Hcrts and arousal/wakefulness stabilisation has led to the development of a new class of drugs, Hcrt receptor antagonists to treat insomnia, based on the assumption that blocking orexin-induced arousal will facilitate sleep. This has been clinically validated: currently, two Hcrt receptor antagonists are approved to treat insomnia (suvorexant and lemborexant), with a New Drug Application recently submitted to the US Food and Drug Administration for a third drug (daridorexant). Other therapeutic applications under investigation include reduction of cravings in substance-use disorders and prevention of neurodegenerative disorders such as Alzheimer's disease, given the apparent bidirectional relationship between poor sleep and worsening of the disease. Circuit neuroscience findings suggest that the Hcrt system is a hub that integrates diverse inputs modulating arousal (e.g., circadian rhythms, metabolic status, positive and negative emotions) and conveys this information to multiple output regions. This neuronal architecture explains the wealth of physiological functions associated with Hcrts and highlights the potential of the Hcrt system as a therapeutic target for a number of disorders. We discuss present and future possible applications of drugs targeting the Hcrt system for the treatment of circuit-related neuropsychiatric and neurodegenerative conditions.
Topics: Humans; Intracellular Signaling Peptides and Proteins; Narcolepsy; Neuropeptides; Orexins; Sleep Initiation and Maintenance Disorders
PubMed: 35043499
DOI: 10.1111/joim.13406 -
Cell Reports Oct 2022Non-alcoholic steatohepatitis (NASH) occasionally occurs under obesity; however, factors modulating the natural history of fatty liver disease remain unknown. Since...
Non-alcoholic steatohepatitis (NASH) occasionally occurs under obesity; however, factors modulating the natural history of fatty liver disease remain unknown. Since hypothalamic orexin that regulates physical activity and autonomic balance prevents obesity, we investigate its role in NASH development. Male orexin-deficient mice fed a high-fat diet (HFD) show severe obesity and progression of NASH with fibrosis in the liver. Hepatic fibrosis also develops in ovariectomized orexin-deficient females fed an HFD but not ovariectomized wild-type controls. Moreover, long-term HFD feeding causes hepatocellular carcinoma (HCC) in orexin-deficient mice. Intracerebroventricular injection of orexin A or pharmacogenetic activation of orexin neurons acutely activates hepatic mTOR-sXbp1 pathway to prevent endoplasmic reticulum (ER) stress, a NASH-causing factor. Daily supplementation of orexin A attenuates hepatic ER stress and inflammation in orexin-deficient mice fed an HFD, and autonomic ganglionic blocker suppresses the orexin actions. These results suggest that hypothalamic orexin is an essential factor for preventing NASH and associated HCC under obesity.
Topics: Female; Mice; Male; Animals; Non-alcoholic Fatty Liver Disease; Carcinoma, Hepatocellular; Orexins; Liver Neoplasms; Obesity; TOR Serine-Threonine Kinases
PubMed: 36261021
DOI: 10.1016/j.celrep.2022.111497