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دورية أكاديمية

New Developments in Insomnia Medications of Relevance to Mental Health Disorders

المصدر: Psychiatric Clinics of North America. 38(4)

الوصف: Many insomnia medications with high specificity have become available recently. They provide a window into the clinical effects of modulating specific brain systems and establish a new guiding principal for conceptualizing insomnia medications: "mechanism matters." A new paradigm for insomnia therapy in which specific drugs are selected to target the specific type of sleep difficulty for each patient includes administering specific treatments for patients with insomnia comorbid with particular psychiatric disorders. This article reviews insomnia medications and discusses the implications for optimizing the treatment of insomnia occurring comorbid with psychiatric conditions.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/3466f1n5Test

View record in eScholarship

2

Dual orexin receptor antagonists for insomnia in youth with neurodevelopmental disorders: a case series and review

المؤلفون: Aaron D Besterman, Shafali S Jeste

المصدر: European child & adolescent psychiatry, vol 32, iss 3

مصطلحات موضوعية: Bioinformatics, Doras, Sleep Initiation and Maintenance Disorders, Developmental and Educational Psychology, Psychology, Child, Pediatric, education.field_of_study, Dual orexin receptor antagonists, biology, Neurodevelopmental disorders, General Medicine, Sleep disorders, Psychiatry and Mental health, Mental Health, 5.1 Pharmaceuticals, 6.1 Pharmaceuticals, Orexin Receptor Antagonists, Sleep onset, Development of treatments and therapeutic interventions, Sleep Research, medicine.drug, Insomnia, Combination therapy, Adolescent, Intellectual and Developmental Disabilities (IDD), Population, Clinical Trials and Supportive Activities, Clinical Sciences, Developmental & Child Psychology, Clinical Research, mental disorders, Behavioral and Social Science, medicine, Humans, education, business.industry, Research, Suvorexant, Neurosciences, Trazodone, Evaluation of treatments and therapeutic interventions, biology.organism_classification, medicine.disease, Comorbidity, Orexin, Brain Disorders, Pediatrics, Perinatology and Child Health, business, Sleep

الوصف: Insomnia is a common, impairing, and difficult-to-treat comorbidity in children with neurodevelopmental disorders (NDDs). Behavioral interventions can be challenging because of developmental and behavioral features that interfere with treatment. Medication management also can be difficult due to a high burden of side effects, a high rate of paradoxical responses, and frequent treatment resistance. Therefore, new treatment options for insomnia in children with NDDs are needed. Dual orexin receptor antagonists (DORAs) are a relatively new class of pharmacotherapeutics that induce sleep by inhibiting the orexin signaling pathway. To date, there is little safety or efficacy data on the use of DORAs in children with NDDs. We present four patients with NDDs and insomnia that we treated with the DORA, suvorexant. We found that patients had a wide range of responses, with one patient displaying a robust improvement in sleep onset and maintenance, while another had significant improvement in insomnia symptoms on combination therapy with trazodone. Our final two patients had mild or no benefit from suvorexant therapy. Further research is necessary to establish the safety and efficacy of DORAs in this population and to identify predictive factors, such as specific neurogenetic diagnoses or clinical features, of a positive treatment response.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3c9c31b67449ade8c16636c26473ce2cTest
https://escholarship.org/uc/item/8769g7sfTest

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Increase in the Level of Orexin Receptor 1 (OX1R) mRNA in the Brain Structures of Rats Prone to Impulsivity in Behavior

المؤلفون: E.A. Sekste, E. R. Bychkov, K E Gramota, M. I. Airapetov, Andrei A. Lebedev, Petr Dmitriyevich Shabanov, I Yu Thyssen

المصدر: Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry. 16:38-44

الوصف: Orexin and its receptors are involved in the mechanisms of pathological craving for alcohol and psychoactive drugs. The orexin system is also involved in the mechanisms of non-chemical forms of addiction: binge eating and gambling. The aim of this work was to study the level of orexin receptor mRNA in the hypothalamus, hippocampus, and prefrontal cortex of rats prone to impulsivity in behavior in a model for studying the elements of gambling addiction (a variant of the Iowa Gambling Task test). Brain structures were isolated on the 22nd day of the experiment. The expression of the OX1R gene was higher in the hypothalamus by 122% and in the hippocampus by 149% in rats that preferred to receive a high reward, but with a low probability as compared with a group of animals that preferred a low level of reinforcement, but with a 100% probability. In the prefrontal cortex, on the contrary, no significant changes were observed in the level of OX1R mRNA. The level of OX2R mRNA insignificantly changed in the hypothalamus, hippocampus, and prefrontal cortex of rats prone to impulsivity in behavior. The data indicate involvement of OX1R in the hypothalamus and hippocampus in mechanisms mediating impulsive behavior and the choice of the significance of positive reinforcement in terms of its varying strength and probability.Oreksin i ego retseptory vovlecheny v mekhanizmy patologicheskogo vlecheniia k alkogoliu i psikhoaktivnym veshchestvam. Sistema oreksina takzhe uchastvuet v mekhanizmakh nekhimicheskikh form zavisimosti — pishchevoĭ i igrovoĭ. Tsel'iu nastoiashchego issledovaniia bylo izuchenie urovnia mRNK retseptorov oreksina v gipotalamuse, gippokampe i prefrontal'noĭ kore mozga krys, sklonnykh k povyshennoĭ impul'sivnosti v povedenii, v modeli dlia izucheniia élementov igrovoĭ zavisimosti. Dlia étogo ispol'zovali variant metoda Iowa Gambling Task v trekhluchevom labirinte. Struktury mozga vydeliali na 22 den' éksperimenta. Ékspressiia gena oreksinovogo retseptora pervogo tipa (OX1R) byla vyshe v gipotalamuse na 122% i gippokampe — na 149% u krys, predpochitavshikh poluchat' vysokoe voznagrazhdenie, no s nizkoĭ doleĭ veroiatnosti po sravneniiu s gruppoĭ zhivotnykh, predpochitavshikh nizkiĭ uroven' podkrepleniia, no so 100% stepen'iu veroiatnosti. V prefrontal'noĭ kore, naprotiv, ne nabliudalos' dostovernykh izmeneniĭ v urovne mRNK OX1R. Pri issledovanii urovnia mRNK oreksinovogo retseptora vtorogo tipa (OX2R) dostovernykh izmeneniĭ u krys, sklonnykh k povyshennoĭ impul'sivnosti v povedenii, v gipotalamuse, gippokampe i prefrontal'noĭ kore otmecheno ne bylo. Dannye ukazyvaiut na vovlechennost' OX1R v gipotalamuse i gippokampe v mekhanizmy, oposreduiushchie impul'sivnoe povedenie i vybor zhivotnymi znachimosti polozhitel'nogo podkrepleniia v usloviiakh ego razlichnoĭ sily i veroiatnosti.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c85ef0dd2d549194823c4c71a7529c28Test
https://doi.org/10.1134/s1990750822010085Test

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Orexins: A promising target to digestive cancers, inflammation, obesity and metabolism dysfunctions

المؤلفون: Alain Couvineau, Anne Blais, Thierry Voisin, Valérie Gratio, Pascal Nicole

المصدر: World Journal of Gastroenterology

الوصف: Hypothalamic neuropeptides named hypocretin/orexins which were identified in 1998 regulate critical functions such as wakefulness in the central nervous system. These past 20 years had revealed that orexins/receptors system was also present in the peripheral nervous system where they participated to the regulation of multiple functions including blood pressure regulation, intestinal motility, hormone secretion, lipolyze and reproduction functions. Associated to these peripheral functions, it was found that orexins and their receptors were involved in various diseases such as acute/chronic inflammation, metabolic syndrome and cancers. The present review suggests that orexins or the orexin neural circuitry represent potential therapeutic targets for the treatment of multiple pathologies related to inflammation including intestinal bowel disease, multiple sclerosis and septic shock, obesity and digestive cancers.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2582e4066ba692318d91789585f9c02bTest
https://doi.org/10.3748/wjg.v27.i44.7582Test

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Orexin (hypocretin) and addiction

المؤلفون: Michelle M. Bilotti, Jacqueline B. Mehr, Morgan H. James

المصدر: Trends Neurosci

الوصف: 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.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::785af0e74164c94355d0e537e469781eTest
https://doi.org/10.1016/j.tins.2021.09.002Test

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Pharmacokinetic and pharmacodynamic interactions between daridorexant, a dual orexin receptor antagonist, and citalopram in healthy subjects

المؤلفون: Rüdiger Kornberger, Benjamin Berger, Jasper Dingemanse

المصدر: European Neuropsychopharmacology. 51:90-104

الوصف: Daridorexant (ACT-541468) is a new dual orexin receptor antagonist being evaluated for the treatment of insomnia, which is a common comorbidity of depression and anxiety. Therefore, daridorexant is likely to be administered concomitantly with agents (e.g., citalopram) used to treat these disorders. In this single-centre, single-blind, randomized, placebo-controlled, sequential design Phase 1 study with the inclusion of two double-blind crossover parts, the pharmacokinetic (PK; blood sampling at regular intervals) and pharmacodynamic (PD; battery of objective and subjective PD tests performed at regular intervals) interactions between daridorexant (50 mg) and citalopram (20 mg, single dose and at steady state) as well as the safety/tolerability in healthy subjects were investigated. There were no relevant effects of citalopram (single dose/steady state) on daridorexant exposure and vice versa. PD variables measured after morning administration of daridorexant alone showed effects consistent with a sleep-promoting compound. Only co-administration of daridorexant with citalopram at steady state led to relevant changes in objective (unstable tracking) and subjective (visual analogue scale alertness and Karolinska Sleepiness Scale) PD endpoints compared to daridorexant alone. No serious or severe adverse events were reported, while no clinically relevant treatment-emergent effects on ECG parameters, clinical laboratory, or vital signs were observed. In conclusion, the co-administration of daridorexant and citalopram lead to only minor changes in PK parameters, while performance of PD assessments following co-administration were mainly driven by the expected central nervous system effects of daridorexant. Doses up to 50 mg daridorexant can be safely co-administered with citalopram.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fd9f9245670717330f545cd9619d54e6Test
https://doi.org/10.1016/j.euroneuro.2021.05.005Test

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Orexin-A and endocannabinoids are involved in obesity-associated alteration of hippocampal neurogenesis, plasticity, and episodic memory in mice

المؤلفون: Fabio Arturo Iannotti, Roberta Imperatore, Luigia Cristino, Serena Boccella, Raffaele Capasso, Fabiana Piscitelli, Monica Iannotta, Maria De Risi, Elvira De Leonibus, Vincenzo Di Marzo, Paolo de Girolamo, Nicola Forte, Sabatino Maione, Lea Tunisi, Alba Clara Fernández-Rilo

المساهمون: Forte, N., Boccella, S., Tunisi, L., Fernandez-Rilo, A. C., Imperatore, R., Iannotti, F. A., De Risi, M., Iannotta, M., Piscitelli, F., Capasso, R., De Girolamo, P., De Leonibus, E., Maione, S., Di Marzo, V., Cristino, L.

المصدر: Nature Communications, Vol 12, Iss 1, Pp 1-20 (2021)
Nature communications 12 (2021). doi:10.1038/s41467-021-26388-4
info:cnr-pdr/source/autori:Forte N.; Boccella S.; Tunisi L.; Fernandez-Rilo A.C.; Imperatore R.; Iannotti F.A.; De Risi M.; Iannotta M.; Piscitelli F.; Capasso R.; De Girolamo P.; De Leonibus E.; Maione S.; Di Marzo V.; Cristino L./titolo:Orexin-A and endocannabinoids are involved in obesity-associated alteration of hippocampal neurogenesis, plasticity, and episodic memory in mice/doi:10.1038%2Fs41467-021-26388-4/rivista:Nature communications/anno:2021/pagina_da:/pagina_a:/intervallo_pagine:/volume:12
Nature Communications

مصطلحات موضوعية: Male, Cannabinoid receptor, Neurogenesis, Memory, Episodic, Science, General Physics and Astronomy, Hippocampus, Mice, Obese, Hippocampal formation, Biology, General Biochemistry, Genetics and Molecular Biology, Article, neuroscience, Orexin-A, Mice, Endocrinology, Hippocampu, Receptor, Cannabinoid, CB1, Orexin Receptors, mental disorders, Animals, Humans, metabolic disorders, Obesity, endocannabinoids, Episodic memory, Endocannabinoid, Neurons, Orexins, Multidisciplinary, Neuronal Plasticity, Animal, Dentate gyrus, digestive, oral, and skin physiology, General Chemistry, Neuron, Orexin Receptor, Endocannabinoid system, nervous system, Orexin, Female, Neurogenesi, Neuroscience, Human, Signal Transduction

الوصف: The mammalian brain stores and distinguishes among episodic memories, i.e. memories formed during the personal experience, through a mechanism of pattern separation computed in the hippocampal dentate gyrus. Decision-making for food-related behaviors, such as the choice and intake of food, might be affected in obese subjects by alterations in the retrieval of episodic memories. Adult neurogenesis in the dentate gyrus regulates the pattern separation. Several molecular factors affect adult neurogenesis and exert a critical role in the development and plasticity of newborn neurons. Orexin-A/hypocretin-1 and downstream endocannabinoid 2-arachidonoylglycerol signaling are altered in obese mice. Here, we show that excessive orexin-A/2-arachidonoylglycerol/cannabinoid receptor type-1 signaling leads to the dysfunction of adult hippocampal neurogenesis and the subsequent inhibition of plasticity and impairment of pattern separation. By inhibiting orexin-A action at orexin-1 receptors we rescued both plasticity and pattern separation impairment in obese mice, thus providing a molecular and functional mechanism to explain alterations in episodic memory in obesity.
The authors show that adult hippocampal neurogenesis is altered in the dentate gyrus of obese mice with subsequent inhibition of long-term potentiation and impairment of pattern separation. Inhibition of orexin-A action at orexin-1 receptors rescued both impairments in obese mice.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::93a24d23cc7a5a38d30f7916ae7e129bTest
https://doaj.org/article/cc36a8296dcb45b6b3ee6a982be5d94eTest

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Hypothalamic kinin B1 receptor mediates orexin system hyperactivity in neurogenic hypertension

المؤلفون: Jeffrey B. Eells, Korin E. Leffler, Srinivas Sriramula, Rohan Umesh Parekh, Acacia White, Abdel A. Abdel-Rahman, Vinicia C. Biancardi

المصدر: Scientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
Scientific Reports

الوصف: Brain orexin system hyperactivity contributes to neurogenic hypertension. We previously reported upregulated neuronal kinin B1 receptor (B1R) expression in hypertension. However, the role of central B1R activation on the orexin system in neurogenic hypertension has not been examined. We hypothesized that kinin B1R contributes to hypertension via upregulation of brain orexin-arginine vasopressin signaling. We utilized deoxycorticosterone acetate (DOCA)-salt hypertension model in wild-type (WT) and B1R knockout (B1RKO) mice. In WT mice, DOCA-salt-treatment increased gene and protein expression of orexin A, orexin receptor 1, and orexin receptor 2 in the hypothalamic paraventricular nucleus and these effects were attenuated in B1RKO mice. Furthermore, DOCA-salt- treatment increased plasma arginine vasopressin levels in WT mice, but not in B1RKO mice. Cultured primary hypothalamic neurons expressed orexin A and orexin receptor 1. B1R specific agonist (LDABK) stimulation of primary neurons increased B1R protein expression, which was abrogated by B1R selective antagonist R715 but not by the dual orexin receptor antagonist, ACT 462206, suggesting that B1R is upstream of the orexin system. These data provide novel evidence that B1R blockade blunts orexin hyperactivity and constitutes a potential therapeutic target for the treatment of salt-sensitive hypertension.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::17084c6b6313f64ece099c8f9d73e9f4Test
https://doaj.org/article/0f24aa450bba48339c5666834dc98b1bTest

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Orexin receptors: Targets and applications

المؤلفون: Mirunalini Ravichandran, Subhiksha Subramanian

المصدر: Fundamental & Clinical Pharmacology. 36:72-80

الوصف: Over the years, elucidating targets from the neural circuits that can be used to treat disorders pertaining to the nervous system and extending their scope to other systems has always proved interesting to researchers. The role of various peptides and neurotransmitters have been elucidated and are being developed as therapeutic targets. Out of these, orexins are neuropeptides produced in the hypothalamus that stimulate a specific type of G-Protein coupled receptors (GPCR) called orexin receptors and bring about various physiological and pathological roles. Orexin receptors are of interest not only because of their wide applications such as insomnia, obesity, inflammatory disorders, etc. but also because of their contribution to promising aspects of drug discovery such as optogenetics and their tremendous growth from the stage of being orphans to orexins. This review will discuss in detail the structure of orexin receptors, their physiological role and various applications in disease states adding a note on agonists and antagonists and finally summarizing the recent drug approvals in the field.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3940a00d6a047f0695b9a1c4ed9a95caTest
https://doi.org/10.1111/fcp.12723Test

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Orexin receptors 1 and 2 in serotonergic neurons differentially regulate peripheral glucose metabolism in obesity

المؤلفون: Anna Sieben, F. Thomas Wunderlich, Dong Kong, Xing Xiao, Peter Kloppenburg, André Kleinridders, Thomas E. Scammell, Gagik Yeghiazaryan, Simon Hess, A. Christine Hausen, Paul Klemm, Bradford B. Lowell, Jens C. Brüning, Kamal Rahmouni, Donald A. Morgan

المصدر: Nature Communications, Vol 12, Iss 1, Pp 1-20 (2021)
Nature Communications

مصطلحات موضوعية: Blood Glucose, medicine.medical_specialty, Median raphe nucleus, Lateral hypothalamus, Science, General Physics and Astronomy, Diet, High-Fat, Serotonergic, Neural circuits, General Biochemistry, Genetics and Molecular Biology, Article, Mice, Nerve Fibers, Dorsal raphe nucleus, Adipose Tissue, Brown, Orexin Receptors, Internal medicine, mental disorders, medicine, Animals, Homeostasis, Glucose homeostasis, Humans, Obesity, Serotonin Plasma Membrane Transport Proteins, Orexins, Multidisciplinary, Raphe, Chemistry, Diabetes, digestive, oral, and skin physiology, General Chemistry, Orexin receptor, Orexin, Glucose, Endocrinology, Liver, nervous system, Hypothalamic Area, Lateral, Raphe Nuclei, Insulin Resistance, Fat metabolism, hormones, hormone substitutes, and hormone antagonists, psychological phenomena and processes, Serotonergic Neurons, Signal Transduction

الوصف: The wake-active orexin system plays a central role in the dynamic regulation of glucose homeostasis. Here we show orexin receptor type 1 and 2 are predominantly expressed in dorsal raphe nucleus-dorsal and -ventral, respectively. Serotonergic neurons in ventral median raphe nucleus and raphe pallidus selectively express orexin receptor type 1. Inactivation of orexin receptor type 1 in serotonin transporter-expressing cells of mice reduced insulin sensitivity in diet-induced obesity, mainly by decreasing glucose utilization in brown adipose tissue and skeletal muscle. Selective inactivation of orexin receptor type 2 improved glucose tolerance and insulin sensitivity in obese mice, mainly through a decrease in hepatic gluconeogenesis. Optogenetic activation of orexin neurons in lateral hypothalamus or orexinergic fibers innervating raphe pallidus impaired or improved glucose tolerance, respectively. Collectively, the present study assigns orexin signaling in serotonergic neurons critical, yet differential orexin receptor type 1- and 2-dependent functions in the regulation of systemic glucose homeostasis.
The wake-active orexin system plays a central role in the dynamic regulation of glucose homeostasis. Here the authors report that inactivation of the orexin receptor type 1 or 2 in serotonergic neurons differentially regulate systemic glucose homeostasis in the context of diet induced obesity.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::39018121014cacedc640165017f559f8Test
https://doaj.org/article/526ad1da292b4e9a9a66f3e0635380a6Test

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