نتائج البحث

1

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

2

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

3

Evidence‐based insomnia treatment strategy using novel orexin antagonists: A review

المؤلفون: Margaret Moline, Makoto Okuya, Takehiro Taninaga, Nakao Iwata, Kenzo Muramoto, Michinori Koebis, Ikuo Nomura, Maika Nishida, Taro Kishi, Naoki Kubota, Kenji Sakuma

المصدر: Neuropsychopharmacology Reports

الوصف: Most conventional insomnia medications are gamma‐aminobutylic acid receptor agonists. However, physical dependence is a concern and one of the major limiting factors for long‐term treatment. The dual orexin receptor antagonists, suvorexant and lemborexant, were recently approved for treating chronic insomnia, giving a novel pharmacotherapeutic option. Because there are no comparative studies on these drugs, a network meta‐analysis was conducted, which is suitable for comparing interventions. According to this analysis, 5‐ and 10‐mg lemborexant were superior to 20‐mg suvorexant because of the greater improvement in initiating sleep after 1‐week administration. Furthermore, 5‐mg lemborexant (not 10 mg) and suvorexant were similarly well tolerated, without requiring discontinuation due to adverse events. We also overviewed the pharmacological and pharmacokinetic properties of lemborexant and suvorexant that may support these clinical outcomes. When compared to suvorexant, lemborexant quickly binds to the orexin receptors. The time to reach the maximum concentration after multiple administrations is shorter for lemborexant than for suvorexant. Considering these results, we recommend 5‐mg lemborexant as an initial treatment for insomnia, followed by 10‐mg lemborexant or suvorexant.
A network meta‐analysis of the dual orexin receptor antagonists, suvorexant, and lemborexant, showed that 5‐ and 10‐mg lemborexant were superior to 20‐mg suvorexant, with greater improvement in sleep onset after 1 week of treatment. In addition, 5‐mg (but not 10‐mg) lemborexant and suvorexant were similarly well tolerated. We have overviewed the pharmacological and pharmacokinetic properties of lemborexant and suvorexant that may support these clinical results, and recommended 5‐mg lemborexant as initial treatment for insomnia, followed by 10‐mg lemborexant or suvorexant.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c19e5bc56db988660805f4504e7c3a7dTest
http://europepmc.org/articles/PMC8698673Test

4

Narcolepsy Type 1: A Remitting Disease? An Unusual Case Report

المؤلفون: Marie-Pia d'Ortho, Justine Frija-Masson, Geoffroy Vellieux, Anny Rouvel-Tallec, Xavier Drouot

المصدر: Nature and Science of Sleep

الوصف: We describe the case of a male patient who was diagnosed with narcolepsy type 1 on the basis of sleep and wake symptoms, and the results of investigations including video-polysomnography, multiple sleep latency test, human leukocyte antigen status and orexin level in cerebrospinal fluid. During the first years after disease onset, the patient did not show any significant improvement despite treatment with a variety of stimulant and anti-cataplectic drugs. However, spontaneous remission of disease occurred after 15 years.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dfdf3ca06c32c55c15361dc7fd19dcb5Test
http://europepmc.org/articles/PMC8478422Test

5

Nonclinical pharmacology of daridorexant: a new dual orexin receptor antagonist for the treatment of insomnia

المؤلفون: Giorgio Bergamini, Michel A. Steiner, Catherine Roch, Martine Clozel

المصدر: Psychopharmacology

الوصف: Dual orexin receptor antagonists (DORAs) represent a novel type of sleep medication that provide an alternative to the traditionally used positive allosteric gamma-aminobutyric acid (GABA)-A receptor modulators. Daridorexant is a new DORA that exhibited in phase 3 trials in insomnia not only a beneficial effect on sleep variables, measured objectively and assessed subjectively, but also an improvement in daytime functioning. Daridorexant was discovered through a tailored research program aimed at identifying an optimized sleep-promoting molecule with pharmacokinetic properties appropriate for covering the whole night while avoiding next-morning residual activity at efficacious doses. By specific binding to both orexin receptors, daridorexant inhibits the actions of the wake-promoting orexin (also called hypocretin) neuropeptides. This mechanism avoids a more widespread inhibition of neuronal pathways and associated side effects that are intrinsic to positive allosteric GABA-A receptor modulators. Here, we review the general pharmacology of daridorexant, based on nonclinical pharmacology studies of daridorexant, unpublished or already described, or based on work with other DORAs. Some unique features of daridorexant will be highlighted, such as the promotion of natural and surmountable sleep, the preservation of memory and cognition, the absence of tolerance development or risk of physical dependence, and how it can benefit daytime functioning. Supplementary Information The online version contains supplementary material available at 10.1007/s00213-021-05954-0.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::98223dcb1d64e58042db5b10ea52358eTest
https://doi.org/10.1007/s00213-021-05954-0Test

6

Sleep dysregulation in binge eating disorder and 'food addiction': the orexin (hypocretin) system as a potential neurobiological link

المؤلفون: Deborah Mitchison, Jacqueline B. Mehr, Hannah E. Bowrey, Morgan H. James

المصدر: Neuropsychopharmacology

الوصف: It has been proposed that binge eating reflects a pathological compulsion driven by the “addictive” properties of foods. Proponents of this argument highlight the large degree of phenomenological and diagnostic overlap between binge eating disorder (BED) and substance use disorders (SUDs), including loss of control over how much is consumed and repeated unsuccessful attempts to abstain from consumption, as well as commonalities in brain structures involved in food and drug craving. To date, very little attention has been given to an additional behavioral symptom that BED shares with SUDs—sleep dysregulation—and the extent to which this may contribute to the pathophysiology of BED. Here, we review studies examining sleep outcomes in patients with BED, which collectively point to a heightened incidence of sleep abnormalities in BED. We identify the orexin (hypocretin) system as a potential neurobiological link between compulsive eating and sleep dysregulation in BED, and provide a comprehensive update on the evidence linking this system to these processes. Finally, drawing on evidence from the SUD literature indicating that the orexin system exhibits significant plasticity in response to drugs of abuse, we hypothesize that chronic palatable food consumption likewise increases orexin system activity, resulting in dysregulated sleep/wake patterns. Poor sleep, in turn, is predicted to exacerbate binge eating, contributing to a cycle of uncontrolled food consumption. By extension, we suggest that pharmacotherapies normalizing orexin signaling, which are currently being trialed for the treatment of SUDs, might also have utility in the clinical management of BED.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3b85510d72a11b3721467aec00f30615Test
https://doi.org/10.1038/s41386-021-01052-zTest

7

Paired-pulse Inhibition and Disinhibition of the Dentate Gyrus Following Orexin Receptors Inactivation in the Basolateral Amygdala

المؤلفون: Motahareh Rouhi Ardeshiri, Narges Hosseinmardi, Esmaeil Akbari

المصدر: Basic and Clinical Neuroscience Journal. 12:827-836

مصطلحات موضوعية: Clinical neuroscience, Pulse (signal processing), Dentate gyrus, Molecular neuroscience, Orexin receptor, Cellular and Molecular Neuroscience, medicine.anatomical_structure, nervous system, Disinhibition, Cellular neuroscience, medicine, Neurology (clinical), medicine.symptom, Neuroscience, Basolateral amygdala

الوصف: The Basolateral Amygdala (BLA) substantially affects neuronal transmission and synaptic plasticity processes through the dentate gyrus. Orexin neuropeptides play different roles in the sleep/wakefulness cycle, feeding, learning, and memory. The present study aimed to investigate the function of the orexin receptors of the BLA in the hippocampal local interneuron circuits.For this, the region's paired-pulse responses from the Dentate Gyrus (DG) were recorded. Within the procedure, SB-334867-A (12μg/0.5μL) and TCS-OX2-29 (10μg/0.5μL (orexin 12 receptors antagonists, respectively), were administered into both sides of the BLA areas of the rat brain. Dimethyl Sulfoxide (DMSO) was used as the solvent in the control animals with a volume of 0.5μL.Our data indicated that the Paired-pulse (PP) responses were not affected by the inactivation of the orexin receptors of the BLA.Due to not observing any significant changes in the short form of synaptic plasticity, after inactivation of the orexin system of the BLA, we hypothesize that the orexinergic fibers to the basolateral part of the amygdala influence the long-term synaptic efficacy; however, the primary processing of information in short-term plasticity model is not affected by the same system. The elementary processing of the data by the amygdala might happen through the action of other neurotransmitter systems.The neuronal transmission of DG following orexin receptors antagonism of the BLA.Paired-pulse responses were not affected by the orexin 1 receptors antagonism.Paired-pulse responses were not affected by the orexin 2 receptors antagonism.The orexinergic system has modulatory effects by sending projection fibers to several parts of the brain, such as the hippocampus and amygdala. Orexin neuropeptides activate basolateral amygdala neural circuits during different arousal states. Although, this system plays a vital role in creating appropriate behavioral reactions, the primary processing of the information in short-term plasticity model is not affected by it.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::61a5724f3ff4022d92634fa870cb0e7bTest
https://doi.org/10.32598/bcn.12.6.1460.1Test

8

Antinociceptive effects of oleuropein in experimental models of neuropathic pain in male rats

المؤلفون: Wen Wen, Yi Zhang, Dandan Ma, Renhu Li, Yanhong Tang, Huapeng Zhang, Huayong Chen, Jun Wang

المصدر: The Korean Journal of Pain

الوصف: Background: The present investigation explored the therapeutic actions of oleuropein along with the possible signaling pathway involved in attenuating neuropathic pain in chronic constriction injury (CCI) and vincristine-induced neuropathic pain in male rats. Methods: Four loose ligatures were placed around the sciatic nerve to induce CCI, and vincristine (50 μg/kg) was injected for 10 days to develop neuropathic pain. The development of cold allodynia, mechanical allodynia, and mechanical hyperalgesia was assessed using different pain-related behavioral tests. The levels of H2S, cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), orexin, and nuclear factor erythroid-2-related factor 2 (Nrf2) were measured in the sciatic nerve. Results: Treatment with oleuropein for 14 days led to significant amelioration of behavioral manifestations of neuropathic pain in two pain models. Moreover, oleuropein restored both CCI and vincristine-induced decreases in H2S, CSE, CBS, orexin, and Nrf2 levels. Co-administration of suvorexant, an orexin receptor antagonist, significantly counteracted the pain-attenuating actions of oleuropein and Nrf2 levels without modulating H2S, CSE and CBS. Conclusions: Oleuropein has therapeutic potential to attenuate the pain manifestations in CCI and vincristine-induced neuropathic pain, possibly by restoring the CSE, CBS, and H2S, which may subsequently increase the expression of orexin and Nrf2 to ameliorate behavioral manifestations of pain.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9f0dc093e3adce3e434bf6e536c79c48Test
http://europepmc.org/articles/PMC7783854Test

9

Preclinical and clinical efficacy of orexin receptor antagonist Lemborexant (Dayvigo®) on insomnia patients

المؤلفون: Kenzo Muramoto, Noriyuki Koyama, Michinori Koebisu, Maika Nishida

المصدر: Folia Pharmacologica Japonica. 156:114-119

مصطلحات موضوعية: 0301 basic medicine, Pharmacology, business.industry, Lemborexant, Antagonist, Orexin receptor, Orexin, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, mental disorders, medicine, Insomnia, medicine.symptom, Receptor, business, Adverse effect, 030217 neurology & neurosurgery, Somnolence

الوصف: Orexin receptor antagonists have been approved for insomnia, and the insomnia pharmacotherapy is being greatly progressed. Orexin is a neuropeptide produced in the lateral hypothalamic area, and its physiological role has been suggested to be a key mediator controlling the sleep-wake state. Orexin receptor antagonists are thought to induce physiological sleep by acting specifically on the sleep-wake cycle. Lemborexant is a dual antagonist acting on both two orexin receptors, the orexin 1 (OX1R) and 2 receptor (OX2R), with stronger inhibitory effects on OX2R. Since it binds to and dissociates from orexin receptors rapidly, the pharmacokinetics of its blood concentration may have an impact on its pharmacological action. In rats, lemborexant exhibited a sleep-inducing effect without altering sleep architecture. In the phase III studies in patients with insomnia, lemborexant significantly improved difficulties in falling asleep and maintaining sleep. While somnolence occurred as treatment-related adverse events in a dose-dependent manner, lemborexant was generally well-tolerated. Also, the effects on body sway and driving skills 8-9 hours after administration did not differ from those in the placebo group, suggesting little next morning residual effects. Subgroup analysis has shown that efficacy and safety of lemborexant were similar in patients with insomnia with comorbidities, suggesting lemborexant may also be useful for those patients. Based on the above results and others, lemborexant has been approved for the indication of insomnia in January 2020 in Japan. Lemborexant will give a new treatment option for patients with insomnia.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::f08b5f41d71b13caee8533023c580547Test
https://doi.org/10.1254/fpj.20093Test

10

Current Management of Residual Excessive Daytime Sleepiness Due to Obstructive Sleep Apnea: Insights for Optimizing Patient Outcomes

المؤلفون: Pablo R. Castillo, Reena Mehra, Raphael Heinzer

المصدر: Neurology and Therapy

الوصف: Although excessive daytime sleepiness (EDS) attributable to obstructive sleep apnea (OSA) can be resolved by consistent usage of and effective treatment (often with the use of continuous positive airway pressure therapy), 12-58% of patients report residual EDS (REDS). While REDS is difficult to treat, a proportion of cases are possibly due to reversible issues, and wake-promoting medications can prove useful for the remaining cases. Given the challenges associated with effective management of REDS and its relationship to multiple comorbidities, multidisciplinary management of patients with REDS is often recommended. Here we aim to bridge the knowledge gap on the burden, risk factors, prevalence, and potential pathophysiologic mechanisms of REDS in patients with OSA after first-line treatment. The roles of primary care physicians and sleep specialists, as well as the importance of the use of objective assessment tools for the evaluation of REDS and the effective management of comorbidities, are discussed. An update of approved treatments and emerging candidate treatments is also presented.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b3d8dc2116c65faeacd2143dffeb1c1eTest
http://europepmc.org/articles/PMC8520824Test

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