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#35043499   2022/01/19 To Up

Hypocretins (orexins): The ultimate translational neuropeptides.

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.
Laura H Jacobson, Daniel Hoyer, Luis de Lecea

2228 related Products with: Hypocretins (orexins): The ultimate translational neuropeptides.

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#35041942   2022/01/15 To Up

Essential structure of orexin 1 receptor antagonist YNT-707: Conversion of the 16-cyclopropylmethyl group to the 16-sulfonamide group in D-nor-nalfurafine derivatives.

The five-membered D-ring nalfurafine (D-nor-nalfurafine) derivatives with a 16-sulfonamide group were synthesized. Conversion of the 16-cyclopropylmethyl group to the 16-benzenesulfonamide group in the D-nor-nalfurafine derivatives drastically improved the orexin 1 receptor (OXR) antagonist activities. The intramolecular hydrogen bond between the 14-hydroxy and the 16-sulfonamide groups may play an important role in increasing the probability that the 6-amide group would be located at the lower side of the C-ring, leading to an active conformation for OXR. The assay results and the conformational analyses of the 14-OH, 14-H, and 14-dehydrated D-nor-nalfurafine derivatives suggested that the 14- and 16-substituents of the D-nor-nalfurafine derivatives had a greater effect on the affinities for the OXR than did the 14- and 17-substituents of nalfurafine derivatives.
Koki Katoh, Noriki Kutsumura, Naoshi Yamamoto, Yasuyuki Nagumo, Tsuyoshi Saitoh, Yukiko Ishikawa, Yoko Irukayama-Tomobe, Ryuji Tanimura, Masashi Yanagisawa, Hiroshi Nagase

1002 related Products with: Essential structure of orexin 1 receptor antagonist YNT-707: Conversion of the 16-cyclopropylmethyl group to the 16-sulfonamide group in D-nor-nalfurafine derivatives.

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#35029758   2022/01/14 To Up

Characterization of orexin input to dopamine neurons of the ventral tegmental area projecting to the medial prefrontal cortex and shell of nucleus accumbens.

Orexin neurons are involved in homeostatic regulatory processes, including arousal and feeding, and provide a major input from the hypothalamus to the ventral tegmental area (VTA) of the midbrain. VTA neurons are a central hub processing reward and motivation and target the medial prefrontal cortex (mPFC) and the shell part of nucleus accumbens (NAcs). We investigated whether subpopulations of dopamine (DA) neurons in the VTA projecting either to the mPFC or the medial division of shell part of nucleus accumbens (mNAcs) receive differential input from orexin neurons and whether orexin exerts differential electrophysiological effects upon these cells. VTA neurons projecting to the mPFC or the mNAcs were traced retrogradely by Cav2-Cre virus and identified by expression of yellow fluorescent protein (YFP). Immunocytochemical analysis showed that a higher proportion of all orexin-innervated DA neurons projected to the mNAcs (34.5%) than to the mPFC (5.2%). Of all sampled VTA neurons projecting either to the mPFC or mNAcs, the dopaminergic (68.3 vs. 79.6%) and orexin-innervated DA neurons (68.9 vs. 64.4%) represented the major phenotype. Whole-cell current clamp recordings were obtained from fluorescently labeled neurons in slices during baseline periods and bath application of orexin A. Orexin similarly increased the firing rate of VTA dopamine neurons projecting to mNAcs (1.99 ± 0.61 Hz to 2.53 ± 0.72 Hz) and mPFC (0.40 ± 0.22 Hz to 1.45 ± 0.56 Hz). Thus, the hypothalamic orexin system targets mNAcs and to a lesser extent mPFC-projecting dopaminergic neurons of the VTA and exerts facilitatory effects on both clusters of dopamine neurons.
Imre Kalló, Azar Omrani, Frank J Meye, Han de Jong, Zsolt Liposits, Roger A H Adan

1689 related Products with: Characterization of orexin input to dopamine neurons of the ventral tegmental area projecting to the medial prefrontal cortex and shell of nucleus accumbens.

5 G 5 G100 U1 moduleML1 module1 kit(96 Wells)0.1 mg

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#35023323   2021/09/15 To Up

Orexin, serotonin, and energy balance.

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.
Vijayakumar Mavanji, Brianna Pomonis, Catherine M Kotz

1846 related Products with: Orexin, serotonin, and energy balance.

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#35022783   2022/01/11 To Up

A double-blind, randomized, placebo-controlled trial of suvorexant for the treatment of vasomotor symptom-associated insomnia disorder in midlife women.

The neuropeptide orexin promotes wakefulness, modulates thermoregulation, increases after menopause, and is normalized in women receiving estrogen therapy, suggesting a role for orexin antagonism as a treatment for vasomotor symptom (VMS)-associated insomnia disorder. We tested the efficacy of the dual orexin receptor antagonist suvorexant for chronic insomnia related to nighttime VMS.
Shadab A Rahman, Margo D Nathan, Aleta Wiley, Sybil Crawford, Aviva Y Cohn, Jessica A Harder, Leilah K Grant, Athena Erickson, Akanksha Srivastava, Kathleen McCormick, Suzanne M Bertisch, John W Winkelman, Hadine Joffe

1790 related Products with: A double-blind, randomized, placebo-controlled trial of suvorexant for the treatment of vasomotor symptom-associated insomnia disorder in midlife women.

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#35022128   2022/01/13 To Up

Narcolepsy-like symptoms triggered by lemborexant in the context of hyperactive delirium in a patient with bipolar depression: a case report.

Lemborexant is a dual orexin antagonist (DORA) and is considered a safe and effective hypnotic. DORAs induce physiological sleep by blocking orexin receptors. Although the blockade of orexin signaling has triggered narcolepsy-like symptoms in rodents, there is currently no evidence of lemborexant inducing narcolepsy-like symptoms in humans. We describe the case of a 79-year-old Japanese woman with bipolar depression who experienced lemborexant-induced cataplexy and sleep attack. Her previous results on the Multiple Sleep Latency Test excluded the diagnosis of narcolepsy. She experienced narcolepsy-like symptoms on two occasions after she was administered lemborexant, in the context of hyperactive delirium, but not in a relaxed state. Her case suggests that lemborexant could trigger narcolepsy-like symptoms in patients with hyperactive delirium, even those with no history of narcolepsy. This case also emphasizes that clinicians must be very careful when they prescribe lemborexant to patients who experience hyperactive delirium.
Shintaro Shibata, Yasunori Oda, Nozomi Ohki, Yuki Ikemizu, Ryunosuke Hayatsu, Yuki Hirose, Masaomi Iyo

2249 related Products with: Narcolepsy-like symptoms triggered by lemborexant in the context of hyperactive delirium in a patient with bipolar depression: a case report.



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#35013906   2022/01/11 To Up

Overexpression of ORX or MCH Protects Neurological Function Against Ischemic Stroke.

In recent years, orexin (ORX) and melanin-concentrating hormone (MCH) have been demonstrated to exert neuroprotective roles in cerebral ischemia. Hence, this study investigated the regulatory function of ORX and MCH in neurological function following ischemic stroke and explored the molecular mechanism underlying these functions. A rat model of ischemic stroke was developed by middle cerebral artery occlusion (MCAO), and Longa scoring was employed to evaluate the degree of neurological function deficit. The expression patterns of ORX and MCH were examined by real-time polymerase chain reaction in the brain tissues of rats with ischemic stroke induced by middle cerebral artery occlusion (MCAO). Moreover, electroencephalography (EEG) analysis and high-performance liquid chromatography (HPLC) were respectively performed to detect rapid-eye movement (REM) sleep, the glutamate (Glu) uptake, and the expression of γ-aminobutyric acid B receptor (GABA). Immunoblotting was performed to test the levels of autophagic markers LC3, BECLIN-1, and p62. Immunohistochemistry (IHC) staining and TUNEL assays were respectively used to assess the autophagy and neuronal apoptosis. Results demonstrated that ORX and MCH were lowly expressed in brain of rats with ischemic stroke. ORX or MCH overexpression decreased neuronal apoptosis and autophagy, and improved the sleep architecture of post-stroke rats, while rescuing Glu uptake and GABA expression. ORX or MCH upregulation exerted protective effects on neurological function. Taken together, ORX and/or MCH protect against ischemic stroke in a rat model, highlighting their value as targets for the clinical treatment of ischemic stroke.
Gang Wu, Xi'an Zhang, Shijun Li, Dan Zhou, Jie Bai, Hanxiang Wang, Qing Shu

1152 related Products with: Overexpression of ORX or MCH Protects Neurological Function Against Ischemic Stroke.

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