Plasma orexin-A is lower in patients with narcolepsy

Higuchi, Shunichi; A, Usui; Murasaki, Mitsukuni; Matsushita, Satoru; Nishioka, Naritomo; Yoshino, Aihide; Matsui, Toshifumi; Muraoka, Hiroko; Ishizuka, Y.; Kanba, Shigenobu; Sakurai, Takeshi

doi:10.1016/s0304-3940(01)02476-4

Cited by 76 publications

(44 citation statements)

References 17 publications

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“…Only recently, investigators have begun to address the potential role of several molecules (serotonin, adenosine or leptin) in the pathogenesis of OSAS [3, 4, 5]. Recent studies have established the presence of low orexin-A levels in patients with narcolepsy, both in cerebrospinal fluid [8, 9, 10]and in plasma [11], and abnormal secretion of orexin-A in OSAS patients [16, 17, 18]. Our results are in concordance with Nishijiama et al [16]and Sakurai et al [18]by showing a decrease in orexin-A plasma levels in patients with OSAS.…”

Section: Discussionmentioning

confidence: 99%

“…Because patients with OSAS present a phenotype likely to be influenced by orexin-A (obesity, excessive daytime sleepiness and frequent arousals during sleep) we hypothesized that they may present abnormal orexin-A levels. Several recent reports have shown reduced plasma and cerebrospinal fluid levels of orexin-A in patients with narcolepsy [8, 9, 10, 11], another sleep disorder that shares some clinical features (e.g. daytime somnolence) with OSAS.…”

Section: Introductionmentioning

confidence: 99%

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Decreased Plasma Levels of Orexin-A in Sleep Apnea

et al. 2004

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Background: Orexin-A, also known as hypocretin, is a neuropeptide implicated in appetite and sleep regulation. Because the obstructive sleep apnea syndrome (OSAS) is characterized by obesity and excessive daytime sleepiness, we hypothesized that orexin-A levels may be abnormal in patients with OSAS. Further, since treatment with continuous positive airway pressure (CPAP) in patients with OSAS is very effective in normalizing daytime sleepiness, we also hypothesized that the chronic use of CPAP may influence plasma levels of orexin-A in these patients. Objective: To evaluate plasma levels of orexin-A in patients with OSAS and the effect of CPAP treatment. Patients and Methods: We compared the plasma levels of orexin-A in 13 healthy controls, 27 untreated patients with OSAS and 14 patients treated with CPAP during at least 1 year (4.5 ± 0.5 h/night; mean ± SEM). All patients had severe OSAS (apnea-hypopnea index, 57 ± 4 h^–1). Results: Orexin-A plasma levels were significantly lower in untreated (9.4 ± 1.9 pg·ml^–1, p < 0.01) and treated patients with OSAS (4.2 ± 1.5 pg·ml^–1, p < 0.001) than in healthy subjects (20.6 ± 4.5 pg·ml^–1). In untreated patients, orexin-A levels were not significantly related to daytime somnolence assessed by Epworth scale (r = –0.18, p = 0.37) or the body mass index (r = –0.13, p = 0.52). Conclusions: Orexin-A plasma levels are abnormally low in patients with OSAS, independently of the level of somnolence and/or presence of obesity. These results suggest that these low orexin-A levels may be related to the pathogenesis of OSAS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Decreased Plasma Levels of Orexin-A in Sleep Apnea

et al. 2004

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“…It is characterized by daytime sleepiness, sleep fragmentation, abnormal rapid eye movement (REM) sleep [Overseem et al, 2001], occasional paralytic attacks (cataplexy) in response to positive emotions, REM-associated atonia and hallucinations [Kadotani et al, 1998;Lin et al, 1999;Siegel, 1999]. While the majority of narcoleptics have low cerebrospinal fluid (CSF) or low serum levels of orexin-A/ hypocretin-1 [Allen, 2000;Mignot, 2000;Nishino et al, 2000;Dalal et al, 2001;Lin et al, 2001;Scammell et al, 2001;Higuchi et al, 2002], most patients do not exhibit disruptions of the prepro-orexin gene [Nakayama et al, 2000].…”

Section: Introductionmentioning

confidence: 99%

Variants of the orexin2/hcrt2 receptor gene identified in patients with excessive daytime sleepiness and patients with Tourette's syndrome comorbidity

Thompson

Comings²,

Abu-Ghazalah

et al. 2004

American J of Med Genetics Pt B

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The orexin-2/hypocretin-2 (OX2R) receptor gene is mutated in canine narcolepsy and disruption of the prepro-orexin/hypocretin ligand gene results in both an animal model of narcolepsy and sporadic cases of the human disease. This evidence suggests that the structure of the OX2R gene, and its homologue, the OX1R gene, both members of the G protein-coupled receptor (GPCR) family, and the gene encoding the peptide ligands, the prepro-orexin/hypocretin gene, may be variables in the etiology of sleep disorders. We report a single stranded conformational polymorphism (SSCP) analysis of the coding regions of these genes in idiopathic sleep disorder patients diagnosed with excessive daytime sleepiness (EDS) (n = 28), narcolepsy (n = 28), Tourette's syndrome/chronic vocal or motor tic disorder (n = 70), and control subjects (n = 110). Two EDS patients showed a Pro11Thr change. One Tourette's syndrome patient was found to have a Pro10Ser alteration. The Pro10Ser and Pro11Thr variants were not found in non-disease populations. Analysis of the ability of the mutant receptors to mobilize calcium compared to the wild-type receptor in response to orexin agonists indicated that they resulted in decreased potency at high (etaM) concentrations of orexin ligands. Further work is warranted to study the variability of the orexin/hypocretin system in a variety of disorders characterized by EDS.

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“…More recent papers indicated that orexins may induce calcium mobilization at much lower concentrations [47,48]. Indeed, the EC 50 of orexin-A in CHO cells expressing human OX 1 R is 1 or 2 nM in the studies by Lund et al [47] and Darker et al [48], respectively.…”

Section: Signal Transductionmentioning

confidence: 98%

Orexins and their receptors: structural aspects and role in peripheral tissues

Voisin¹,

Rouet‐Benzineb²,

Reuter³

et al. 2003

Cellular and Molecular Life Sciences (CMLS)

110

112

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Orexins, also named hypocretins, were discovered in 1998 by subtractive cDNA cloning or orphan receptor technologies. Prepro-orexin is enzymatically matured into two peptides, orexin-A and orexin-B which are 33- and 28-amino-acid peptides, respectively. Two cloned orexin receptors OX1R and OX2R are serpentine G-protein-coupled receptors, both of which bind orexins and are coupled to Ca2+ mobilization. Orexins are neuropeptides present in hypothalamic neurons that project throughout the central nervous system to nuclei involved in the control of feeding, sleep-wakefulness, neuroendocrine homeostasis and autonomic regulation. The interest of investigators in orexins has focused on narcolepsy, since genetic or experimental alterations of the orexin system are associated with this sleep disorder. However, orexins are not restricted to the hypothalamus and together with their receptors they are expressed in peripheral tissues. This new multifaceted aspect of orexin biology is reviewed here in descriptions of (i) the proform, maturation and structure of orexins, (ii) the structure, signal transduction and pharmacology of orexin receptors and (iii) the expression of orexins and orexin receptors as well as their biological role in the hypothalamus-pituitary-adrenal axis, gastrointestinal tract, endocrine pancreas and other peripheral tissues.

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Plasma orexin-A is lower in patients with narcolepsy

Cited by 76 publications

References 17 publications

Decreased Plasma Levels of Orexin-A in Sleep Apnea

Decreased Plasma Levels of Orexin-A in Sleep Apnea

Variants of the orexin2/hcrt2 receptor gene identified in patients with excessive daytime sleepiness and patients with Tourette's syndrome comorbidity

Orexins and their receptors: structural aspects and role in peripheral tissues

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