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Esmaili-Shahzade-Ali-Akbari P, Ghaderi A, Sadeghi A, Nejat F, Mehramiz A. The Role of Orexin Receptor Antagonists in Inhibiting Drug Addiction: A Review Article. ADDICTION & HEALTH 2024; 16:130-139. [PMID: 39051042 PMCID: PMC11264478 DOI: 10.34172/ahj.2024.1491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Accepted: 04/15/2024] [Indexed: 07/27/2024]
Abstract
The orexinergic system and its receptors are involved in many physiological processes. Their functions in energy homeostasis, arousal, cognition, stress processing, endocrine functions, and pain modulation have been investigated. Many studies have shown that the orexinergic system cooperates with the dopaminergic system in the addiction process. Emerging evidence suggests that the orexinergic system can be effective in the induction of drug dependence and tolerance. Therefore, several researches have been conducted on the effect of orexin receptor (OXR) antagonists on reducing tolerance and dependence caused by drug abuse. Due to the significant growth of the studies on the orexinergic system, the current literature was conducted to collect the findings of previous studies on orexin and its receptors in the induction of drug addiction. In addition, cellular and molecular mechanisms of the possible role of orexin in drug tolerance and dependence are discussed. The findings indicate that the administration of OXR antagonists reduces drug dependence. OXR blockers seem to counteract the addictive effects of drugs through multiple mechanisms, such as preventing neuronal adaptation. This review proposes the potential clinical use of OXR antagonists in the treatment of drug dependence.
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Affiliation(s)
- Peyman Esmaili-Shahzade-Ali-Akbari
- Department of Addiction Studies, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Ghaderi
- Department of Addiction Studies, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Atena Sadeghi
- Department of Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Fatemeh Nejat
- Department of Biology and Health Sciences, Meredith College, Raleigh, North Carolina, USA
| | - Alireza Mehramiz
- Department of Physical Therapy, Faculty of Paramedical and Rehabilitation Science, Mashhad University of Medical Sciences, Mashhad, Iran
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Goldstein N, Tsuneki H, Bhandarkar N, Aimaretti E, Haim Y, Kon K, Sato K, Wada T, Liberty IF, Kirshtein B, Dukhno O, Maixner N, Gepner Y, Sasaoka T, Rudich A. Human adipose tissue is a putative direct target of daytime orexin with favorable metabolic effects: A cross-sectional study. Obesity (Silver Spring) 2021; 29:1857-1867. [PMID: 34472713 DOI: 10.1002/oby.23262] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/03/2021] [Accepted: 07/03/2021] [Indexed: 11/09/2022]
Abstract
OBJECTIVE Orexin/hypocretin (Ox) and its receptors (OxR), a neuroendocrine system centrally regulating sleep/wakefulness, were implicated in the regulation of peripheral metabolism. It was hypothesized that human adipose tissue constitutes a direct target of the OxA/OxR system that associates with distinct metabolic profile(s). METHODS Serum Ox levels and abdominal subcutaneous and visceral adipose tissue expression of Ox/HCRT, OxR1/HCRTR1, and OxR2/HCRTR2 were measured in n = 81 patients. RESULTS Higher morning circulating Ox levels were associated with improved lipid profile and insulin sensitivity, independently of BMI (β = -0.363, p = 0.018 for BMI-adjusted homeostatic model of insulin resistance). Adipose HCRT mRNA was detectable in <20% of patients. Visceral HCRT expressers were mostly (80%) males and, compared with nonexpressers, had lower total and LDL cholesterol. HCRTR1 was readily detectable, and HCRTR2 was undetectable. HCRTR1 mRNA and OxR1 protein expression were higher in subcutaneous than visceral adipose tissue, and among nonobese patients, patients with obesity, and patients with obesity and T2DM were 3.4 (1.0), 0.7 (0.1), 0.6 (0.1) (AU) (p < 0.001) and 1.0 (0.2), 0.5 (0.1), 0.4 (0.1) (AU) (p = NS), respectively. Higher visceral HCRTR1 expression was associated with lower fasting insulin and homeostatic model of insulin resistance, also after adjusting for BMI. In human adipocytes, HCRTR1 expression did not exhibit significant oscillation. CONCLUSIONS Human adipose tissue is a putative direct target of the OxA-OxR1 system, with higher morning input being associated with improved metabolic profile.
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Affiliation(s)
- Nir Goldstein
- Department of Clinical Biochemistry and Pharmacology and the National Institute of Biotechnology in the Negev, Ben-Gurion University, Beer-Sheva, Israel
- Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Sylvan Adams Sports Institute, Tel-Aviv University, Tel-Aviv, Israel
| | - Hiroshi Tsuneki
- Department of Clinical Pharmacology, University of Toyama, Sugitani, Toyama, Japan
| | - Nikhil Bhandarkar
- Department of Clinical Biochemistry and Pharmacology and the National Institute of Biotechnology in the Negev, Ben-Gurion University, Beer-Sheva, Israel
| | - Eleonora Aimaretti
- Department of Clinical Biochemistry and Pharmacology and the National Institute of Biotechnology in the Negev, Ben-Gurion University, Beer-Sheva, Israel
- Department of Drug Science and Technology, University of Turin, Turin, Italy
| | - Yulia Haim
- Department of Clinical Biochemistry and Pharmacology and the National Institute of Biotechnology in the Negev, Ben-Gurion University, Beer-Sheva, Israel
| | - Kanta Kon
- Department of Clinical Pharmacology, University of Toyama, Sugitani, Toyama, Japan
| | - Kiyofumi Sato
- Department of Clinical Pharmacology, University of Toyama, Sugitani, Toyama, Japan
| | - Tsutomu Wada
- Department of Clinical Pharmacology, University of Toyama, Sugitani, Toyama, Japan
| | - Idit F Liberty
- Soroka University Medical Center and Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Boris Kirshtein
- Soroka University Medical Center and Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Oleg Dukhno
- Soroka University Medical Center and Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Nitzan Maixner
- Department of Clinical Biochemistry and Pharmacology and the National Institute of Biotechnology in the Negev, Ben-Gurion University, Beer-Sheva, Israel
| | - Yftach Gepner
- Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Sylvan Adams Sports Institute, Tel-Aviv University, Tel-Aviv, Israel
| | - Toshiyasu Sasaoka
- Department of Clinical Pharmacology, University of Toyama, Sugitani, Toyama, Japan
| | - Assaf Rudich
- Department of Clinical Biochemistry and Pharmacology and the National Institute of Biotechnology in the Negev, Ben-Gurion University, Beer-Sheva, Israel
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3
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Kousi C, Lampri E, Voulgaris S, Vougiouklakis T, Galani V, Mitselou A. Expression of orexin-A (hypocretin-A) in the hypothalamus after traumatic brain injury: A postmortem evaluation. Forensic Sci Int 2021; 327:110961. [PMID: 34454377 DOI: 10.1016/j.forsciint.2021.110961] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/16/2021] [Accepted: 08/17/2021] [Indexed: 01/01/2023]
Abstract
Traumatic brain injury (TBI) is one of the leading causes of mortality and morbidity. The key component of TBI pathophysiology is traumatic axonal injury (TAI), commonly referred to as diffuse axonal injury (DAI). Coma is a serious complication which can occur following traumatic brain injury (TBI). Recently, studies have shown that the central orexinergic/ hypocretinergic system exhibit prominent arousal promoting actions. Therefore, the purpose of this study is to investigate by immunohistochemistry the expression of beta-amyloid precursor protein (β-APP) in white matter of parasagittal region, corpus callosum and brainstem and the expression of orexin-A (ORXA) in the hypothalamus after traumatic brain injury. RESULTS: DAI was found in 26 (53.06%) cases, assessed with β-APP immunohistochemical staining in parasagittal white matter, corpus callosum and brainstem. Orexin-A immunoreactivity in hypothalamus was completely absent in 5 (10.2%) of the cases; moderate reduction of ORXA was observed in 9 (18.4%) of the cases; and severe reduction was observed in 7 (14.3%) of the cases. A statistically significant correlation was found between β-APP immunostaining in white matter, corpus callosum and brainstem in relation to survival time (p < 0.002, p < 0.003 and p < 0.005 respectively). A statistically positive correlation was noted between ORX-A immunoreactivity in hypothalamus to survival time (p < 0.003). An inverse correlation was noted between the expression of β-APP in the regions of brain studied to the expression of ORX-A in the hypothalamus of the cases studied (p < 0.005). CONCLUSIONS: The present study demonstrated by immunohistochemistry that reduction of orexin-A neurons in the hypothalamus, involved in coma status and arousal, enhanced the immunoexpression of β-APP in parasagital white matter, corpus callosum and brainstem.
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Affiliation(s)
- Chrysavgi Kousi
- Department of Forensic Medicine and Toxicology Health Sciences, School of Medicine, University of Ioannina, Greece
| | - Evangeli Lampri
- Department of Pathology Health Sciences, School of Medicine, University of Ioannina, Greece
| | - Spyridon Voulgaris
- Department of Neurosurgery, Health Sciences, School of Medicine, University of Ioannina, Greece
| | - Theodoros Vougiouklakis
- Department of Forensic Medicine and Toxicology Health Sciences, School of Medicine, University of Ioannina, Greece
| | - Vassiliki Galani
- Department of Anatomy-Histology-Embryology, University of Ioannina, Greece.
| | - Antigony Mitselou
- Department of Forensic Medicine and Toxicology Health Sciences, School of Medicine, University of Ioannina, Greece
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Xiang J, Zhang S, Xu R, Chu H, Biswas S, Yu S, Miao D, Li W, Li S, Brown AJ, Yang H, Xu Y, Li B, Liu H. Elevated HB-EGF expression in neural stem cells causes middle age obesity by suppressing Hypocretin/Orexin expression. FASEB J 2021; 35:e21345. [PMID: 33715219 DOI: 10.1096/fj.202001945r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 12/03/2020] [Accepted: 12/21/2020] [Indexed: 11/11/2022]
Abstract
Obesity is common in the middle aged population and it increases the risks of diabetes, cardiovascular diseases, certain cancers, and dementia. Yet, its etiology remains incompletely understood. Here, we show that ectopic expression of HB-EGF, an important regulator of neurogenesis, in Nestin+ neuroepithelial progenitors with the Cre-LoxP system leads to development of spontaneous middle age obesity in male mice accompanied by hyperglycemia and insulin resistance. The Nestin-HB-EGF mice show decreases in food uptake, energy expenditure, and physical activity, suggesting that reduced energy expenditure underlies the pathogenesis of this obesity model. However, HB-EGF expression in appetite-controlling POMC or AgRP neurons or adipocytes fails to induce obesity. Mechanistically, HB-EGF suppresses expression of Hypocretin/Orexin, an orexigenic neuropeptide hormone, in the hypothalamus of middle aged Nestin-HB-EGF mice. Hypothalamus Orexin administration alleviates the obese and hyperglycemic phenotypes in Nestin-HB-EGF mice. This study uncovers an important role for HB-EGF in regulating Orexin expression and energy expenditure and establishes a midlife obesity model whose pathogenesis involves age-dependent changes in hypothalamus neurons.
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Affiliation(s)
- Jinnan Xiang
- Bio-X-Renji Hospital Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Shaoyang Zhang
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Ruiyao Xu
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Hongshang Chu
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Soma Biswas
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Shuxiang Yu
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Dengshun Miao
- State Key Laboratory of Reproductive Medicine, Department of Anatomy, Histology and Embryology, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, China
| | - Weidong Li
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Shentian Li
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Andrew J Brown
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, Australia
| | - Hongyuan Yang
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, Australia
| | - Yuhong Xu
- Pharmacy School, Shanghai Jiao Tong University, Shanghai, China
| | - Baojie Li
- Bio-X-Renji Hospital Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.,Center for Traditional Chinese Medicine and Stem Cell Research, The Chengdu University of Traditional Chinese Medicine, Sichuan, China
| | - Huijuan Liu
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
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Rique GLN, Rique MC, Augusto de Souza Bonifácio T, Andrade MJO, dos Santos NA. Effects of vertical gastrectomy on sleep quality, eating behavior, and metabolic parameters in obese adults: a case study. BIOL RHYTHM RES 2021. [DOI: 10.1080/09291016.2021.1906504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- Gabriela Lemos Negri Rique
- Perception, Neurosciences, and Behavior Laboratory, Psychology Department, Federal University of Paraiba, João Pessoa, Brazil
| | | | | | - Michael Jackson Oliveira Andrade
- Neurosciences, Chronobiology, and Sleep Psychology Laboratory, Psychology Department, Minas Gerais State University, Divinópolis, Brazil
| | - Natanael Antonio dos Santos
- Perception, Neurosciences, and Behavior Laboratory, Psychology Department, Federal University of Paraiba, João Pessoa, Brazil
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Mohammadi S, Moosaie F, Saghazadeh A, Mahmoudi M, Rezaei N. Metabolic profile in patients with narcolepsy: a systematic review and meta-analysis. Sleep Med 2021; 81:268-284. [PMID: 33740593 DOI: 10.1016/j.sleep.2021.02.040] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/10/2021] [Accepted: 02/16/2021] [Indexed: 11/25/2022]
Abstract
Narcolepsy, a sleep disorder characterized by loss of hypocretin neurons, has been associated with metabolic disturbances. Although the metabolic alterations in narcolepsy patients are widely investigated in the literature, the results are controversial. We performed a systematic search of literature to identify metabolic profiling studies in narcolepsy patients. A total of 48 studies were included in the meta-analysis. Narcolepsy patients exhibited higher prevalence of obesity (log OR = 0.93 [0.73-1.13], P < 0.001), diabetes mellitus (log OR = 0.64 [0.34, 0.94], P < 0.001), hypertension (log OR = 0.33 [0.11, 0.55], P < 0.001), and dyslipidemia (log OR = 1.19 [0.60, 1.77], P < 0.001) compared with non-narcoleptic controls. Narcolepsy was associated with higher BMI (SMD = 0.50 [0.32-0.68], P < 0.001), waist circumference (MD = 8.61 [2.03-15.19], P = 0.01), and plasma insulin (SMD = 0.61 [0.14-1.09], P = 0.01). Levels of fasting blood glucose (SMD = -0.25 [-0.61,0.10], P = 0.15), BMR-RMR (SMD = -0.17 [-0.52-0.18], P = 0.34), systolic blood pressure (SMD = 0.29 [-0.39-0.97], P = 0.40), diastolic blood pressure (SMD = 0.39 [-0.62, 1.40], P = 0.45), CSF melanin-concentrating hormone (MD = 5.56 [-30.79-41.91], P = 0.76), serum growth hormone (SMD = 7.84 [-7.90-23.57], P = 0.33), as well as plasma and CSF leptin (SMD = 0.10 [-1.32-1.51], P = 0.89 and MD = 0.01 [-0.02-0.04], P = 0.56, respectively) did not significantly differ between narcolepsy patients and controls. These findings necessitate early screening of metabolic alterations and cardiovascular risk factors in narcolepsy patients to reduce the morbidity and mortality rates.
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Affiliation(s)
- Soheil Mohammadi
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; NeuroImaging Network (NIN), Universal Scientific Education and Research Network (USERN), Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Moosaie
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; NeuroImaging Network (NIN), Universal Scientific Education and Research Network (USERN), Tehran University of Medical Sciences, Tehran, Iran
| | - Amene Saghazadeh
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; MetaCognition Interest Group (MCIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Maryam Mahmoudi
- Department of Cellular Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran; Dietitians and Nutrition Experts Team (DiNET), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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7
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Adeghate E, Lotfy M, D'Souza C, Alseiari SM, Alsaadi AA, Qahtan SA. Hypocretin/orexin modulates body weight and the metabolism of glucose and insulin. Diabetes Metab Res Rev 2020; 36:e3229. [PMID: 31655012 DOI: 10.1002/dmrr.3229] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 08/16/2019] [Accepted: 10/06/2019] [Indexed: 12/18/2022]
Abstract
The hypocretin/orexin (Hcrt/orexin) unit affects the functions of the nervous, cardiovascular, gastrointestinal, and reproductive systems. Hcrt/orexin ligands and receptors have been localized to different parts of the central and peripheral nervous systems, cerebrospinal fluid and blood, exocrine (pancreas, salivary, lacrimal) as well as endocrine (pancreatic islets, pituitary, adrenal) glands. Several factors including stress, glucagon-like peptide-1 agonists, glutamate, nicotine, glucose, and hypoglycaemia stimulate the expression of Hcrt/orexin system, but it is inhibited by ageing, bone morphogenetic protein, hypoxia/hypercapnia, melanocortin receptor accessory protein 2, and glucagon. Literature reports show that Hcrt/orexin can significantly increase insulin secretion from normal and diabetic rat pancreata. Hcrt/orexin decreases blood glucose concentration and reduces insulin resistance partly via increased tissue expression of glucose transporter type 4. It reduces obesity by increasing browning of fat cells and energy expenditure. Taken together, Hcrt/orexin modulates obesity and the metabolism of glucose and insulin. The Hcrt/orexin system may thus be a target in the development of new therapies for the treatment of diabetes mellitus.
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Affiliation(s)
- Ernest Adeghate
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Mohamed Lotfy
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Crystal D'Souza
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Saleh Meqbel Alseiari
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Abdulla Ali Alsaadi
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Saif Abdo Qahtan
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
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8
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Untangling narcolepsy and diabetes: Pathomechanisms with eyes on therapeutic options. Brain Res 2019; 1718:212-222. [DOI: 10.1016/j.brainres.2019.04.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 03/23/2019] [Accepted: 04/13/2019] [Indexed: 12/14/2022]
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9
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Nakashima H, Umegaki H, Yanagawa M, Komiya H, Watanabe K, Kuzuya M. Plasma orexin-A-like immunoreactivity levels and renal function in patients in a geriatric ward. Peptides 2019; 118:170092. [PMID: 31163198 DOI: 10.1016/j.peptides.2019.170092] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 05/26/2019] [Accepted: 05/28/2019] [Indexed: 10/26/2022]
Abstract
Orexin-A is a neuropeptide mainly produced by hypothalamic neurons with functions in the central nervous system such as regulation of the sleep-wake cycle. Recent studies suggest that orexin-A also plays major roles in peripheral tissues. Although a few studies have reported a role for the kidney in the dynamics of orexin-A, little is known about the association between plasma orexin-A-like immunoreactivity (orexin-A-LI) levels and renal function. We evaluated this association, and also explored other clinical characteristics associated with plasma orexin-A-LI levels. In this cross-sectional study, we included 70 consecutive patients aged ≥65 years admitted to the geriatric ward of Nagoya University Hospital from December 2017 to January 2018. Patients taking suvorexant (an orexin receptor antagonist) were excluded. On hospital days 2-4, fasting blood was collected in the morning. We evaluated associations between plasma orexin-A-LI levels and renal function and other clinical characteristics. Renal function was evaluated in two ways: the estimated glomerular filtration rate (eGFR) using serum creatinine, and estimated creatinine clearance (eCrCl) using the Cockroft-Gault formula. Pearson's correlation coefficient revealed that plasma orexin-A-LI levels were negatively correlated with the eGFR (r = -0.351, p = 0.003) and eCrCl (r = -0.342, p = 0.004). There were no significant associations between plasma orexin-A-LI levels and the primary diagnosis, body mass index, duration of fasting, or other clinical characteristics. In conclusion, plasma orexin-A-LI levels were negatively correlated with renal function in patients in a geriatric ward. Renal function may affect the study design and data interpretation in studies of plasma orexin-A-LI.
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Affiliation(s)
- Hirotaka Nakashima
- Department of Geriatrics, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan; Centre for Community Liaison and Patient Consultations, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan.
| | - Hiroyuki Umegaki
- Department of Community Healthcare and Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan.
| | - Madoka Yanagawa
- Department of Community Healthcare and Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan.
| | - Hitoshi Komiya
- Department of Community Healthcare and Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan.
| | - Kazuhisa Watanabe
- Department of Community Healthcare and Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan.
| | - Masafumi Kuzuya
- Centre for Community Liaison and Patient Consultations, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan; Department of Community Healthcare and Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan; Institute of Innovation for Future Society, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi, 464-8601, Japan.
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10
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Barandas R, Landgraf D, McCarthy MJ, Welsh DK. Circadian Clocks as Modulators of Metabolic Comorbidity in Psychiatric Disorders. Curr Psychiatry Rep 2015; 17:98. [PMID: 26483181 DOI: 10.1007/s11920-015-0637-2] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Psychiatric disorders such as schizophrenia, bipolar disorder, and major depressive disorder are often accompanied by metabolic dysfunction symptoms, including obesity and diabetes. Since the circadian system controls important brain systems that regulate affective, cognitive, and metabolic functions, and neuropsychiatric and metabolic diseases are often correlated with disturbances of circadian rhythms, we hypothesize that dysregulation of circadian clocks plays a central role in metabolic comorbidity in psychiatric disorders. In this review paper, we highlight the role of circadian clocks in glucocorticoid, dopamine, and orexin/melanin-concentrating hormone systems and describe how a dysfunction of these clocks may contribute to the simultaneous development of psychiatric and metabolic symptoms.
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Affiliation(s)
- Rita Barandas
- Department of Psychiatry, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal
- Faculty of Medicine, University of Lisbon, Lisbon, Portugal
- VA San Diego Healthcare System Psychiatry Service, La Jolla, CA, USA
- Department of Psychiatry and Center for Circadian Biology, University of California, San Diego, 9500 Gilman Drive MC-0603, La Jolla, CA, 92093-0603, USA
| | - Dominic Landgraf
- VA San Diego Healthcare System Psychiatry Service, La Jolla, CA, USA.
- Department of Psychiatry and Center for Circadian Biology, University of California, San Diego, 9500 Gilman Drive MC-0603, La Jolla, CA, 92093-0603, USA.
| | - Michael J McCarthy
- VA San Diego Healthcare System Psychiatry Service, La Jolla, CA, USA
- Department of Psychiatry and Center for Circadian Biology, University of California, San Diego, 9500 Gilman Drive MC-0603, La Jolla, CA, 92093-0603, USA
| | - David K Welsh
- VA San Diego Healthcare System Psychiatry Service, La Jolla, CA, USA
- Department of Psychiatry and Center for Circadian Biology, University of California, San Diego, 9500 Gilman Drive MC-0603, La Jolla, CA, 92093-0603, USA
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11
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"Non-dipping" is equally frequent in narcoleptic patients and in patients with insomnia. Sleep Biol Rhythms 2015; 14:31-36. [PMID: 26855609 PMCID: PMC4732675 DOI: 10.1007/s41105-015-0004-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2014] [Accepted: 06/02/2015] [Indexed: 11/24/2022]
Abstract
Narcolepsy with cataplexy (NC) is a neurological sleep disorder characterized by very low or undetectable concentration of hypocretin-1 in the cerebrospinal fluid. It has been recently found that patients with NC have disturbed circadian pattern of blood pressure, with more frequent non-dipping, compared to healthy controls. It has been hypothesized that lack of hypocretin may lead to increase in nocturnal blood pressure. This increase may result also from disturbed sleep architecture regardless of the deficiency of hypocretin. The aim of this study was to compare changes in values of daytime and nighttime blood pressure in NC patients and in patients with disturbed nocturnal sleep due to other sleep disorders. We have retrospectively compared polysomnographic and clinical data of 8 NC patients and 7 age- and sex controls suffering from insomnia. We have compared sleep architecture, mean blood pressure values and dipping pattern in both groups. The groups did not differ in terms of disturbances of sleep architecture. We have not found any statistical differences in values of daytime and nocturnal blood pressure. Non-dipping was equally frequent in both groups (87.5 and 85.7 %). Our results suggest that observed abnormalities in circadian changes of blood pressure values result from disturbed sleep architecture than from deficiency of hypocretin. Patients with sleep disorders should be carefully observed for the presence of increased blood pressure and other vascular risk factors.
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Nishizawa D, Kasai S, Hasegawa J, Sato N, Yamada H, Tanioka F, Nagashima M, Katoh R, Satoh Y, Tagami M, Ujike H, Ozaki N, Inada T, Iwata N, Sora I, Iyo M, Yamada M, Kondo N, Won MJ, Naruse N, Uehara-Aoyama K, Itokawa M, Ohi K, Hashimoto R, Tanisawa K, Arai T, Mori S, Sawabe M, Naka-Mieno M, Yamada Y, Yamada M, Sato N, Muramatsu M, Tanaka M, Irukayama-Tomobe Y, Saito YC, Sakurai T, Hayashida M, Sugimura H, Ikeda K. Associations between the orexin (hypocretin) receptor 2 gene polymorphism Val308Ile and nicotine dependence in genome-wide and subsequent association studies. Mol Brain 2015; 8:50. [PMID: 26289589 PMCID: PMC4546081 DOI: 10.1186/s13041-015-0142-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Accepted: 08/12/2015] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Many genetic and environmental factors are involved in the etiology of nicotine dependence. Although several candidate gene variations have been reported by candidate gene studies or genome-wide association studies (GWASs) to be associated with smoking behavior and the vulnerability to nicotine dependence, such studies have been mostly conducted with subjects with European ancestry. However, genetic factors have rarely been investigated for the Japanese population as GWASs. To elucidate genetic factors involved in nicotine dependence in Japanese, the present study comprehensively explored genetic contributors to nicotine dependence by using whole-genome genotyping arrays with more than 200,000 markers in Japanese subjects. RESULTS The subjects for the GWAS and replication study were 148 and 374 patients, respectively. A two-stage GWAS was conducted using the Fagerström Test for Nicotine Dependence (FTND), Tobacco Dependence Screener (TDS), and number of cigarettes smoked per day (CPD) as indices of nicotine dependence. For the additional association analyses, patients who underwent major abdominal surgery, patients with methamphetamine dependence/psychosis, and healthy subjects with schizotypal personality trait data were recruited. Autopsy specimens with various diseases were also evaluated. After the study of associations between more than 200,000 marker single-nucleotide polymorphisms (SNPs) and the FTND, TDS, and CPD, the nonsynonymous rs2653349 SNP (located on the gene that encodes orexin [hypocretin] receptor 2) was selected as the most notable SNP associated with FTND, with a p value of 0.0005921 in the two-stage GWAS. This possible association was replicated for the remaining 374 samples. This SNP was also associated with postoperative pain, the initiation of methamphetamine use, schizotypal personality traits, and susceptibility to goiter. CONCLUSIONS Although the p value did not reach a conventional genome-wide level of significance in our two-stage GWAS, we obtained significant results in the subsequent analyses that suggest that the rs2653349 SNP (Val308Ile) could be a genetic factor that is related to nicotine dependence and possibly pain, schizotypal personality traits, and goiter in the Japanese population.
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Affiliation(s)
- Daisuke Nishizawa
- Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
| | - Shinya Kasai
- Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
| | - Junko Hasegawa
- Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
| | - Naomi Sato
- Department of Clinical Nursing, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan.
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan.
| | - Hidetaka Yamada
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan.
| | - Fumihiko Tanioka
- Department of Pathology, Iwata City Hospital, Iwata, 438-8550, Japan.
| | - Makoto Nagashima
- Department of Surgery, Toho University Sakura Medical Center, Sakura, 285-8741, Japan.
| | - Ryoji Katoh
- Department of Surgery, Toho University Sakura Medical Center, Sakura, 285-8741, Japan.
| | - Yasuo Satoh
- Department of Anesthesiology, Toho University Sakura Medical Center, Sakura, 285-8741, Japan.
| | - Megumi Tagami
- Department of Anesthesiology, Toho University Sakura Medical Center, Sakura, 285-8741, Japan.
| | - Hiroshi Ujike
- Ujike Nishiguchi Clinic, Okayama, 700-0024, Japan.
- Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan.
| | - Norio Ozaki
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
- Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan.
| | - Toshiya Inada
- Department of Psychiatry, Seiwa Hospital, Institute of Neuropsychiatry, Tokyo, 162-0851, Japan.
- Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan.
| | - Nakao Iwata
- Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, 470-1192, Japan.
- Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan.
| | - Ichiro Sora
- Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
- Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan.
- Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan.
| | - Masaomi Iyo
- Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan.
- Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan.
| | - Mitsuhiko Yamada
- Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, 187-8553, Japan.
- Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan.
| | - Naoki Kondo
- Seimei Hospital, Fuji City, 417-0801, Japan.
- Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan.
| | - Moo-Jun Won
- Koujin Hospital, Nagoya, 463-8530, Japan.
- Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan.
| | - Nobuya Naruse
- Saitama Seishin-iryo Center, Kita-adachi, Saitama, 362-0806, Japan.
- Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan.
| | - Kumi Uehara-Aoyama
- Kanagawa Psychiatric Center, Serigaya Hospital, Kanagawa, 233-0006, Japan.
- Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan.
| | - Masanari Itokawa
- Schizophrenia and Depression Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan.
| | - Kazutaka Ohi
- Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
- National Hospital Organization, Yamato Mental-Medical Center, Nara, 639-1042, Japan.
| | - Ryota Hashimoto
- Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
- Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University, Chiba University, and Fukui University School of Medicine, Osaka, 565-0871, Japan.
| | - Kumpei Tanisawa
- Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan.
- Graduate School of Sport Sciences, Waseda University, Tokyo, 359-1192, Japan.
| | - Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, 173-0015, Japan.
| | - Seijiro Mori
- Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Tokyo, 173-0015, Japan.
| | - Motoji Sawabe
- Molecular Pathophysiology, Department of Molecular-genetic Sciences, Division of Biomedical Laboratory Sciences, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, 101-0062, Japan.
| | - Makiko Naka-Mieno
- Department of Medical Informatics, Center for Information, Jichi Medical University, Shimotsuke, 329-0498, Japan.
| | - Yoshiji Yamada
- Department of Human Functional Genomics, Life Science Research Center, Mie University, Tsu, 514-8507, Japan.
| | - Miki Yamada
- Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 101-0062, Japan.
| | - Noriko Sato
- Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 101-0062, Japan.
| | - Masaaki Muramatsu
- Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 101-0062, Japan.
| | - Masashi Tanaka
- Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan.
- Department of Clinical Laboratory, Tokyo Metropolitan Geriatric Hospital, Tokyo, 173-0015, Japan.
| | | | - Yuki C Saito
- Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Ishikawa, 920-8640, Japan.
| | - Takeshi Sakurai
- Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Ishikawa, 920-8640, Japan.
| | - Masakazu Hayashida
- Department of Anesthesiology and Pain Medicine, Juntendo University School of Medicine, Tokyo, 113-8421, Japan.
| | - Haruhiko Sugimura
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan.
| | - Kazutaka Ikeda
- Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
- Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan.
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Surani S, Brito V, Surani A, Ghamande S. Effect of diabetes mellitus on sleep quality. World J Diabetes 2015; 6:868-873. [PMID: 26131327 PMCID: PMC4478581 DOI: 10.4239/wjd.v6.i6.868] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Revised: 02/21/2015] [Accepted: 05/18/2015] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus (DM) is a highly prevalent condition affecting about 347 million people worldwide. In addition to its numerous clinical implications, DM also exerts a negative effect on patient’s sleep quality. Impaired sleep quality disrupts the adequate glycemic control regarded as corner stone in DM management and also lead to many deleterious effects causing a profound impact on health related quality of life. This article outlines various factors leading to impaired sleep quality among diabetics and delineates how individual factor influences sleep. The article also discusses potential interventions and lifestyle changes to promote healthy sleep among diabetics.
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Gupta A, Miegueu P, Lapointe M, Poirier P, Martin J, Bastien M, Tiwari S, Cianflone K. Acute post-bariatric surgery increase in orexin levels associates with preferential lipid profile improvement. PLoS One 2014; 9:e84803. [PMID: 24400115 PMCID: PMC3882247 DOI: 10.1371/journal.pone.0084803] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Accepted: 11/19/2013] [Indexed: 01/06/2023] Open
Abstract
CONTEXT Orexin is a recently identified neuropeptide hormone. OBJECTIVES Acute and long-term post-bariatric changes in Orexin and relationship to post-operative metabolic outcomes. DESIGN AND PARTICIPANTS Men and women undergoing biliopancreatic diversion with duodenal switch bariatric surgery (n = 76, BMI≥35 kg/m(2)) were evaluated for body composition and plasma parameters at baseline, acutely (1 and 5 days) and long-term (6 and 12 months) post-surgery. SETTING University Hospital Centre, Canada. INTERVENTIONS AND MAIN OUTCOME MEASURES Groups were subdivided based on acute (average 1 and 5 day) changes in Orexin prior to weight loss: (i)>10% Orexin decrease (n = 33, OrexinDEC) and (ii)>10% Orexin increase (n = 20, OrexinINC), to evaluate impact on long-term changes. RESULTS Both groups had comparable preoperative Orexin levels, BMI, age, sex distribution, diabetes and lipid lowering medication, plasma glucose and lipid parameters except for apolipoproteinB (p<0.007). Orexin increase was rapid and maintained throughout one year, while OrexinDEC subjects remained significantly lower throughout. Over 12 months, changes in BMI, fat mass, and %fat mass were comparable. Fasting glucose and insulin increased immediately 1-day post-operatively, decreasing rapidly (5-day) and declining thereafter with the OrexinINC group remaining lower than the OrexinDEC group throughout (p = 0.001). Similarly, plasma cholesterol, triglyceride, LDL-C and HDL-C decreased at 1-day, increased slightly (5-day), except HDL-C, then decreased over 1 year, with greater decreases in OrexinINC group relative to OrexinDEC group. CONCLUSION Rapid postoperative increases in plasma Orexin are associated with better improvement of glucose and lipid profiles following bariatric surgery.
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Affiliation(s)
- Abhishek Gupta
- Centre de Recherche Institut Universitaire de Cardiologie & Pneumologie de Québec, Université Laval, Québec, Canada
- Department of Physiology, King George’s Medical University, Lucknow, India
| | - Pierre Miegueu
- Centre de Recherche Institut Universitaire de Cardiologie & Pneumologie de Québec, Université Laval, Québec, Canada
| | - Marc Lapointe
- Centre de Recherche Institut Universitaire de Cardiologie & Pneumologie de Québec, Université Laval, Québec, Canada
| | - Paul Poirier
- Centre de Recherche Institut Universitaire de Cardiologie & Pneumologie de Québec, Université Laval, Québec, Canada
- Faculté de pharmacie, Université Laval, Québec, Canada
| | - Julie Martin
- Centre de Recherche Institut Universitaire de Cardiologie & Pneumologie de Québec, Université Laval, Québec, Canada
- Faculté de pharmacie, Université Laval, Québec, Canada
| | - Marjorie Bastien
- Centre de Recherche Institut Universitaire de Cardiologie & Pneumologie de Québec, Université Laval, Québec, Canada
- Faculté de pharmacie, Université Laval, Québec, Canada
| | - Sunita Tiwari
- Department of Physiology, King George’s Medical University, Lucknow, India
| | - Katherine Cianflone
- Centre de Recherche Institut Universitaire de Cardiologie & Pneumologie de Québec, Université Laval, Québec, Canada
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15
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Stasi LP, Artusi R, Bovino C, Buzzi B, Canciani L, Caselli G, Colace F, Garofalo P, Giambuzzi S, Larger P, Letari O, Mandelli S, Perugini L, Pucci S, Salvi M, Toro P. Discovery, synthesis, selectivity modulation and DMPK characterization of 5-azaspiro[2.4]heptanes as potent orexin receptor antagonists. Bioorg Med Chem Lett 2013; 23:2653-8. [PMID: 23535328 DOI: 10.1016/j.bmcl.2013.02.093] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Revised: 02/17/2013] [Accepted: 02/20/2013] [Indexed: 11/18/2022]
Abstract
Starting from a orexin 1 receptor selective antagonist 4,4-disubstituted piperidine series a novel potent 5-azaspiro[2.4]heptane dual orexin 1 and orexin 2 receptor antagonist class has been discovered. SAR and Pharmacokinetic optimization of this series is herein disclosed. Lead compound 15 exhibits potent activity against orexin 1 and orexin 2 receptors along with low cytochrome P450 inhibition potential, good brain penetration and oral bioavailability in rats.
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Affiliation(s)
- Luigi Piero Stasi
- Rottapharm Madaus, Medicinal Chemistry Department, via Valosa di Sopra 9, 20900 Monza, Italy.
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