Plasma orexin-A Concentrations Research Articles

Increased plasma orexin-A concentrations are associated with the non-motor symptoms in Parkinson’s disease patients

BackgroundOrexin, a neuropeptide primarily secreted by neurons in the lateral hypothalamus, has been implicated in Parkinson’s disease (PD). Studies on the relationship between plasma orexin-A levels and PD are rare. ObjectivesThis study aimed to assess levels of plasma orexin-A in the progression of PD and to evaluate the correlation between orexin-A levels and non-motor symptoms. MethodsEnzyme-linked immunosorbent assay was used to determine plasma orexin-A levels in 117 healthy controls and 121 PD patients, including those with early (n = 68), medium (n = 40) and advanced (n = 13) stages of the disease. Evaluation of motor symptoms and non-motor symptoms in PD patients, such as sleep disorders, cognitive dysfunction, neuropsychiatric symptoms, autonomic nervous dysfunction, hyposmia and PD-related pain, were assessed by the associated scales. ResultsPlasma orexin-A levels were significantly higher in PD patients compared to healthy controls. Orexin-A levels were elevated in early-stage and medium-stage PD compared to healthy controls, but were decreased in advanced-stage PD. Orexin-A levels were negatively correlated with the Unified Parkinson’s Disease Rating Scale Part III scores, disease duration, and dopamine receptor agonist doses, and were positively correlated with the Pittsburgh Sleep Quality Index, REM-sleep Behavior Disorder Questionnaire, 14-item Hamilton Anxiety Scale, Mini-Mental State Examination, and Non-motor Symptom Scale items 22–24 scores. ConclusionsWe found for the first time that plasma orexin-A levels were increased in early-stage and medium-stage PD and were decreased in advanced-stage PD. Furthermore, orexin-A levels were correlated with the non-motor symptoms of insomnia, REM-sleep behavior disorder, anxiety, cognitive dysfunction, and renal dysfunction.

A higher body mass index in Chinese inpatients with chronic schizophrenia is associated with elevated plasma orexin-A levels and fewer negative symptoms

Objective: Orexin-A is involved in numerous physiological functions, such as feeding behavior and energy balance. Yet, the associations among the orexin system, weight changes and the clinical symptoms of schizophrenia patients remain uncertain, especially in inpatients with chronic schizophrenia (CS). The purpose of this study was to investigate the relationship between the orexin-A levels, body mass index (BMI) and clinical symptoms of CS inpatients. Methods: Altogether, 324 inpatients were enrolled in our study. The clinical symptoms of all inpatients were measured using a 30-item Positive and Negative Syndrome Scale (PANSS), and then we calculated the BMI of each subject and tested the orexin-A levels by ELISA methods. Results: The orexin-A levels of the CS inpatients in the obesity group (1.24 ± 1.45 ng/ml, n = 52) were significantly higher than those in the non-overweight group (0.85 ± 1.18 ng/ml, n = 176) and the overweight group (0.97 ± 1.15 ng/ml, n = 96). Spearman’s correlation analysis showed that higher BMIs were associated with higher plasma orexin-A levels and fewer negative symptoms. Furthermore, the multiple regression analysis indicated that the orexin-A level could be a contributor to BMI (F = 30.21, p < 0.001). However, there was no correlation between plasma orexin-A concentrations and clinical symptoms in our research. Conclusion: A higher plasma orexin-A level may be a factor influencing the BMI of inpatients with CS, and fewer negative symptoms seem to be correlated with higher BMI, but the causality among BMI, orexin-A and clinical symptoms of schizophrenia requires further clinical research.

Reduced Plasma Orexin-A Concentrations are Associated with Cognitive Deficits in Anorexia Nervosa

Orexins/hypocretins are neuropeptides implicated in numerous processes, including food intake and cognition. The role of these peptides in the psychopathology of anorexia nervosa (AN) remains poorly understood. The aim of the current study was to evaluate the associations between plasma orexin-A (OXA) concentrations and neuropsychological functioning in adult women with AN, and a matched control group. Fasting plasma OXA concentrations were taken in 51 females with AN and in 51 matched healthy controls. Set-shifting was assessed using the Wisconsin Card Sorting Test (WCST), whereas decision making was measured using the Iowa Gambling Task (IGT). The AN group exhibited lower plasma OXA levels than the HC group. Lower mean scores were obtained on the IGT in AN patients. WCST perseverative errors were significantly higher in the AN group compared to HC. In both the AN and HC group, OXA levels were negatively correlated with WCST non-perseverative errors. Reduced plasma OXA concentrations were found to be associated with set-shifting impairments in AN. Taking into consideration the function of orexins in promoting arousal and cognitive flexibility, future studies should explore whether orexin partly underpins the cognitive impairments found in AN.

Plasma Orexin-A Levels Do Not Undergo Circadian Rhythm in Young Healthy Male Subjects.

Orexin-A (OXA) has been originally isolated from a precursor peptide prepro-orexin from the lateral hypothalamus. The orexin system has been attributed to important functions in sleep, arousal and regulation of energy homeostasis. In addition to its high levels in cerebrospinal fluid, OXA is present in blood. However, reported peptide concentrations in plasma vary significantly depending on the method used. Therefore, a specific and sensitive OXA radioimmunoassay (RIA) with solid phase extraction method was developed to determine whether plasma OXA concentrations is affected by acute feeding and/or wake and sleep in young healthy males. Blood samples were collected for 24 h from nine healthy males (aged 20–24 years; BMI 20.7–26.5) every 2 h starting at 11 a.m. Food was served at 12 p.m, 5:30 p.m, 8 p.m and 8 a.m and the sleep time was between 10 p.m and 7 a.m. Plasma samples were analyzed in addition for cortisol and melatonin levels. Blood pressure was monitored through the experimental period. OXA antibody was raised in rabbits. OXA antiserum had only minor cross-reactivity with prepro-orexin precursor (<0.001%), amino-terminal peptide (<0.001%), carboxy-terminal peptide (0.001%), and orexin-B (0.3%) with high sensitivity (0.15 pg/tube). Plasma OXA levels varied between 0.5 and 16 pg/ml in seven subjects and were undetectable (below 0.5 pg/ml) in two subjects. The OXA concentrations did not correlate to feeding nor wake/sleep, whereas cortisol, melatonin and mean arterial blood pressure presented a clear circadian rhythm in each subject. In conclusion, OXA is present in blood in low amounts and its levels do not follow autonomic nor neuroendocrine circadian rhythms. Thereby, studies examining regulatory mechanisms and influences of OXA from blood samples should interpret results very cautiously.

Role of orexin-A in doxapram-induced promotion of emergence from general anesthesia

Objective To investigate the role of orexin-A in doxapram-induced promotion of emergence from general anesthesia in patients. Methods Forty-four patients of both sexes, aged 18-60 yr, with body mass index of 21-25 kg/m2, of American Society of Anesthesiology physical status Ⅰ or Ⅱ, scheduled for elective lumbar surgery under general anesthesia, were divided into 2 groups (n=22 each) using a random number table: control group and doxapram group.Anesthesia was induced by intravenously injecting propofol, sufentanil and cisatracurium.The patients were mechanically ventilated after tracheal intubation.Anesthesia was maintained by inhaling sevoflurane and target-controlled infusion of remifentanil.Sevoflurane inhalation and remifentanil infusion were stopped at the end of operation, oxygen flow rate was adjusted to 6 L/min, doxapram 0.5 mg/kg were intravenously injected at the same time in doxapram group, and the equal volume of normal saline was given in control group.The emergence time and extubation time were recorded.On admission to operating room (T0), at 1 h after anesthesia induction (T1) and 5 and 30 min after tracheal extubation (T2, 3), arterial blood samples were collected for determination of blood glucose concentrations and plasma orexin-A concentrations (by radioimmunoassay). Results Compared with the baseline at T0, blood glucose concentrations were significantly decreased at T1 and increased at T3, and plasma orexin-A concentrations were increased at T2 in two groups (P 0.05). Conclusion The mechanism by which doxapram promotes emergence from general anesthesia may be related to increasing plasma orexin-A concentrations in patients. Key words: Doxapram; Anesthesia, general; Emergence; Orexin

Interaction Between Orexin-A and Sleep Quality in Females in Extreme Weight Conditions.

The current study examined the relationship between plasma orexin-A and sleep in obesity. Concentrations of orexin-A and sleep were evaluated in 26 obese, 40 morbid obese and 32 healthy-weight participants. The sleep monitor Actiwatch AW7 and the Pittsburgh Sleep Quality Index were used to evaluate sleep. The Symptom Checklist-90-Revised was administered to assess symptoms of psychopathology. A higher weight status was associated with elevated orexin-A levels (p = .050), greater depression, anxiety and somatization symptoms (all: p < .001), and impoverished self-reported sleep quality (p < .001). A quadratic trend was found in objective sleep time, being longest in the obese group (p = .031). Structural equation modelling showed plasma orexin-A to be related to poor total sleep quality, which in turn was associated with elevated body mass index. Our data confirm an interaction between elevated plasma orexin-A concentrations and poor sleep that contributes to fluctuations in body mass index. Copyright © 2016 John Wiley & Sons, Ltd and Eating Disorders Association.

Orexin-A facilitates emergence of the rat from isoflurane anesthesia via mediation of the basal forebrain

Previous studies have demonstrated that orexinergic neurons involve in promoting emergence from anesthesia of propofol, an intravenous anesthetics, while whether both of orexin-A and orexin-B have promotive action on emergence via mediation of basal forebrain (BF) in isoflurane anesthesia has not been elucidated. In this study, we observed c-Fos expressions in orexinergic neurons following isoflurane inhalation (for 0, 30, 60, and 120min) and at the time when the righting reflex returned after the cessation of anesthesia. The plasma concentrations of orexin-A and -B in anesthesia-arousal process were measured by radioimmunoassay. Orexin-A and -B (30 or 100pmol) or the orexin receptor-1 and -2 antagonist SB-334867A and TCS-OX2-29 (5 or 20μg) were microinjected into the basal forebrain respectively. The effects of them on the induction (loss of the righting reflex) and the emergence time (return of the righting reflex) under isoflurane anesthesia were observed. The results showed that the numbers of c-Fos-immunoreactive orexinergic neurons in the hypothalamus decreased over time with continued isoflurane inhalation, but restored at emergence. Similar alterations were observed in changes of plasma orexin-A concentrations but not in orexin-B during emergence. Administration of orexins had no effect on the induction time, but orexin-A facilitated the emergence of rats from isoflurane anesthesia while orexin-B didn't. Conversely, microinjection of the orexin receptor-1 antagonist SB-334867A delayed emergence from isoflurane anesthesia. The results indicate that orexin-A plays a promotive role in the emergence of isoflurane anesthesia and this effect is mediated by the basal forebrain.

Orexin and sleep quality in anorexia nervosa: Clinical relevance and influence on treatment outcome

Background and aimsOrexins/hypocretins are orexigenic peptides implicated in the regulation of feeding behavior and the sleep/wake cycle. Little is known about the functioning of these peptides in anorexia nervosa (AN). The aims of the current study were to evaluate the extent to which orexin-A might be linked to sleep and treatment outcome in AN. MethodFasting plasma orexin-A concentrations were measured in 48 females with AN at the start of a day hospital treatment and in 98 normal-eater/healthy-weight controls. The Pittsburgh Sleep Quality Index was administered at the beginning of the treatment as a measure of sleep quality. Other psychopathological variables were evaluated with the Symptom Checklist-Revised (SCL90R) and the Eating Disorder Inventory-2 (EDI). Patients were assessed at the start and end of treatment by means of commonly used diagnostic criteria and clinical questionnaires. ResultsThe AN patients presented more sleep disturbances and poorer overall sleep quality than did the healthy controls (p=.026) but there were no global differences between groups in plasma orexin-A concentrations (p=.071). In the AN sample, orexin-A concentrations were associated with greater sleep disturbances (|r|=.30), sleep inefficiency (|r|=.22) and poorer overall sleep (|r|=.22). Structural Equation Modeling (SEM) showed that both elevated orexin-A concentrations and inadequate sleep predicted poorer treatment outcome. ConclusionPlasma orexin-A concentrations contribute to poor sleep quality in AN, and both of these variables are associated with therapy response.

Glucagon regulates orexin A secretion in humans and rodents.

Orexin A (OXA) modulates food intake, energy expenditure, and lipid and glucose metabolism. OXA regulates the secretion of insulin and glucagon, while glucose regulates OXA release. Here, we evaluate the role of glucagon in regulating OXA release both in vivo and in vitro. In a double-blind crossover study, healthy volunteers and type 1 diabetic patients received either intramuscular glucagon or placebo. Patients newly diagnosed with type 2 diabetes underwent hyperinsulinaemic-euglycaemic clamp experiments, and insulin-hypoglycaemia tests were performed on healthy volunteers. The primary endpoint was a change in OXA levels after intramuscular glucagon or placebo administration in healthy participants and patients with type 1 diabetes. Secondary endpoints included changes in OXA in healthy participants during insulin tolerance tests and in patients with type 2 diabetes under hyperinsulinaemic-euglycaemic conditions. Participants and staff conducting examinations and taking measurements were blinded to group assignment. OXA secretion in response to glucagon treatment was assessed in healthy and obese mice, the streptozotocin-induced mouse model of type 1 diabetes, and isolated rat pancreatic islets. Plasma OXA levels declined in lean volunteers and in type 1 diabetic patients injected with glucagon. OXA levels increased during hyperinsulinaemic hypoglycaemia testing in healthy volunteers and during hyperinsulinaemic euglycaemic conditions in type 2 diabetic patients. Plasma OXA concentrations in healthy lean and obese mice and in a mouse model of type 1 diabetes were lower after glucagon treatment, compared with vehicle control. Glucagon decreased OXA secretion from isolated rat pancreatic islets at both low and high glucose levels. OXA secretion declined in pancreatic islets exposed to diazoxide at high and low glucose levels, and after exposure to an anti-insulin antibody. Glucagon further reduced OXA secretion in islets pretreated with diazoxide or an anti-insulin antibody. Glucagon inhibits OXA secretion in humans and animals, irrespective of changes in glucose or insulin levels. Through modifying OXA secretion, glucagon may influence energy expenditure, body weight, food intake and glucose metabolism.

Orexin-A Facilitates Emergence from Propofol Anesthesia in the Rat

Hypothalamic orexinergic neurons play a critical role in the promotion and maintenance of wakefulness in mammals. Previous studies have demonstrated that activities of orexinergic neurons were inhibited by isoflurane and sevoflurane, and microinjection of orexin facilitated the emergence from volatile anesthesia. In this study we first examined the hypothesis that the activity of orexin neurons is inhibited by propofol anesthesia. Moreover, the role of the orexinergic signals in basal forebrain in regulating the anesthesia-arousal cycle of propofol anesthesia is also elucidated. Rats were killed at 0, 30, 60, and 120 minutes of propofol infusion as well as at the time the righting reflex returned after the termination of anesthesia. Activated orexinergic neurons were detected by c-Fos expression. The plasma concentrations of orexin-A were measured by radioimmunoassay. Orexin-A (30 or 100 pmol) or the orexin-1 receptor antagonist, SB-334867A (5 or 20 μg), was microinjected into the basal forebrain 15 minutes before propofol infusion, or 15 minutes before the termination of propofol infusion. The loss and the return of the righting reflex time were recorded as the induction and the emergence time. Propofol anesthesia resulted in an inhibition of orexinergic neuron activity as demonstrated by the reduced numbers of c-Fos-immunoreactive orexinergic neurons. The activities of orexinergic neurons were restored when rats emerged from anesthesia. Propofol anesthesia decreased plasma orexin-A concentrations. Intrabasalis microinjection of orexin-A had no effect on the induction time but facilitated the emergence from propofol anesthesia. Inversely, intrabasalis microinjection of the orexin-1 receptor antagonist SB-334867A delayed the emergence from propofol anesthesia. Our findings indicate that activity of orexinergic neurons is inhibited by propofol anesthesia, and the orexin signals in basal forebrain are involved in anesthesia-arousal regulation from propofol anesthesia.

Low cerebrospinal fluid and plasma orexin-A (hypocretin-1) concentrations in combat-related posttraumatic stress disorder

The hypothalamic neuropeptide, orexin-A has a number of regulatory effects in humans and pre-clinical evidence suggests a link to neuroendocrine systems known to be pathophysiologically related to posttraumatic stress disorder (PTSD). However, there are no reports of central nervous system (CNS) or peripheral orexin-A concentrations in patients with PTSD, or any anxiety disorder. Cerebrospinal fluid (CSF) and plasma levels of orexin-A were serially determined in patients with PTSD and healthy comparison subjects to characterize the relationships between orexin-A (in the CNS and peripheral circulation) and central indices of monoaminergic neurotransmission and to determine the degree to which CNS orexin-A concentrations reflect those in the circulating blood. CSF and plasma samples were obtained serially over a 6-h period in 10 male combat veterans with chronic PTSD and 10 healthy male subjects through an indwelling subarachnoid catheter. Orexin-A concentrations were determined in plasma and CSF and CSF levels of the serotonin metabolite, 5-hydroxyindolacetic acid (5-HIAA), and the dopamine metabolite, homovanillic acid (HVA), were determined over the sampling period. CSF and plasma orexin-A concentrations were significantly lower in the patients with PTSD as compared with healthy comparison subjects at all time points. In addition, CSF orexin-A concentrations strongly and negatively correlated with PTSD severity as measured by the Clinician-Administered PTSD Scale (CAPS) in patients with PTSD. Peripheral and CNS concentrations of orexin-A were correlated in the healthy comparison subjects and peripheral orexin-A also correlated with CNS serotonergic tone. These findings suggest low central and peripheral orexin-A activity in patients with chronic PTSD are related to symptom severity and raise the possibility that orexin-A is part of the pathophysiological mechanisms of combat-related PTSD.

Role of the orexinergic system in acute haemorrhage in the rat

Orexins (OXs) stimulate sympathetic nerve activity to increase arterial pressure (AP) and heart rate (HR). We have previously reported that the OX(1)-receptor antagonist SB-334867 reversed the sympathomimetic actions of orexin A (OXA). In the present study we have investigated the role(s) of the orexinergic system in sympathetic activation during haemorrhage in rats. Sixteen Wistar rats, anaesthetised with pentobarbital, were assigned to 2 groups: saline i.p. (group S) and SB-334867 30 mg/kg i.p. (group SB) n=8 each. Haemorrhagic shock was established by acute withdrawal of 10 ml/kg of blood via an arterial catheter three times with a 30 min interval between each withdrawal. Haemodynamics were assessed 30 min after 10, 20, and 30 ml/kg of blood withdrawal. In addition, plasma orexin A and catecholamine concentrations in the shed blood were determined. In both groups, mean AP (MAP) and HR decreased significantly. Plasma catecholamine concentrations significantly increased following blood withdrawal. The reduction in MAP/HR and elevation of catecholamine levels were dependent on the total amount of shed blood. There were no differences between the groups. Plasma OXA concentrations increased to a greater extent in group SB than group S in response to haemorrhage. There was a significant correlation between plasma catecholamines and %change in MAP (epinephrine: r=0.553, p=0.0001, norepinephrine: r=0.374, p=0.0087) and HR (epinephrine: r=0.403, p=0.005, norepinephrine: r=0.436, p=0.002). There was no correlation with plasma orexin A levels. These data suggest that despite a weak activation the orexinergic system is unlikely to make a major contribution to the response to haemorrhage.

Clinical Significance of Daytime Plasma Orexin-A-Like Immunoreactivity Concentrations in Patients with Obstructive Sleep Apnea Hypopnea Syndrome

Background: Polysomnography (PSG) tests are very complicated and time consuming, despite their clinical benefits in the diagnosis of patients with obstructive sleep apnea hypopnea syndrome (OSAHS). A plasma marker would be desirable to select patients suspected of OSAHS for further PSG studies. We have recently reported that orexin-A concentrations in plasma collected immediately after waking early in the morning were significantly lower in patients with OSAHS than in controls. Objectives: We conducted the present study to assess the clinical usefulness of the measurement of orexin-A concentrations in plasma obtained in the daytime as a diagnostic predictor to screen patients with OSAHS. Methods: Blood samples were collected in the daytime from 19 male patients with suspected sleep-disordered breathing. Plasma orexin-A concentrations were measured by radioimmunoassay before performing PSG. Results: PSG was conducted in all 19 subjects. PSG showed that 14 subjects had OSAHS and 5 subjects did not. Plasma orexin-A concentrations were significantly lower in patients with OSAHS (4.9 ± 0.8 pmol/l, mean ± SE, n = 14) than in control subjects (12.3 ± 1.9 pmol/l, n = 5) (p = 0.0004). Conclusions: These findings suggest that the orexin-A concentration in plasma obtained even in the daytime may be a useful plasma marker for screening OSAHS.

Age-related changes in plasma orexin-A concentrations

To study the effect of aging on orexin-A, we measured plasma orexin-A concentrations in 82 healthy volunteers (55 men and 27 women) over a wide range of ages (mean 50.2±13.9 years, ranging from 23 to 79 years). Correlation analyses revealed that plasma orexin-A concentrations correlated with age ( r=0.50, P<0.01). When comparing three age groups, it appeared that the concentrations in the group of more than 60 years were significantly higher than those in the group of less than 39 years in both genders ( P<0.05). These findings suggest that orexin-A could be involved in aging in a healthy population.