Orexin Levels Research Articles

Reduction of Orexin-A Is Associated With Anxiety and the Level of Depression of Male Methamphetamine Users During the Initial Withdrawal Period

BackgroundOrexin has been linked to the regulation of reward and motivation in animals, but there have been few human studies to validate its regulatory effects. We aimed to determine how orexin-A levels changed during different stages of withdrawal, as well as the relationship between orexin-A levels and withdrawal symptoms in male METH users.MethodsThis study included 76 METH users and 35 control participants. The METH users were divided into three groups: group 1 (abstinence within 1 week, n = 23), group 2 (abstinence between 1 week and 3 months, n = 38), and group 3 (abstinence over 3 months, n = 15). At baseline and 1 month of enrollment, the plasma orexin-A level was examined. To track the withdrawal symptoms, self-report questionnaires (anxiety, depression, craving, and sleep quality) were collected at two points.ResultsThe orexin-A levels of groups 1 (p < 0.001) and 2 (p < 0.001) were lower than that of the controls at baseline but not group 3. One month later, the orexin-A levels of group 2 (p < 0.05) significantly increased, while no significant changes in those of groups 1 and 3 were observed. Furthermore, the orexin-A levels of group 1 were positively linked with depression (p < 0.01) and anxiety (p < 0.01) at baseline.ConclusionsThe decrease in orexin-A levels was only transitory during the initial abstinence phase, and it was eventually restored near to normal with continued abstinence among the male METH users. Furthermore, a lower concentration of orexin-A may serve as a risk factor for negative emotions during METH withdrawal.

Association of Body Mass Index with Orexin- A Levels in Reproductive Age Group Women

Background and Aim: Orexin-A are hypothalamic neuropeptides contributing to regularization of neuroendocrine homeostasis, feeding behavior and sleep-wakefulness rhythm. Blood pressure, sympathetic activation, blood glucose level, and metabolic status is controlled by neuropeptide. The present study aimed to evaluate the association of body mass index with Orexin-A levels in reproductive age group women. Methodology: This cross-sectional study was carried out on 120 healthy reproductive age group women at the Department of Physiology, Lady Reading Hospital, Peshawar from November 2020 to April 2021. Prior to study conduction, ethical approval was taken from the institute ethical committee. Informed written consent was obtained from each individual. All the healthy women of reproductive age group with age range from 18 years to 40 years were enrolled. Women with obstetrical problems and had pregnancy were excluded from the study. A pro-designed proforma was used for taking medical history and complications of each participant. All the participants underwent standardized questionnaire based interview regarding medical history, menstrual history, and obstetrical history. Anthropometric parameters of each participant was measured. Orexin-A/hypocretin-enzyme immunoassay kit was utilized for the measurement of fasting serum orexin levels. For data analysis and descriptive statistics, SPSS version 25 was used. Results: Of the total 120 reproductive age group women, about 66 (53%) were in age group 18 to 25 years followed by 25 (20.8%) between 26 and 30 years, 17 (14.2%) in 31 to 35 years, and 12 (10%) in 35 to 40 years. Based on different age group women, the mean serum orexin-A levels ranged from 47.26±16.48 pgm/ml for women aged above 35 years to 51.31±13.89 pgm/ml for 26 to 30 years. However, no significant association were revealed in both group with statistically significant of P=0.781. A positive correlation was found between women BMI with serum orexin levels r=0.172, p=0.05 and weight of the women with orexin serum levels r=-.179, p=0.41. Conclusion: The current study concluded that mean orexin-A levels was significantly associated with BMI. But no statistical significant association between women age and mean serum orexin level has been reported. Keywords: Body mass index, Orexin-A levels, Reproductive age group women.

Leptin, ghrelin, nesfatin-1, and orexin-A plasma levels in girls with premature thelarche.

Reducing the mean age of puberty onset in recent years has crucial public health, clinical, and social implications. This study aimed to evaluate the serum levels of appetite-related peptides (leptin, ghrelin, nesfatin-1, and orexin-A) and anthropometric data in girls with premature thelarche (PT). We enrolled 44 girls aged 4-8years diagnosed with PT and 33 age-matched healthy girls as controls. The demographic data of the girls were obtained using a questionnaire. Anthropometric data were measured and fasting blood samples were collected. Body weight, height, body mass index (BMI), body fat mass, and basal metabolic rate (BMR) were higher in the PT group than in the control group (p < 0.05). Serum leptin (p < 0.001), nesfatin-1 (p = 0.001), and orxein-A (p < 0.001) levels were significantly higher in the PT group than in healthy controls. However, there were no significant differences in the serum ghrelin levels between the groups (p > 0.05). The results of multivariate logistic regression revealed that serum leptin level (OR (95% CI): 42.0 (10.91, 173.06), p < 0.001), orexin-A (OR (95% CI): 1.14 (1.04, 1.24), p = 0.006), and BMI for age z-score (OR (95% CI): 6.97 (1.47, 33.4), p = 0.014) elevated the risk of incidence of PT at 4-8 girls. These results suggest that in addition to serum leptin levels, serum orexin-A and nesaftin-1 can take part in the initiation of PT. Few studies have investigated the relationship between nesfatin-1 and orexin-A levels and age at onset of puberty; hence, it should be a subject for future studies.

Relation between orexin A and epileptic seizures

IntroductionOne of the unknown mechanisms in epilepsy pathogenesis is the involvement of the hypothalamic neuropeptide orexin. Although the relationship between orexin and sleep has been revealed, its effect in epilepsy has not been fully clarified. In this study, we aimed to show the relationship between orexin A and the seizures that occur during sleep and wakefulness. Material and methodsThis study included 40 patients with drug-resistant focal epilepsy and 37 healthy controls. Night basal orexin (NBO) and morning basal orexin (MBO) levels were measured using enzyme-linked immunosorbent assay in patients and controls. Serum samples were collected from patients after epileptic seizures during sleep and wakefulness. ResultsIn both patients and controls, MBO levels (median: 1039 pg/mL, interquartile ranges [IQR] (899–1078)) were higher than NBO levels (median 989 pq/mL, IQR (893–1078) (p = 0.02). Basal orexin levels were lower in patients than in controls (p < 0.001). However, while the duration of seizures was shortened in awake seizures, the level of orexin increased (p = 0.007). Additionally, orexin levels after nocturnal seizure were higher in patients who had an ictal electroencephalography onset in the left hemisphere or a lesion in the left temporal lobe (p = 0.02; p = 0.01, respectively). There was no relationship between postictal somnolence and orexin levels. Although there was no significant difference, the level of post-seizure orexin increased compared to the basal values, especially in seizures during sleep. DiscussionThe increase in serum orexin levels, especially after seizures, suggests that orexin may be associated with the epileptogenic effect. In further studies, determination of orexin from cerebrospinal fluid (CSF) and correlation of CSF and serum orexin levels may provide more useful information regarding the relationship between orexin and epilepsy.

Effects of Vestibular Damage on the Sleep and Expression Level of Orexin in the Hypothalamus of Rats and Its Correlation with Autophagy and Akt Tumor Signal Pathway.

The aim of this study was to investigate the effect of vestibular disruption on autophagy-related proteins and the tumour-associated pathway P13K/Akt in rat sleep and its hypothalamus tissue and to examine whether catechins trigger tumour autophagy. Healthy adult male rats were randomly selected and divided into the vestibular damage group, the sham operation group, and the control group, with 8 rats in each group. A vestibular damage model was established through penetrating the tympanic membrane of the external auditory canal by injecting sodium p-aminophenylarsonate. The electroencephalogram (EGG) activity was used to record the sleep-wakefulness cycle of rats, and the expression levels of hypothalamic orexin (orexin) mRNA and autophagy proteins were detected. Primary hippocampal neurons were intervened with orexin at different concentrations and at different times to detect cell viability and the expression of autophagy protein and P13K/Akt signal pathway protein. The results showed that compared with the control group and the sham operation group, NREM duration in the vestibular damage group decreased significantly (P < 0.05), while its W time increased significantly (P < 0.05). The expression level of orexin mRNA in the hypothalamus of the vestibular damage group was significantly higher than that of the other two groups (P < 0.05), the expression of autophagy microtubule-related proteins LC3B and Beclin-1 increased significantly (P < 0.05), and the protein expression level of p62 decreased significantly (P < 0.05). After orexin intervention, compared with the control group, the expression of Beclin-1 protein that positively correlated with autophagy decreased significantly (P < 0.05) and the expression of mTOR, PDK1, and Akt protein increased significantly (P < 0.05). Compared with the orexin intervention group, the expression of Beclin-1 and LC3B proteins in cells of the orexin receptor inhibitor (Almorexant) group, the autophagy activator (Rapamycin) group, the orexin + Almorexant group, and the orexin + Rapamycin group increased significantly (P < 0.05), and the expression of mTOR, PDK1, and Akt proteins decreased significantly (P < 0.05). Catechins trigger autophagy in part by regulating the p-Akt/p-mTOR and P13K pathways and by stimulating the MAPK pathway. Catechins initiate apoptosis in common tumour types of hepatocellular carcinoma cells by activating autophagy-related pathways. The conclusion is that vestibular damage can affect the sleep-wakefulness cycle of rats; the level of autophagy in hypothalamic tissue is upregulated and may affect cell proliferation and activity through mTOR-P13K/Akt, which has a certain reference value for tumor formation and provides a basis for the research of insomnia or sleep disorders caused by tumors. Autophagy activation is a key process by which catechins promote apoptosis in tumour cells, providing an avenue for more research on the use of catechins-rich diets for cardiovascular protection in the treatment of tumours.

Orexins and bipolar disorder: A review

IntroductionBipolar disorder (BD) is a chronic deteriorating illness which has a strong impact on functionality. In the past few years, orexins have gained importance as possible biomarkers of circadian rhythms, affected in BD. Up to this date, we have not found any bibliographical review evaluating the association of orexins and BD.ObjectivesTo review published literature in relation to the associaton of orexins and BD.MethodsA bibliographical search was conducted in PubMed. Inclusion criteria were a) the study evaluated orexins in plasma or cerebrospinal fluid, and b) patients with BD were included within the subjects of study.Reference lists of the articles that met inclusion criteria were also examined.ResultsTen articles were retrieved from the initial search. Only three met inclusion criteria and another one was selected from the reference list examination. One study observed significantly higher levels of orexin A in plasma of BD patients versus depression and controls. Other found higher concentration of orexin A of unipolar and bipolar depression versus controls, but this result was not statistically significant. Another one did not find differences in orexin A concentration between mania, depression and controls. The remaining study detected significantly lower concentration of orexin A in BD versus depression, schizophrenia and controls.ConclusionsDespite being heterogenous, the results point out there are differences in orexin levels in BD when compared to other diagnostic groups or controls. This sets a starting point to focus research on this subject and continue analyzing the role of orexins as biomarkers in BD.DisclosureNo significant relationships.

Orexin-A levels in reproductive age group women and its association with body mass index

Objectives: Orexins are hypothalamic neuropeptides, which are involved in feeding behaviour, sleep-wakefulness, and neuroendocrine homeostasis in the body. The study was conducted with the aim to estimate the serum orexin levels in reproductive age group (RAG) women and to determine the association of serum orexin levels with body mass index (BMI) in females of RAG. Materials and Methods: One hundred and forty apparently healthy women of RAG (20–40 years) were randomly selected. Fasting serum orexin levels were measured using ELISA and BMI was calculated in women based on their height and weight. Results: Serum orexin levels were significantly higher in women with BMI ≥ 25 kg/m2 (P = 0.035) as compared to women with BMI &lt; 25 kg/m2. Conclusion: In the present study, BMI correlated significantly with mean serum orexin levels. However, serum orexin levels did not correlate with the age of women.

0384 Clinical Utilization of a CSF Orexin Test: First Two Years of Data from Mayo Clinic

Abstract Introduction Orexin deficiency in cerebrospinal fluid (CSF) was first reported in human narcolepsy in 2001, included in diagnostic criteria for narcolepsy in 2014, and made clinically available at the Mayo Clinic in 2019. The purpose of this publication is to report orexin test utilization and results, and other clinically relevant findings from patients evaluated at Mayo Clinic. Methods We retrospectively reviewed CSF orexin samples and clinical records from patients evaluated at Mayo Clinic from 2019 to 2021. Results A total of 98 internal samples (Rochester, n=56; Arizona, n=25, and Florida, n=17) from 95 patients (mean age 32.4 +/- 16.6 years with 20 %, 52 %, and 28 % of patients &amp;lt; 18, 18 – 40, and &amp;gt; 40 years, respectively, at time of CSF collection; 62 % female) have been submitted for CSF orexin measurement (mean CSF orexin 335.17 +/- 158.3 pg/ml; deficient &amp;lt; 110 pg/ml, n=11, 64 % &amp;lt;=40 years with mean age 32.9 +/- 17.0 years; intermediate 110 – 200 pg/ml, n=8, 100 % &amp;lt;= 40 years with mean age 21.1 +/- 12.8 years; normal &amp;gt; 200 pg/ml, n=79, 57 % &amp;lt;=40 years with mean age 33.5 +/- 16.7). No significant correlation was found between orexin levels, and time of collection (i.e., diurnal variation), gender, or age. Repeat testing was performed on three individuals (ages 10, 14, and 19 years) with a change in category of orexin level found in one patient from an intermediate to a normal level. Conclusion Orexin deficiency was found in 12 % of the patients (64 % of the deficient samples were found at ages &amp;lt;= 40 years). This result may reflect the fact that this test is frequently pursued in clinical patients presenting with inconclusive findings and/or comorbidities. Intermediate orexin levels found in 8 % of the samples (100 % &amp;lt;= 40 years). Although most of the patients tested were female (62.2%) and most were 40 years or younger (72%), no significant correlation was found between orexin levels, and time of collection (i.e., diurnal variation), gender, or age. Support (If Any) none

0301 Does Orexin Influence Sleep Fragmented Brain Inflammation? A Pilot Study

Abstract Introduction Fragmented sleep occurs when there are repetitive, short interruptions of sleep, resulting in less than six hours of sleep per day. Overall, however, in the United States, sleep fragmentation is reported by 30% of employed adults. Sleep fragmentation may be a risk factor for Alzheimer's disease, and orexin reduction appears effective in reducing amyloid plaque formation in mice with transgenic Alzheimer's disease. Orexin is a neuropeptide that regulates arousal, wakefulness, and appetite. Thus we hypothesized that loss of orexin might also be protective against sleep disruption injury in non-Alzheimer's mice. This study aims to combine sleep fragmentation with orexin loss to see if brain health is severely reduced. Methods The 24 mice in this study were split into four groups: B6 rested, B6 sleep fragmented, orexin knockout rested, orexin knockout sleep fragmented. The sleep fragmented mice were placed on a shaker table for 10½ weeks to initiate chronic sleep loss. The mice were all perfused within five to eight months of birth, and then the brains were cryopreserved and sliced. These sections were immunolabeled with different protein antibodies using immunohistochemistry techniques. The stained brains were either analyzed through microscope stereology counts or computer image analysis. Results Two-way ANOVA analysis for tyrosine hydroxylase, ionized calcium binding adaptor, and vesicular acetylcholine transporter had p&amp;lt;0.05 for the sleep fragmentation variable, showing differences in these antibodies for rested and sleep loss mice. ANOVA for cluster of differentiation 68, cofilin, postsynaptic density protein, and RanBP had p&amp;lt;0.05 for the genotype variable, showing differences in these antibodies for knockout and normal orexin mice. ANOVA for glial fibrillary acidic protein and amyloid-beta had p&amp;lt;0.05 for both variables, showing differences for sleep and orexin levels. There was no ANOVA significance for synapsin. Conclusion Our results show that knocking out orexinergic neurons causes hippocampal tissue damage, dampens the functioning of synapses, and diminishes the ability of the brain to adapt through plasticity and memory. Sleep fragmentation, however, increases phagocytic activity, and harms the acetylcholine and norepinepherine neurotransmitter pathways. When combined, cell communication worsens and the blood brain barrier loses function, resemblant of neurodegenerative diseases. Support (If Any) NIH AG054104; AG064231

0280 Orexins play a dual role in immobility episodes on taiep rats a model of H-ABC

Abstract Introduction Leukodystrophies are a heterogenous group of congenital myelin alterations with more than 30 classified diseases was described until now. Among them there are several mutations in the a and b tubulins the so called tubulinophaties, that affect the central nervous system. The hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is due to a mutation in the tubulin b 4a (TUBB4A) and the taiep rats is the only available model of this human disease with similar magnetic resonance changes and a punctual mutation in the TUBB4A. Taiep rats had immobility episodes (IEs) with a peak between at 9 months of age. Importantly, electroencephalographic recordings shown that IEs had a rapid eye movement (REM) sleep characteristic pattern supporting that are equal to human cataplexy episodes that are key sign of narcolepsy. It is possible to induced IEs when taiep rats are manipulated from the tail or the thorax. Narcolepsy in humans and narcoleptic dogs had a significant decreased in orexin levels in the cerebrospinal fluid (CSF) and a concomitantly decreased of orexin neurons in the lateral hypothalamus. Methods We used 21 male rats from taiep at 9 months of age. All rats were kept in standard conditions and were implanted for EEG, EMG and EOG recordings to characterize IEs. We administered orexin A and B agonists and characterized the sleep-wake cycle and frequency of IEs, the peptides were administered by a intracerebroventricular (i.c.v.) injections diluted in artificial CSF. We also measured the number or positive orexin neurons in the lateral hypothalamus through immunohistochemistry. Results The i.c.v. administration of [Ala11, D-Leu 15] orexin B agonist significantly decrease the frequency of IEs with 3 and 10 nM doses (P≤0.05 and P≤0.03, respectively), without affecting the sleep-wake pattern. However, the i.c.v. administration of Orexin A (17-33) an agonist did not affect the sleep-wake pattern or the frequency of IEs. It is relevant that the number of orexins neurons did not differ between taiep and control Sprague-Dawley (SD) male rats. Conclusion Our results showed that IEs had a REM sleep EEG characteristic pattern with cataplexic-like atonia, there are sensible to orexin B agonist, but the number of orexin positive neurons do not differ with respect to SD male rats. In conclusion taiep rats a model of H-ABC is an adequate model of cataplexy-like episodes due to myelin disease. Support (If Any) Partially supported by PRONACES-CONACYT grant 194171, and VIEP-BUAP 2021 to CA in Neuroendocrinología. KGE is fellowship from CONACYT No. 772626.

Correlation of Orexin-A and brain-derived neurotrophic factor levels in metabolic syndrome and cognitive impairment in schizophrenia treated with clozapine

Orexin-A and brain-derived neurotrophic factor (BDNF) are implicated in regulating metabolic syndrome (MetS) and cognitive impairment of schizophrenia. However, the associations among them remains unclear. Here, we aimed to investigate the relationship between Orexin-A levels, BDNF, MetS, clinical symptom profile, and cognitive function in schizophrenia patients following long-term clozapine treatment. We measured Orexin-A and BDNF levels in 140 schizophrenia patients with and without MetS. We assessed clinical symptoms on the Positive and Negative Syndrome Scale and cognitive function by the assessment of Neuropsychological Status (RBANS), and examined their associations with Orexin-A. Patients with MetS had significantly lower Orexin-A levels and higher coding test, attention span and delayed retention in RBANS (P < 0.05). Correlation analysis showed that Orexin-A was associated with BDNF, TG, HDLC, PANSS active social avoidance and emotional withdrawal significantly. Besides, Orexin-A significantly interacted with BDNF for metabolic and cognitive profiles including waist circumference, delayed retention and list recognition. Logistic regression analysis showed that Orexin-A level (odds ratio [OR] = 0.380, 95% confidence interval [CI]: 0.151–0.952, P = 0.039) and total illness duration (OR = 0.932, 95% CI: 0.875–0.991, P = 0.025) were predictive variables of MetS. However, there was no significant relationship between Orexin-A and cognitive function after adjustment for age, sex and educational levels. Totally, a lower plasma Orexin-A level seems to be related to metabolic parameters more than cognitive profiles. The interaction of Orexin-A with BDNF may be partly responsible for worse MetS and better cognition of elderly schizophrenia, but the causal relationship needs further clarification.

Supplementation with Fermented Feedstuff Enhances Orexin Expression and Secretion Associated with Increased Feed Intake and Weight Gain in Weaned Pigs.

Simple SummaryIn weaned pigs, finding a strategy to improve the health status while also enhancing the growth performance of piglets under weaning stress through nutritional measures is an important issue that needs to be solved. Supplementation with fermented feedstuff improves the feed intake and growth performance of weaned pigs, but the exact mechanism behind this remains unclear. Hence, the present study evaluated the effects of fermented feedstuff on the performance and gastrointestinal hormones involved in feed intake and growth in weaned pigs. The results of our study showed that dietary supplementation with fermented feedstuff improved the growth performance of weaned pigs by increasing orexin, IGF-1, and IGFR levels.The health status of weaned pigs is crucial for their subsequent growth performance. Supplementation with fermented feedstuff is able to improve the feed intake and growth of weaned pigs; however, the exact mechanism behind this is not clear. Hence, in the present study a total of 320 Duroc × Landrace × Yorkshire weaned pigs were selected and allocated to the following two groups: unfermented diet group (UFD) and fermented diet group (FD). The experimental period lasted 21 days. At the end of the experiment, feces, blood, and gastrointestinal tissue samples (including the stomach, jejunum, and ileum) were collected and used for further analysis. The results of growth performance suggested that the FD group had significantly increased (p < 0.05) average daily feed intake (ADFI) and average daily gain (ADG) during the first week, during the last two weeks, and over the entire three-week period compared with the UFD group. The results of the apparent nutrient digestibility of pigs showed that, compared with the UFD group, the FD group showed increased phosphorus (p < 0.05) and CP (p < 0.1) digestibility. There were no significant differences in the serum biochemical parameters between the UFD and FD groups. Moreover, our results showed that the FD group showed significantly increased gene expression of SGLT1 and PepT1 in the jejunum (p < 0.05). Compared with the UFD group, the FD group showed an increased (p < 0.05) serum orexin level and prepro-orexin (PPOX) expression in the gastric fundus, jejunum, and ileum mucosa and increased IGF-1 and IGFR expression in the jejunum. Collectively, these results indicated that supplementation with fermented feedstuff in the diet effectively enhanced the feed intake and growth of weaned pigs and that this may have been caused by the increased orexin, IGF-1, and IGFR serum levels.

Effects of caffeine ingestion and thermotherapy on blood orexin circulation in humans.

Caffeine and orexin can affect awakening, neuroendocrine, and sympathetic nerve function. Our previous study has reported that caffeine intake can increase human body temperature. However, little is known about the combined effects of thermotherapy and caffeine intake on human serum orexin concentrations. Forty-two healthy male subjects with age of 26.72 ± 5.05 years, height of 174.10 ± 7.09 cm, and body weight of 74.68 ± 8.91 kg participated in this study. They were randomly assigned to a control (CON) group (n = 21) and a caffeine (CAFF) group (n = 21). After thermotherapy (half-body immersion in a hot water bath at 42 ± 0.5 °C, circulating orexin level increased more (p < 0.05) in the CAFF group than in the CON group. Positive relationships between mean body temperature and orexin were observed before and after heat stimulation (p < 0.001). Caffeine intake boosted the upregulation of serum orexin concentrations in subjects undergoing thermotherapy.

Lateral Hypothalamus Corticotropin-releasing Hormone Receptor-1 Inhibition and Modulating Stress-induced Anxiety Behavior.

Stress is a reaction to unwanted events disturbing body homeostasis and its pathways and target areas. Stress affects the brain through the lateral hypothalamic area (LHA), the orexinergic system that mediates the effect of corticotropin-releasing hormone (CRH) through CRH Receptor Type 1 (CRHr1). Therefore, this study explores the outcome of stress exposure on anxiety development and the involvement of the LHA through LHA-CRHr1. Male Wistar rats (220-250 g) implanted with a cannula on either side of the LHA received acute or chronic stress. Subsequently, exploratory behavior was examined using the Open Field (OF), and anxiety was tested by Elevated Plus Maze (EPM). Before sacrifice, the cerebrospinal fluid (CSF) and the blood were sampled. Nissl stain was performed on fixed brain tissues. Acute stress reduced exploration in of and increased anxiety in EPM. LHA-CRHr1 inhibition reversed the variables to increase the exploration and decrease anxiety. In contrast, chronic stress did not show any effect on anxiety-related behaviors. Chronic stress decreased the cell population in the LHA, which was prevented by the CRHr1 inhibition. However, the CRHr1 inhibition could not reverse the chronic stress-induced increase in the CSF orexin level. Furthermore, plasma corticosterone levels increased through acute or chronic stress, impeded by the inhibition of CRHr1. Our results recognize LHA-CRHr1 as a capable candidate that modulates acute stress-induced anxiety development and chronic stress-induced changes in the cellular population of the region. Acute stress, increased immobility of the rat in open field and elevated plus maze.Chronic stress, increased orexin production while decreasing neuronal survival.The anxiety and immobility were not developed in presence of CRHr1.CRHr1 blocking reversed the chronic stress changes in corticosterone and orexin. Lateral Hypothalamus (LH) is a region involved in sleep and appetite regulation and recently known to play role in stress pathophysiology. The stress mediating function of the LH is performed through Corticotropin Releasing Hormone Receptor type-1 (CRHr1). This study explored the role of LH- CRHr1 in anxiety development and orexin production. Acute and chronic stress affected the behavior and molecular changes, differently. The acute stress increased the anxiety condition, while the chronic stress could only change the molecular criteria. Although we assumed that the inability of the chronic stress to develop anxiety may be attributable to habituation, the chronic stress could increase the plasma corticosterone and orexin level. All of the stress mal-changes in behavior and molecular level prevented by antagonising CRHr1 in the LH, indicating a gating function of LH-CRHr1 for stress development.

Insulin-like Growth Factor I Couples Metabolism with Circadian Activity through Hypothalamic Orexin Neurons.

Uncoupling of metabolism and circadian activity is associated with an increased risk of a wide spectrum of pathologies. Recently, insulin and the closely related insulin-like growth factor I (IGF-I) were shown to entrain feeding patterns with circadian rhythms. Both hormones act centrally to modulate peripheral glucose metabolism; however, whereas central targets of insulin actions are intensely scrutinized, those mediating the actions of IGF-I remain less defined. We recently showed that IGF-I targets orexin neurons in the lateral hypothalamus, and now we evaluated whether IGF-I modulates orexin neurons to align circadian rhythms with metabolism. Mice with disrupted IGF-IR activity in orexin neurons (Firoc mice) showed sexually dimorphic alterations in daily glucose rhythms and feeding activity patterns which preceded the appearance of metabolic disturbances. Thus, Firoc males developed hyperglycemia and glucose intolerance, while females developed obesity. Since IGF-I directly modulates orexin levels and hepatic expression of KLF genes involved in circadian and metabolic entrainment in an orexin-dependent manner, it seems that IGF-I entrains metabolism and circadian rhythms by modulating the activity of orexin neurons.

Orexin-a elevation in antipsychotic-treated compared to drug-free patients with schizophrenia: A medication effect independent of metabolic syndrome

Orexin-A levels are reportedly increased in antipsychotic (APD)-treated patients with schizophrenia compared to healthy controls and have been associated with metabolic abnormalities. It is not clear whether the orexin-A elevation is related specifically to the drug (APDs) effect, which should be clarified by including a drug-free group for comparison, or related to drug-induced metabolic abnormalities. Blood orexin-A levels and metabolic profiles were compared between 37 drug-free, 45 aripiprazole-treated, and 156 clozapine-treated patients with schizophrenia. The association between orexin-A and metabolic outcomes were examined. We explored the effects of APDs treatment and metabolic status on orexin-A levels by linear regression. Patients under APDs treatment had increased orexin-A levels compared to drug-free patients, with aripiprazole-treated group having higher orexin-A levels than clozapine-treated group. Higher orexin-A levels reduced the risks of metabolic syndrome (MS) and type 2 diabetes mellitus, indicating a relationship between orexin-A levels and metabolic problems. After adjusting the effect from metabolic problems, we found APD treatment is still associated with orexin-A regulation, with aripiprazole more significantly than clozapine. With the inclusion of drug-free patients rather than healthy controls for comparison, we demonstrated that orexin-A is upregulated following APD treatment even after we controlled the potential effect from MS, suggesting an independent effect of APDs on orexin-A levels. Furthermore, the effect differed between APDs with dissimilar obesogenicity, i.e. less obesogenicity likely associated with higher orexin-A levels. Future prospective studies exploring the causal relationship between APDs treatment and orexin-A elevation as well as the underlying mechanisms are warranted.

Cerebrospinal Fluid Histamine Levels in Healthy Children and Potential Implication for SIDS: Observational Study in a French Tertiary Care Hospital.

ObjectiveA defect of the waking systems could constitute a factor of vulnerability for sudden infant death syndrome (SIDS). A decrease in orexin levels, which promotes wakefulness and activates histaminergic neurons (another hypothalamic wake-promoting system) has already been demonstrated between 2 and 6 months. This work aims to study the levels of histamine (HA), tele-methylhistamine (t-MeHA), its direct metabolite, and t-MeHA/HA ratio in the cerebrospinal fluid (CSF) of healthy children, to evaluate the maturation of the histaminergic system and its possible involvement in SIDS.MethodsSeventy Eight French children between 0 and 20 years (48.7% boys) were included, all of whom had a clinical indication for lumbar puncture, but subsequently found to be normal. Measurements of HA and t-MeHA in CSF were performed by reverse phase liquid chromatography coupled to mass spectrometry detection. Statistical analyses were performed using Spearman correlations and Non-parametric pairwise ranking tests.ResultsA negative correlation was found between age and CSF HA (r = −0.44, p < 10−4) and t-MeHA (r = −0.70, p < 10−4) levels. In pairwise comparisons, no difference in CSF HA and t-MeHA levels was observed between youngest age groups (i.e., 0–2 mo vs. 3–6 mo), but CSF HA and t-MeHA levels were significantly lower in older children (i.e., >6 mo vs. 0–6 mo). The CSF HA decrease with age was only observed in boys, who also presented global lower CSF HA levels than girls.ConclusionCSF HA and t-MeHA levels decrease with age in boys, and global levels are lower in boys than in girls. These results reveal changes in histaminergic transmission and metabolism during maturation. Whether lower CSF histamine values in boys compared to girls could contribute to their higher risk of SIDS warrants further research.

Linking clinical complaints and objective measures of disrupted nighttime sleep in narcolepsy type 1.

Despite its high frequency in narcolepsy type 1(NT1), disrupted nocturnal sleep (DNS) remains understudied, and its determinants have been poorly assessed. We aimed to determine the clinical, polysomnographic (PSG), and biological variables associated with DNS in a large sample of patients with NT1, and to evaluate the effect of medication on DNS and its severity. Two hundred and forty-eight consecutive adult patients with NT1 (145 untreated, 103 treated) were included at the National Reference Center for Narcolepsy-France; 51 drug-free patients were reevaluated during treatment. DNS, assessed with the Narcolepsy Severity Scale (NSS), was categorized in four levels (absent, mild, moderate, severe). Clinical characteristics, validated questionnaires, PSG parameters (sleep fragmentation markers: sleep (SB) and wake bouts (WB), transitions), objective sleepiness, and orexin-A levels were assessed. In drug-free patients, DNS severity was associated with higher scores on NSS, higher sleepiness, anxiety/depressive symptoms, autonomic dysfunction, worse quality of life (QoL). Patients with moderate/severe DNS (59%) had increased sleep onset REM periods, lower sleep efficiency, longer wake after sleep onset, more N1, SB, WB, sleep instability, transitions. In treated patients, DNS was associated with the same clinical data, and antidepressant use; but only with longer REM sleep latency on PSG. During treatment, sleepiness, NSS scores, depressive symptoms decreased, as well as total sleep time, WB, SB, transitions. DNS improved in 55% of patients, without predictors except more baseline anxiety. DNS complaint is frequent in NT1, associated with disease severity based on NSS, several PSG parameters, and objective sleepiness in untreated and treated conditions. DNS improves with treatment. We advocate the systematic assessment of this symptom and its inclusion in NT1 management strategy.

Association of fasting Orexin-A levels with energy intake at breakfast and subsequent snack in Chilean adolescents

Orexin-A, a hormone secreted by orexin neurons, is involved in caloric-intake regulation. Current understanding is based primarily on animal studies. Studies of orexin in humans are scarce, and to our knowledge there are no prior studies in adolescents. We studied fasting Orexin-A levels related to energy intake at breakfast and a subsequent snack in adolescents (n = 668) from a longitudinal study in Chile. Body-Mass Index (BMI), components of the metabolic syndrome and fasting blood levels of leptin, insulin, ghrelin, and orexin-A were measured. Energy intake was calculated based on food weights before and after the standardized breakfast and subsequent snack. High energy intake was defined as ≥ 75th percentile. We assessed the relationship between orexin-A and high energy intake, adjusting for confounders. Higher orexin levels were associated with high breakfast energy intake (OR: 1.21; 95%CI: 0.98–1.49). Conversely, those with higher orexin levels showed a non-significant trend for lower odds of high energy intake for the snack (OR: 0.87; 95%CI: 0.70–1.07). There was a significant interaction between high breakfast energy intake and orexin levels. Those who ate more calories at breakfast displayed a lower inhibitory effect of orexin on eating at the snack (p < 0.05). There was no significant interaction between weight status and orexin. In conclusion, orexin-A levels were associated with breakfast energy intake and inversely related with subsequent snack energy intake in participants whose caloric intake at breakfast was within the normal range. Based on these findings, it appears that the association of orexin-A with energy intake depends on eating behavior.

Intermediate hypocretin-1 cerebrospinal fluid levels and typical cataplexy: their significance in the diagnosis of narcolepsy type 1.

Study ObjectivesThe diagnosis of narcolepsy type 1 (NT1) is based upon the presence of cataplexy and/or a cerebrospinal fluid (CSF) hypocretin-1/orexin-A level ≤ 110 pg/mL. We determined the clinical and diagnostic characteristics of patients with intermediate hypocretin-1 levels (111–200 pg/mL) and the diagnostic value of cataplexy characteristics in individuals with central disorders of hypersomnolence.MethodsRetrospective cross-sectional study of 355 people with known CSF hypocretin-1 levels who visited specialized Sleep-Wake Centers in the Netherlands. For n = 271, we had full data on cataplexy type (“typical” or “atypical” cataplexy).ResultsCompared to those with normal hypocretin-1 levels (>200 pg/mL), a higher percentage of individuals with intermediate hypocretin-1 levels had typical cataplexy (75% or 12/16 vs 9% or 8/88, p < .05), and/or met the diagnostic polysomnographic (PSG) and Multiple Sleep Latency Test (MSLT) criteria for narcolepsy (50 vs 6%, p < .001). Of those with typical cataplexy, 88% had low, 7% intermediate, and 5% normal hypocretin-1 levels (p < .001). Atypical cataplexy was also associated with hypocretin deficiency but to a lesser extent. A hypocretin-1 cutoff of 150 pg/mL best predicted the presence of typical cataplexy and/or positive PSG and MSLT findings.ConclusionIndividuals with intermediate hypocretin-1 levels or typical cataplexy more often have outcomes fitting the PSG and MSLT criteria for narcolepsy than those with normal levels or atypical cataplexy. In addition, typical cataplexy has a much stronger association with hypocretin-1 deficiency than atypical cataplexy. We suggest increasing the NT1 diagnostic hypocretin-1 cutoff and adding the presence of clearly defined typical cataplexy to the diagnostic criteria of NT1. Clinical trial information: This study is not registered in a clinical trial register, as it has a retrospective database design.