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The purpose of this study was to investigate the effects of neck myoclonus (NM) on sleep quality and daytime sleepiness in patients with narcolepsy (NT) and to further explore possible underlying mechanisms. We included 72 patients with narcolepsy type 1 (NT1), 34 patients with narcolepsy type 2 (NT2) and 33 healthy controls. Patients underwent questionnaires, lumbar puncture procedure, polysomnography, and multiple sleep latency test (MSLT). Healthy controls underwent polysomnography and questionnaires. Orexin-A levels in the cerebrospinal fluid (CSF) were analyzed by radioimmunoassay. Three catecholamines, including dopamine, norepinephrine and epinephrine, in the CSF were measured by high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS). Both the NT1 and NT2 groups displayed a higher level of NM incidence rate and index compared to the control group in PSG. NT1 displayed greater MSLT REM–-NM incidence rate and index than NT2. NM were often associated with arousal or awakening and body movements, which had a prominent influence on sleep quality in both narcoleptic patients and controls. There was a positive correlation between the NM index and the Pittsburgh Sleep Quality Index (PSQI), Stanford Sleepiness Scale (SSS) and Ullanlinna Narcolepsy Scale (UNS) scores in NT1 patients. In MSLT of NT1 patients, REM–NM index were positively correlated with the CSF dopamine levels, and there were elevated dopamine levels but reduced orexin-A levels in patients with REM–NM. NM incidence rate and index were high in patients with narcolepsy, which had a huge effect on sleep quality and aggravated daytime sleepiness. NM should be considered pathological and viewed as a new sleep-related movement disorder. Orexin-A and dopamine may be involved in the development of NM. • The Incidence rate and index of neck myoclonus were high in patients with narcolepsy. • Neck myoclonus affects patients' sleep quality and aggravates daytime sleepiness. • It should be considered pathological and viewed as a sleep-related movement disorder. • Its mechanism may be related to orexin-A and dopamine signaling pathways. [ABSTRACT FROM AUTHOR]

Milk and its derivatives are included in a balanced diet of humans as excellent sources of proteins, vitamins, and essential minerals that are functional nutrients. Knowledge about the nutritional benefits or harms due to milk consumption has been expanding in recent years. We previously explored, in rodent models, the metabolic effects of isoenergetic intake of milk derived from cows, donkeys, or humans, while the impact of goat's milk intake has remained unexplored. The aim of this work was to investigate, in an animal model, the effects of dietary supplementation with goat's milk on energy homeostasis and inflammatory state, focusing on the modulation of mitochondrial functions in most metabolically active organs, such as skeletal muscle and the liver. In addition, we highlighted a link between nutrient intake, substrate metabolism, and the orexinergic system. Our results indicate that goat milk improves mitochondrial oxidative capacity and reduces inflammation and oxidative stress in both organs. Notably, goat milk lowers the circulating levels of Orexin-A, a neuropeptide that plays a crucial role in regulating peripheral energy balance and central nervous system mechanisms. These data provide the first evidence that the anti-inflammatory and antioxidant effects of goat milk are mediated by the modulation of mitochondrial functions and orexinergic signaling. [ABSTRACT FROM AUTHOR]

Orexin-A is a neuropeptide product of the lateral hypothalamus that acts on two receptors, OX1R and OX2R. The orexinergic system is involved in feeding, sleep, and pressure regulation. Recently, orexin-A levels have been found to be negatively correlated with renal function. Here, we analyzed orexin-A levels as well as the incidence of SNPs in the hypocretin neuropeptide precursor (HCRT) and its receptors, HCRTR1 and HCRTR2, in 64 patients affected by autosomal dominant polycystic kidney disease (ADPKD) bearing truncating mutations in the PKD1 or PKD2 genes. Twenty-four healthy volunteers constituted the control group. Serum orexin-A was assessed by ELISA, while the SNPs were investigated through Sanger sequencing. Correlations with the main clinical features of PKD patients were assessed. PKD patients showed impaired renal function (mean eGFR 67.8 ± 34.53) and a statistically higher systolic blood pressure compared with the control group (p < 0.001). Additionally, orexin-A levels in PKD patients were statistically higher than those in healthy controls (477.07 ± 69.42 pg/mL vs. 321.49 ± 78.01 pg/mL; p < 0.001). Furthermore, orexin-A inversely correlated with blood pressure (p = 0.0085), while a direct correlation with eGFR in PKD patients was found. None of the analyzed SNPs showed any association with orexin-A levels in PKD. In conclusion, our data highlights the emerging role of orexin-A in renal physiology and its potential relevance to PKD. Further research is essential to elucidate the intricate mechanisms underlying orexin-A signaling in renal function and its therapeutic implications for PKD and associated cardiovascular complications. [ABSTRACT FROM AUTHOR]

Abstract Background Sepsis-associated encephalopathy (SAE) causes acute and long-term cognitive deficits. However, information on the prevention and treatment of cognitive dysfunction after sepsis is limited. The neuropeptide orexin-A (OXA) has been shown to play a protective role against neurological diseases by modulating the inflammatory response through the activation of OXR1 and OXR2 receptors. However, the role of OXA in mediating the neuroprotective effects of SAE has not yet been reported. Methods A mouse model of SAE was induced using cecal ligation perforation (CLP) and treated via intranasal administration of exogenous OXA after surgery. Mouse survival, in addition to cognitive and anxiety behaviors, were assessed. Changes in neurons, cerebral edema, blood-brain barrier (BBB) permeability, and brain ultrastructure were monitored. Levels of pro-inflammatory factors (IL-1β, TNF-α) and microglial activation were also measured. The underlying molecular mechanisms were investigated by proteomics analysis and western blotting. Results Intranasal OXA treatment reduced mortality, ameliorated cognitive and emotional deficits, and attenuated cerebral edema, BBB disruption, and ultrastructural brain damage in mice. In addition, OXA significantly reduced the expression of the pro-inflammatory factors IL-1β and TNF-α, and inhibited microglial activation. In addition, OXA downregulated the expression of the Rras and RAS proteins, and reduced the phosphorylation of P-38 and JNK, thus inhibiting activation of the MAPK pathway. JNJ-10,397,049 (an OXR2 blocker) reversed the effect of OXA, whereas SB-334,867 (an OXR1 blocker) did not. Conclusion This study demonstrated that the intranasal administration of moderate amounts of OXA protects the BBB and inhibits the activation of the OXR2/RAS/MAPK pathway to attenuate the outcome of SAE, suggesting that OXA may be a promising therapeutic approach for the management of SAE.

Background: Sepsis-associated encephalopathy (SAE) causes acute and long-term cognitive deficits. However, information on the prevention and treatment of cognitive dysfunction after sepsis is limited. The neuropeptide orexin-A (OXA) has been shown to play a protective role against neurological diseases by modulating the inflammatory response through the activation of OXR1 and OXR2 receptors. However, the role of OXA in mediating the neuroprotective effects of SAE has not yet been reported. Methods: A mouse model of SAE was induced using cecal ligation perforation (CLP) and treated via intranasal administration of exogenous OXA after surgery. Mouse survival, in addition to cognitive and anxiety behaviors, were assessed. Changes in neurons, cerebral edema, blood-brain barrier (BBB) permeability, and brain ultrastructure were monitored. Levels of pro-inflammatory factors (IL-1β, TNF-α) and microglial activation were also measured. The underlying molecular mechanisms were investigated by proteomics analysis and western blotting. Results: Intranasal OXA treatment reduced mortality, ameliorated cognitive and emotional deficits, and attenuated cerebral edema, BBB disruption, and ultrastructural brain damage in mice. In addition, OXA significantly reduced the expression of the pro-inflammatory factors IL-1β and TNF-α, and inhibited microglial activation. In addition, OXA downregulated the expression of the Rras and RAS proteins, and reduced the phosphorylation of P-38 and JNK, thus inhibiting activation of the MAPK pathway. JNJ-10,397,049 (an OXR2 blocker) reversed the effect of OXA, whereas SB-334,867 (an OXR1 blocker) did not. Conclusion: This study demonstrated that the intranasal administration of moderate amounts of OXA protects the BBB and inhibits the activation of the OXR2/RAS/MAPK pathway to attenuate the outcome of SAE, suggesting that OXA may be a promising therapeutic approach for the management of SAE. [ABSTRACT FROM AUTHOR]

Background and objective: At present, the etiology of narcolepsy is not fully understood, and it is generally believed to be an autoimmune reaction caused by interactions between environmental and genetic factors. Human leukocyte antigen (HLA) class II genes are strongly associated with this gene, especially HLA-DQB1*0602/DQA1*0102. In this study, we mainly analyzed the correlation between different genotypes of HLA-DQB1*0602/DQA1*0102 and clinical manifestations in Chinese patients with narcolepsy. Experimental method: Narcolepsy patients who were treated at the Department of Neurology, The First Affiliated Hospital of Shandong First Medical University from January 2021 to September 2023 were selected. General information, sleep monitoring data, cerebrospinal fluid (CSF) orexin levels, and human leukocyte antigen gene typing data were collected. The statistical analysis was performed using SPSS 26.0, and the graphs were drawn using GraphPad Prism 9.5. Main results: A total of 78 patients were included in this study. The DQA1 and DQB1 gene loci were detected in 54 patients, and only the DQB1 gene locus was detected in 24 narcoleptic patients. The most common allele at the HLA-DQB1 locus was *0602 (89.7%), and the most common genotype at this locus was *0602*0301 (19.2%), followed by *0602*0602 (17.9%). The most common phenotype of the HLA-DQA1 locus is *0102 (92.6%), and the most common genotype of this locus is *0102*0102 (27.8%), followed by *0102*0505 (14.8%). There were significant differences (p < 0.05) between HLA-DQB1*0602-positive and HLA-DQB1*0602-negative patients in terms of orexin-A levels, presence or absence of cataplexy, UNS, PSG sleep latency, REM sleep latency, N1 sleep percentage, oxygen depletion index, and average REM latency on the MSLT. The HLA-DQA1*0102-positive and HLA-DQA1*0102-negative patients showed significant differences (p<0.05) in disease course, presence or absence of sudden onset, PSG REM sleep latency, N1 sleep percentage, and average REM latency on the MSLT. There were significant differences in the average REM latency of the MSLT between HLA-DQB1*0602/DQA1*0102 homozygous and heterozygous patients p<0.05, and no differences were found in the baseline data, orexin-A levels, scale scores, or other sleep parameters. Conclusion: Different genotypes of HLA-DQA1*0102/DQB1*0602 are associated with symptoms of cataplexy in Chinese narcoleptic patients. Homozygous individuals have a shorter mean REM latency in the MSLT, greater genetic susceptibility, and relatively more severe sleepiness. [ABSTRACT FROM AUTHOR]

Background and Purpose: We evaluated the hypothesis that central orexin application could counteract motion sickness responses through regulating neural activity in target brain areas. Experimental Approach: Thec effects of intracerebroventricular (i.c.v.) injection of orexin‐A and SB‐334867 (OX1 antagonist) on motion sickness‐induced anorexia, nausea‐like behaviour (conditioned gaping), hypoactivity and hypothermia were investigated in rats subjected to Ferris wheel‐like rotation. Orexin‐A responsive brain areas were identified using Fos immunolabelling and were verified via motion sickness responses after intranucleus injection of orexin‐A, SB‐334867 and TCS‐OX2‐29 (OX2 antagonist). The efficacy of intranasal application of orexin‐A versus scopolamine on motion sickness symptoms in cats was also investigated. Key Results: Orexin‐A (i.c.v.) dose‐dependently attenuated motion sickness‐related behavioural responses and hypothermia. Fos expression was inhibited in the ventral part of the dorsomedial hypothalamus (DMV) and the paraventricular nucleus (PVN), but was enhanced in the ventral part of the premammillary nucleus ventral part (PMV) by orexin‐A (20 μg) in rotated animals. Motion sickness responses were differentially inhibited by orexin‐A injection into the DMV (anorexia and hypoactivity), the PVN (conditioned gaping) and the PMV (hypothermia). SB‐334867 and TCS‐OX2‐29 (i.c.v. and intranucleus injection) inhibited behavioural and thermal effects of orexin‐A. Orexin‐A (60 μg·kg−1) and scopolamine inhibited rotation‐induced emesis and non‐retching/vomiting symptoms, while orexin‐A also attenuated anorexia with mild salivation in motion sickness cats. Conclusion and Implications: Orexin‐A might relieve motion sickness through acting on OX1 and OX2 receptors in various hypothalamus nuclei. Intranasal orexin‐A could be a potential strategy against motion sickness. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) represents a prevalent form of primary malignant tumours in the central nervous system, but the options for effective treatment are extremely limited. Ferroptosis, as the most enriched programmed cell death process in glioma, makes a critical difference in glioma progression. Consequently, inducing ferroptosis has become an appealing strategy for tackling gliomas. Through the utilization of multi‐omics sequencing data analysis, flow cytometry, MDA detection and transmission electron microscopy, the impact of orexin‐A on ferroptosis in GBM was assessed. In this report, we provide the first evidence that orexin‐A exerts inhibitory effects on GBM proliferation via the induction of ferroptosis. This induction is achieved by instigating an unsustainable increase in iron levels and depletion of GPX4. Moreover, the regulation of TFRC, FTH1 and GPX4 expression through the targeting of NFE2L2 appears to be one of the potential mechanisms underlying orexin‐A‐induced ferroptosis. [ABSTRACT FROM AUTHOR]

Background: Clozapine is the primary antipsychotic (APD) for treatment-resistant schizophrenia (TRS). However, only 40% of patients with TRS respond to clozapine, constituting a subgroup of clozapine-resistant patients. Recently, the neuropeptide orexin-A was shown to be involved in the pathophysiology of schizophrenia. This study evaluated the association of orexin-A levels with the clozapine response in patients with TRS. Methods: We recruited 199 patients with schizophrenia, including 37 APD-free and 162 clozapine-treated patients. Clozapine-treated patients were divided into clozapine-responsive (n = 100) and clozapine-resistant (n = 62) groups based on whether they had achieved psychotic remission defined by the 18-item Brief Psychiatric Rating Scale (BPRS-18). We compared blood orexin-A levels among the three groups and performed regression analysis to determine the association of orexin-A level with treatment response in clozapine-treated patients. We also explored the correlation between orexin-A levels and cognitive function, assessed using the CogState Schizophrenia Battery. Results: Clozapine-responsive patients had higher orexin-A levels than clozapine-resistant and APD-free patients. Orexin-A level was the only factor significantly associated with treatment response after adjustment. Orexin-A levels were negatively correlated with BPRS-18 full scale and positive, negative, and general symptoms subscale scores. We also observed a positive correlation between orexin-A levels and verbal memory, visual learning and memory, and working memory function. Conclusions: This cross-sectional study showed that higher levels of orexin-A are associated with treatment response to clozapine in patients with TRS. Future prospective studies examining changes in orexin-A level following clozapine treatment and the potential benefit of augmenting orexin-A signaling are warranted. [ABSTRACT FROM AUTHOR]

Background: Constipation is a common symptom in dementia, and the cause is controversial. Rare clinical studies focused on plasma orexin-A levels and constipation in dementia. Objective: To evaluate the associations between orexin-A and constipation in patients with cognitive impairment. Methods: A total of 21 patients with mild cognitive impairment (MCI), 142 with Alzheimer's disease (AD), and 57 with Lewy body dementia (LBD) were conducted. Besides informant-based history, neurological examinations or neuropsychological assessments, plasma levels of orexin-A, and constipation were assessed. The associations between orexin-A and constipation were evaluated by logistic regression models. Results: There were 47/220 (21.36%) cognitive impairment patients having constipation, and the proportion of constipation in LBD (61.40%) was significantly higher than AD (5.63%) and MCI (19.05%). No significant age or sex differences in the prevalence of constipation were found in the MCI, AD, and LBD groups. We found the cognitive impairment patients with constipation had lower levels of plasma orexin-A [1.00 (0.86, 1.28) versus 1.29 (1.01, 1.50) ng/ml, p < 0.001] than those without. And the plasma levels of orexin-A were significantly associated with the occurrence of constipation after adjusting for all variables in all patients with cognitive impairment (OR = 0.151, 95% CI: 0.042–0.537, p = 0.003). And the same finding was more prominent in the LBD group (p = 0.048). Conclusions: The decrease of plasma level of orexin-A is closely associated with the occurrence of constipation. Orexin-A has an intestinal protective effect and is involved in the gastrointestinal symptoms of patients with cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Central Orexin‐A (OXA) modulates gastrointestinal (GI) functions and stress response. This study aimed to investigate whether OXA and CRF interact at hypothalamic level. Methods: Solid gastric emptying (GE), fecal output (FO), plasma corticosterone (CORT), and postprandial antro‐pyloric motility were assessed in rats that underwent acute restraint stress (ARS) and pretreated with central OX1R and/or CRF receptor antagonists SB‐334867 and alpha‐helical CRF9,41. Microdialysis was performed to assess ARS‐induced release of OXA and CRF in PVN and LHA, respectively. Immunofluorescence labeling was performed to detect the stress‐induced changes in OXA and to assess the hypothalamic distribution of OX1R and CRF1/2 receptors. ARS‐induced c‐Fos immunoreactivity was evaluated in PVN and LHA of rats received OX1R and CRF receptor antagonists. Key Results: ARS delayed GE by disturbing the coordination of antro‐pyloric contractions while stimulating FO and CORT secretion. ARS‐induced alterations in GE, FO, plasma CORT, and antro‐pyloric motility were attenuated by OX1R and/or CRF receptor antagonists, however, these changes were completely restored in rats received both antagonists. ARS stimulated release of OXA and CRF which were significantly attenuated by α‐CRF9,41 and SB‐334867, respectively. The OX1R was detected in CRF‐immunoreactive cells, whereas dense expression of CRF2 receptor but not CRF1 was observed in LHA. ARS remarkably increased OXA immunoreactivity in LHA. ARS‐induced c‐Fos expression in LHA and PVN was abolished by α‐CRF9,41 and SB‐334867, respectively. Conclusions & Inferences: Our findings suggest a reciprocal contribution of OXA and CRF which seems to be involved in the mediation of stress‐induced alterations in neuroendocrine and GI motor functions. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the role of neurotrophic factors and neurotransmitters in the neurocognitive impairments observed in Multiple Sclerosis (MS) patients, explore potential biomarkers, and evaluate the impact of computer-assisted cognitive rehabilitation (CCR) on these biomarkers. Materials and Methods: The study included 20 healthy volunteers and 23 relapsing-remitting MS patients with a beck depression inventory score below 17, who could use computers and had no attack in the last 6 months. Serum levels of brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), melatonin, and orexin-A were measured using enzyme-linked immunosorbent assay (ELISA) and compared between patients and controls. MS patients underwent assessment using the brief repeatable battery of neuropsychological tests (BRB-N) before (baseline) and after (sixth month) CCR their biomarker levels were measured again, along with administering neuropsychological tests. Results: Results showed lower levels of BDNF, CREB, melatonin, and orexin-A in MS patients compared to healthy controls before neurorehabilitation. Among the measured cognition-related proteins in the MS group, only BDNF was insignificantly decreased after neurorehabilitation. No significant differences were found in orexin-A, melatonin, and CREB levels before and after neurorehabilitation. Although, correlation analysis revealed no significant correlation between biomarkers and clinical parameters, paced auditory serial addition test and stroop tests which pointed to sustaining attention, information processing speed, verbal fluency, and categorical reasoning were found meaningful after CCR. Conclusions: CCR may have beneficial effects on cognitive functions, particularly executive functions. However, the four examined molecules did not reflect cognitive changes in MS and cannot be used as biomarkers. Further investigation of other molecules related to CREB and BDNF pathways may shed light on cognitive impairment in MS. [ABSTRACT FROM AUTHOR]

Sleep contributes to the energy balance of body. This study aims to investigate how rapid eye movement (REM) sleep deprivation (SD) or recovery sleep affects rat weight and the serum levels of Nesfatin-1, Orexin-A, and Leptin; additionally, seeks to determine the impact of melatonin administration on these parameters. Male, Sprague Dawley rats were randomized into two groups (n=9). REMSD was induced using the modified multiple platform method (MMPM). Melatonin was used as a treatment (20 mg/kg). Study Group I was created to investigate the effectiveness of the treatment during REMSD. Study Group II was established to analyze the possible therapeutic role of melatonin and recovery sleep after REMSD-induced damage. The rats" weights were recorded during the experiments. Blood samples were collected from all rats via decapitation after experiments. The levels of serum Nesfatin-1, Orexin-A, and Leptin were analyzed using the ELISA method. REMSD affected weight of the rats and altered the levels of serum Nesfatin-1 and Leptin. Melatonin administration influenced weight gain and affected Nesfatin-1 and Leptin levels. REMSD or melatonin did not affect Orexin-A levels. REMSD and melatonin play significant roles in the body"s energy balance. This study will contribute to elucidating the role of SD in metabolic processes and will play a role in assessing the impact of melatonin, a commonly used treatment in human and veterinary medicine.

Milk and its derivatives are included in a balanced diet of humans as excellent sources of proteins, vitamins, and essential minerals that are functional nutrients. Knowledge about the nutritional benefits or harms due to milk consumption has been expanding in recent years. We previously explored, in rodent models, the metabolic effects of isoenergetic intake of milk derived from cows, donkeys, or humans, while the impact of goat’s milk intake has remained unexplored. The aim of this work was to investigate, in an animal model, the effects of dietary supplementation with goat’s milk on energy homeostasis and inflammatory state, focusing on the modulation of mitochondrial functions in most metabolically active organs, such as skeletal muscle and the liver. In addition, we highlighted a link between nutrient intake, substrate metabolism, and the orexinergic system. Our results indicate that goat milk improves mitochondrial oxidative capacity and reduces inflammation and oxidative stress in both organs. Notably, goat milk lowers the circulating levels of Orexin-A, a neuropeptide that plays a crucial role in regulating peripheral energy balance and central nervous system mechanisms. These data provide the first evidence that the anti-inflammatory and antioxidant effects of goat milk are mediated by the modulation of mitochondrial functions and orexinergic signaling.

Perinatal undernutrition stress predisposes several disorders in adult life, which could be programed using nutraceuticals. However, the effect of perinatal undernutrition stress on orexin peptides, brain lipids, and its amelioration by a potent antioxidant (Astaxanthin) needs exploration. The present study focussed on the effect of perinatal undernutrition stress on brain fatty acid levels, Orexin peptides A and B, and its amelioration by Astaxanthin. Twenty-four male Wistar rats (Rattus norvegicus) were allocated to four groups (n = 6) as Normal, Perinatally Undernourished (UN), Astaxanthin treated (AsX, 12mg/kg), and perinatally Undernourished-but-Astaxanthin treated (UNA), and are allowed to grow for 1, 6 and 12 months. The fatty acid and orexin peptides A & B at different brain parts were measured and compared. Orexin peptides were assessed using an ELISA kit. Fatty acid levels were estimated using HP 5890 gas chromatograph. Data were analyzed by ANOVA followed by Tukey's posthoc test. P < 0.05 was considered significant. The hair cortisol, Orexin-A, and B were significantly increased (p < 0.001) in the UN group compared to normal and were modulated significantly by AsX in the UNA group. Undernutrition stress during the perinatal period altered the lipid profile, Total SFA, Total MUFA, Total n-3 PUFA, Total n-6 PUFA, n-3: n-6 PUFA, which Astaxanthin effectively modulated at 6 and 12 months of postnatal life. There was no difference between DHA and AA ratio. These results indicate that nutritional enrichment with Astaxanthin during the perinatal period positively contributes to adult health. Further, the mechanism of regulation of brain chemistry by Astaxanthin is warranted. [ABSTRACT FROM AUTHOR]

The prevalence of central precocious puberty (CPP) in girls has increased worldwide and is often associated with obesity in childhood as well as high fat/high glycemic index diets. Evidence suggests that subjects with obesity present with alterations in appetite-regulating hormones. The arcuate and paraventricular nuclei of the hypothalamus are the centers of action of appetite hormones, as well as the location of gonadotropin-releasing hormone (GnRH) neurons, the activation of which results in the onset of puberty. This anatomical proximity raises the question of possible alterations in appetite-regulating hormones in patients with CPP. Furthermore, diet-induced hypothalamic inflammation constitutes a probable mechanism of the pathophysiology of CPP, as well as alterations in appetite-regulating hormones in young children. In this article, we summarize the evidence investigating whether girls with CPP present with alterations in appetite-regulating hormones. We present evidence that leptin concentrations are elevated in girls with CPP, ghrelin concentrations are lower in girls with CPP, nesfatin-1 and orexin-A concentrations are elevated among girls with premature thelarche, and insulin concentrations are increased in girls with early menarche. [ABSTRACT FROM AUTHOR]

Sleep contributes to the energy balance of body. This study aims to investigate how rapid eye movement (REM) sleep deprivation (SD) or recovery sleep affects rat weight and the serum levels of Nesfatin-1, Orexin-A, and Leptin; additionally, seeks to determine the impact of melatonin administration on these parameters. Male, Sprague Dawley rats were randomized into two groups (n=9). REMSD was induced using the modified multiple platform method (MMPM). Melatonin was used as a treatment (20 mg/kg). Study Group I was created to investigate the effectiveness of the treatment during REMSD. Study Group II was established to analyze the possible therapeutic role of melatonin and recovery sleep after REMSD-induced damage. The rats' weights were recorded during the experiments. Blood samples were collected from all rats via decapitation after experiments. The levels of serum Nesfatin-1, Orexin-A, and Leptin were analyzed using the ELISA method. REMSD affected weight of the rats and altered the levels of serum Nesfatin-1 and Leptin. Melatonin administration influenced weight gain and affected Nesfatin-1 and Leptin levels. REMSD or melatonin did not affect Orexin-A levels. REMSD and melatonin play significant roles in the body's energy balance. This study will contribute to elucidating the role of SD in metabolic processes and will play a role in assessing the impact of melatonin, a commonly used treatment in human and veterinary medicine. [ABSTRACT FROM AUTHOR]

Introduction: Chaihu-Longgu-Muli decoction (CLMD) is a well-used ancient formula originally recorded in the "Treatise on Febrile Diseases" written by the founding theorist of Traditional Chinese Medicine, Doctor Zhang Zhongjing. While it has been used extensively as a therapeutic treatment for neuropsychiatric disorders, such as insomnia, anxiety and dementia, its mechanisms remain unclear. Methods: In order to analyze the therapeutic mechanism of CLMD in chronic renal failure and insomnia, An adenine diet-induced chronic kidney disease (CKD) model was established in mice, Furthermore, we analyzed the impact of CLMD on sleep behavior and cognitive function in CKD mice, as well as the production of insomnia related regulatory proteins and inflammatory factors. Results: CLMD significantly improved circadian rhythm and sleep disturbance in CKD mice. The insomnia related regulatory proteins, Orexin, Orexin R1, and Orexin R2 in the hypothalamus of CKD mice decreased significantly, while Orexin and its receptors increased remarkably after CLMD intervention. Following administration of CLMD, reduced neuron loss and improved learning as well as memory ability were observed in CKD mice. And CLMD intervention effectively improved the chronic inflflammatory state of CKD mice. Discussion: Our results showed that CLMD could improve sleep and cognitive levels in CKD mice. The mechanism may be related to the up-regulation of Orexin-A and increased phosphorylation level of CaMKK2/AMPK, which further inhibits NF-ΰB downstream signaling pathways, thereby improving the disordered inflammatory state in the central and peripheral system. However, More research is required to confirm the clinical significance of the study. [ABSTRACT FROM AUTHOR]

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Background/Purpose: 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. Methods: 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. Results: 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. Conclusion: 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.

Background: The lateral hypothalamus (LH), which produces orexin, is vital for body solution homeostasis. Lateral hypothalamus (LH) lesion causes adipsia and its stimulation increases water intake. Objective: This study aimed to investigate the effect of an intracerebroventricular (ICV) injection of orexin-A (OXA) on water-drinking behavior in water-deprived rats. Metods: A total of 32 male Wistar rats (220–250 g) were used and divided into 4 groups, control (no injection), vehicle (Normal saline, 5 µL), OXA (30 µg/rat), SB-334867 (OXA receptor selective antagonist, 30 µg/rat). After the microinjection of drugs or vehicles in the right lateral ventricle, each rat was placed individually into the metabolic cage and the amount of water intake, the delay time for the first water intake, and the referral number for water intake were recorded for 4 h. Findings: This study showed that ICV administration of OXA increased both water intake and the referral number for water intake in water-deprived animals (P

• Exogenous orexin-A (OXA) aggravated cognitive deficits and LTP depression in 3xTg-AD mice. • OXA increased Aβ and tau pathologies in the brain in 3xTg-AD mice. • OXA increased Aβ levels by affecting the expression of BACE1 and NEP. • OXA aggravated the disturbance of the circadian locomotor rhythm in 3xTg-AD mice. Dementia is the main clinical feature of Alzheimer's disease (AD). Orexin has recently been linked to AD pathogenesis, and exogenous orexin-A (OXA) aggravates spatial memory impairment in APP/PS1 mice. However, the effects of OXA on other types of cognitive deficits, especially in 3xTg-AD mice exhibiting both plaque and tangle pathologies, have not been reported. Furthermore, the potential electrophysiological mechanism by which OXA affects cognitive deficits and the molecular mechanism by which OXA increases amyloid β (Aβ) levels are unknown. In the present study, the effects of OXA on cognitive functions, synaptic plasticity, Aβ levels, tau hyperphosphorylation, BACE1 and NEP expression, and circadian locomotor rhythm were evaluated. The results showed that OXA aggravated memory impairments and circadian rhythm disturbance, exacerbated hippocampal LTP depression, and increased Aβ and tau pathologies in 3xTg-AD mice by affecting BACE1 and NEP expression. These results indicated that OXA aggravates cognitive deficits and hippocampal synaptic plasticity impairment in 3xTg-AD mice by increasing Aβ production and decreasing Aβ clearance through disruption of the circadian rhythm and sleep-wake cycle. [ABSTRACT FROM AUTHOR]

Background: Impaired bidirectional communication between the gastrointestinal tract and the central nervous system (CNS) is closely related to the development of irritable bowel syndrome (IBS). Studies in patients with IBS have also shown significant activation of the hypothalamus and amygdala. However, how neural circuits of the CNS participate in and process the emotional and intestinal disorders of IBS remains unclear. Methods: The GABAergic neural pathway projecting from the central amygdala (CeA) to the lateral hypothalamus (LHA) in mice was investigated by retrograde tracking combined with fluorescence immunohistochemistry. Anxiety, depression‐like behavior, and intestinal motility were observed in the water‐immersion restraint stress group and the control group. Furthermore, the effects of the chemogenetic activation of the GABAergic neural pathway of CeA‐LHA on behavior and intestinal motility, as well as the co‐expression of orexin‐A and c‐Fos in the LHA, were explored. Key Results: In our study, Fluoro‐Gold retrograde tracking combined with fluorescence immunohistochemistry showed that GABAergic neurons in the CeA were projected to the LHA. The microinjection of the gamma‐aminobutyric acid (GABA) receptor antagonist into the LHA relieved anxiety, depression‐like behavior, and intestinal motility disorder in the IBS mice. The chemogenetic activation of GABAergic neurons in the CeA‐LHA pathway led to anxiety, depression‐like behavior, and intestinal motility disorder. In addition, GABAergic neurons in the CeA‐LHA pathway inhibited the expression of orexin‐A in the LHA, and orexin‐A was co‐expressed with GABAA receptors. Conclusions & Inferences: The CeA‐LHA GABAergic pathway might participate in the occurrence and development of IBS by regulating orexin‐A neurons. [ABSTRACT FROM AUTHOR]

Objective/background: Orexin has been shown to regulate the sleep-wake cycle, and it may play a major role in the pathogenesis of sleep disorders; however, its role in sleep disorders in pregnant women remains unclear. We aimed to assess the relationship between serum orexin-A (OXA) levels and sleep quality in pregnant women.Patients/methods: This study comprised 214 enrolled pregnant women (poor sleep quality, n = 125; no poor sleep quality, n = 89). We assessed participants' sleep quality and depression and anxiety levels. OXA levels were measured using enzyme-linked immunosorbent assay.Results: Women in the poor sleep quality group showed higher serum OXA levels (0.33[0.3] vs. 0.27[0.11], P < 0.001) than those in the no poor sleep quality group. Binary regression analysis showed that the higher the OXA levels (odds ratio [OR] 1.385, 95% CI [confidence interval] 1.160-1.655) and Zung Self-Rating Anxiety Scale scores (OR 1.073, 95% CI 1.009-1.140), the greater the risk of sleep quality in pregnant women. First-trimester OXA levels differed significantly from those in the second and third trimesters (P < 0.05).Conclusion: Serum OXA levels were higher in pregnant women with poor sleep quality than in those without poor sleep quality. OXA levels were also higher in the second and third trimesters than in the first trimester. [ABSTRACT FROM AUTHOR]

Background/purpose: 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.Methods: 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.Results: 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.Conclusion: 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. [ABSTRACT FROM AUTHOR]

Purpose: The orexigenic peptides, ghrelin, galanin, and orexin-A, have an important role in food intake and energy homeostasis and regulate the higher brain functions including the sleep–wake state. Although the interactions of these neuropeptides affect neuroendocrine systems resulting in obesity, a major risk factor for obstructive sleep apnea syndrome (OSAS), the mechanism has not been fully elucidated. The objective of this study was to evaluate the association of serum ghrelin, galanin, and orexin-A levels with OSAS. Methods: In this cross-sectional study, patients who underwent one-night polysomnography and conformed to the inclusion criteria were asked to participate. A blood sample was obtained from all participants on the morning of the sleep test to evaluate the serum levels of ghrelin, galanin, and orexin-A using the enzyme-linked immunosorbent assay (ELISA) method. Demographic characteristics, polysomnography data, and serum levels of the participants were recorded and analyzed. Comparison between the OSAS groups was performed by independent sample t-test, Mann–Whitney U test, and Kruskal–Wallis test with post hoc K-W test using SPSS 20.0. Results: Of 272 patients, those in the OSAS group (n=210) were older than patients in the non-OSAS group (n=62), p < 0.003, and had increased BMI, p < 0.006. Patients with, serum ghrelin, galanin, and orexin-A levels were significantly elevated in patients with OSAS (635.9 pg/mL vs. 420.7 pg/mL, 91.0 pg/mL vs. 60.0 pg/mL, 600.3 pg/mL vs. 485.6 pg/mL, respectively) and found to be higher in patients with severe OSAS than mild and moderate cases (p < 0.01). In multinomial logistic regression to predict the OSAS severity, levels of serum ghrelin (OR = 1.016 [1.010–1.021]; p < 0.001), galanin (OR = 1.050 [1.020–1.081]; p < 0.001), and orexin-A (OR = 1.021 [1.012–1.030]; p < 0.001) were significantly associated only with a moderate level of OSAS. Conclusion: The orexigenic neuropeptides were found to be an independent determinant of the presence of OSAS and correlate with the severity of OSAS. Increased levels of ghrelin, galanin, and orexin-A were associated with the presence of moderate OSAS. [ABSTRACT FROM AUTHOR]

Objective(s): To investigate the regulatory effects of the nucleus accumbens (NAcSh)-lateral hypothalamus (LHA) GABAergic neural pathway on palatable food (PF) intake via orexin-A expression in diet-induced obesity (DIO) rats. Materials and Methods: NAcSh-LHA GABAergic pathways were observed by fluorogold retrograde tracing combined with fluorescence immunohistochemistry, and the regulatory effects of this neural pathway on PF intake were detected after 1) microinjection of GABA-A receptor agonist muscimol (MUS) or antagonist bicuculine (BIC) into LHA, 2) electrical stimulation NAcSh, and 3) blocking the orexin-A receptor by icv SB334867. Results: Compared with rats on a normal diet (ND), NAcSh-LHA GABAergic neurons in the DIO rats were significantly decreased, and orexin-A expression in LHA significantly increased (p 0.05). After NAcSh electrical stimulation or SB334867 ICV injection, the PF intake was significantly decreased in the DIO rats (p 0.05). Conclusion: This GABAergic pathway could regulate the expression of orexin-A in LHA and PF intake. Orexin-A neurons in LHA of DIO rats might be less sensitive to GABAergic signals and may consequently lead to more hedonic food intake.

Background: This study compared the effect of moderate and high-intensity interval training on plasma levels of orexin-A, insulin, and insulin resistance in women with overweight or obesity. Methods: Thirty-six women were voluntarily selected and optionally assigned into high-intensity interval training (HIIT; BMI = 29.43 ± 3.16 kg/m², n = 12), moderate-intensity interval training (MIIT; BMI = 27.63 ± 2.82 kg/m², n = 12), and control groups (BMI = 28.77 ± 4.28 kg/m², n = 12). The exercise program consisted of selected high-intensity and moderate-intensity exercises with 75 - 95% and 65 - 80% of the heart rate reserve of initial fitness level for 30 - 60 minutes each session and three times a week. Plasm levels of orexin-A and other biochemical parameters were measured pre-and post-interventions. Results: Following exercise interventions, plasma levels of orexin-A improved (MIIT: 23.23% vs. HIIT: 23.27%). Also, glucose (MIIT: -8.83 vs. HIIT: -6.01%), insulin (MIIT: -20.02% vs. HIIT: -25.38%), insulin resistance index (MIIT: -8.37% vs. HIIT: -3.28%), and body fat percentage (MIIT: -6.46% vs. HIIT: -7.23%) reduced in both MIIT and HIIT groups, but between-group differences were not statistically significant (P ≥ 0.05). A significant increase in the cardiorespiratory endurance of participants was observed (MIIT: 10.10 vs. HIIT: 14.83%) in both HIIT and MIIT exercise groups (P ≤ 0.05). Conclusions: The findings showed that HIIT and MIIT could improve orexin and some cardio-metabolic health biomarkers in sedentary women with overweight/obesity. [ABSTRACT FROM AUTHOR]

Background: The lateral hypothalamus (LH), which produces orexin, is vital for body solution homeostasis. Lateral hypothalamus (LH) lesion causes adipsia and its stimulation increases water intake. Objective: This study aimed to investigate the effect of an intracerebroventricular (ICV) injection of orexin-A (OXA) on water-drinking behavior in water-deprived rats. Metods: A total of 32 male Wistar rats (220-250 g) were used and divided into 4 groups, control (no injection), vehicle (Normal saline, 5 µL), OXA (30 µg/rat), SB-334867 (OXA receptor selective antagonist, 30 µg/rat). After the microinjection of drugs or vehicles in the right lateral ventricle, each rat was placed individually into the metabolic cage and the amount of water intake, the delay time for the first water intake, and the referral number for water intake were recorded for 4 h. Findings: This study showed that ICV administration of OXA increased both water intake and the referral number for water intake in water-deprived animals (P<0.05). On the other hand, ICV administration of SB-334867 decreased water intake compared to vehicle and control groups. Conclusion: It can be concluded that OXA has a regulatory role in water drinking behavior in water-depriving states. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect and mechanism of orexin-A(OX-A) on the expression and function of glial glutamate transporter-1(GLT-1) and delayed neuronal death (DND) in hippocampus CA1 region of transient global cerebral ischemia(tGCI) in rats. Methods The rats were randomized into sham group, model group, OX-A group and OX-A+LY294002 group. The binding and glutamate uptake of GLT-1 in hippocampal CA1 region were detected by the [3H]-glutamate labeling method. The content of glutamate in hippocampal CA1 region was determined by the glutamate quantitative kit. The pathological changes of neurons in hippocampal CA1 region were observed by Nissol, NeuN and Fluro-Jade C staining. The expressions of GLT-1, p-PI3K and p-Akt in hippocampal CA1 region were detected by Western blot. Results OX-A promoted the binding and glutamate uptake of GLT-1, increased glutamate content, GLT-1 expression and PI3K/AKT signaling activity, and inhibited DND in the hippocampal CA1 region of tGCI rats (P＜0.05); However, LY294002 attenuated the above therapeutic effects of OX-A(P＜0.05). Conclusions OX-A can increase the expression and function of GLT-1 and reduce DND in the hippocampal CA1 region of tGCI rats by enhancing the activity of I3K/AKT signal.

This research includes the isolation and purification of Orexin-A from the plasma of healthy human via various biochemical techniques, it was proposed the therapeutic role of orexin on hyperlipidemia and lipid peroxidation and it has been suggested to study the effect of isolated orexin A on the metabolism of lipids and glucose in normal and hyperlipidemic rats, a high level of orexin-A had been found only in second peak (B) isolated by gel filtration chromatography (using Sephadex G-50) and showed (34.5) fold of purification, also, the effect of isolated orexin-A on some clinical parameters had been studied in normal and hyperlipidemic male rats. The rats were injected intraperitoneally with orexin-A at a dose of 1μmol/kg of body weight/day for one month. The results, obtained before treatment and after two and four weeks of treatment, had been showing a significant decrease in the concentration of total cholesterol, triglycerides, low and very low-density lipoprotein cholesterol, glucose, malondialdehyde and hyperinsulinemia, while there was a significant increase in the concentration of high-density lipoprotein cholesterol in normal and hyperlipidemic rats. It was concluded that orexin-A had an important role in regulating the metabolism of glucose and lipids, treatment of hyperinsulinemia and insulin resistance, and decreasing lipid peroxidation in normal and hyperlipidemic rats.

Wen Ye,1 Yan Yan,2 Yunliang Tang,1 Xiaoyang Dong,1 Gengfa Chen,1 Junwei Kang,1 Lianghua Huang,1 Qi Xiong,1 Zhen Feng1 1Department of Rehabilitation, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China; 2Department of Nephrology, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of ChinaCorrespondence: Zhen FengDepartment of Rehabilitation, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of ChinaEmail medstu@126.comBackground: Neuronal damage is the main cause of neurological diseases. Neural stem cells (NSCs) have the functions of cell repair and replacement of neurons, secretion of neurotrophic factors, and immune regulation of the neural microenvironment.Objective: Previous study found that Orexin-A had a protective effect on neurons in the central nervous system, but it is lacking in making great efforts on the function of Orexin-A on NSCs. This study aimed to investigate the anti-inflammatory responses and signaling mechanisms of Orexin-A on lipopolysaccharide (LPS)-induced NSCs.Methods: Quantitative real-time polymerase chain reaction was used to detect the mRNA level. Signaling pathway-related protein expression was detected by Western blot. The proliferation and migration of NSCs were investigated by Cell Counting Kit-8 (CCK-8) detection kit and transwell assay. Besides, the staining of hematoxylin and eosin (HE) was performed to study the morphology of cell.Results: Orexin-A decreased the pro-inflammatory cytokines of IL-1β, TNF-α, and IL-6 induced by LPS by regulating nuclear factor-k-gene binding (NF-kB) and phosphorylation of P38/Erk-mitogen-activated protein kinases (MAPKs) pathways, but not p-JNK signaling.Conclusion: Our findings indicate that Orexin-A can alleviate the inflammatory response of NSC. It can provide beneficial help in neural stem cell therapy applications.Keywords: NSCs, Orexin-A, NF-kB, MAPK

Background: Orexins are polypeptides regulating appetite, sleep-wake cycle, and cognition functions, which are commonly disrupted in patients with schizophrenia. Patients with schizophrenia show a decreased connectivity between the prefrontal cortex and midline-anterior thalamus, and orexin can directly activate the axon terminal of cells within the prefrontal cortex and selectively depolarize neurons in the midline intralaminar nuclei of the thalamus. To address the relationship between orexin and schizophrenia, this study performed a meta-analysis on the alteration of plasma orexin-A levels in patients with schizophrenia. Method: We searched eligible studies in PubMed, Embase, Cochrane, and China National Knowledge Infrastructure (CNKI) from 1998 to September 3, 2021. A total of 8 case-control studies were included in the meta-analyses, providing data on 597 patients with schizophrenia and 370 healthy controls. The Stata version 16.0 software was used to calculate the Hedges's adjusted g with 95% confidence intervals (CI). Results: The plasma orexin-A levels were not altered in subjects with schizophrenia (n = 597) when compared to healthy controls (n = 370). Subgroup analyses of gender (male and female vs. only male), country (China vs. other countries), medication (medication vs. non-medication), and the measurement of plasma orexin-A (Enzyme-linked immunosorbent assay vs. radioimmunoassay) revealed heterogeneity ranging from 30.15 to 98.15%, but none showed a significant alteration of plasma orexin-A levels in patients with schizophrenia. Heterogeneity was lower in the other countries and radioimmunoassay subgroup, while other subgroups remained to be highly heterogeneous. No significant evidence of publication bias was found either in Begg's test or the Egger's test. Conclusion: The present meta-analysis indicated that patients with schizophrenia did not show abnormal plasma levels of orexin-A. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display%5frecord.php?ID=CRD42021283455, identifier: CRD42021283455. [ABSTRACT FROM AUTHOR]

When depressive symptoms in bipolar and unipolar patients were compared, a number of studies reported that atypical vegetative features such as hypersomnia and hyperphagia were more common in bipolar patients. Moreover, neuropeptides such as orexin-A (ORX-A), ghrelin (GRL), and neuropeptide Y (NPY) are involved in the regulation of these vegetative functions. A total of 45 unipolar and 24 bipolar depressive patients, and 36 euthymic healthy controls were included in the study. The groups were compared in terms of peripheral blood samples of ORX-A, GRL, and NPY levels, as well as HAM-D, Epworth Sleepiness Scale, Three-Factor Eating Questionnaire-Revised, and Suicide Probability Scale scores. Both unipolar and bipolar patients had lower ORX-A, GRL, and NPY levels compared to the controls, whereas NPY levels of bipolar patients were lower than unipolar patients. There was a negative correlation between NPY levels and emotional eating in the bipolar group. While lower ORX-A, GRL, and NPY levels are associated with depressive episodes regardless of the diagnosis; NPY levels also differ in bipolar and unipolar depression patients. [ABSTRACT FROM AUTHOR]

Noradrenergic neurons of the locus coeruleus (LC) receive projection from hypothalamus orexinergic neurons and express orexin receptor type 1 (OXR1). Orexin-A has a regulatory effect on feeding, sleep, arousal, reward processing, and drug addiction. Orexinergic neurons make excitatory afferent to the LC neurons. However, the underlying mechanism of the orexin effect on LC neurons is not completely discerned. In the current study, the contribution of calcium to orexin-induced excitation of the rat LC neurons was studied in brainstem slice preparations by the whole-cell patch-clamp method. The application of orexin increased the firing rates of action potentials (APs) in normal artificial cerebrospinal fluid (aCSF). In low Ca2+ aCSF orexin enhanced the firing rate higher than in normal aCSF. Orexin increased the mean amplitude of the depolarization and reduced the afterhyperpolarization (AHP) following each action potential in low Ca2+ aCSF compared to normal aCSF. Furthermore, the frequency of spontaneous excitatory postsynaptic currents (sEPSC) is enhanced by orexin in low external Ca2+ compared to normal aCSF but the amplitude of sEPSCs did not change. Current results have unraveled that orexin-A has an excitatory effect on the rat LC neurons. [ABSTRACT FROM AUTHOR]

BackgroundOrexins are polypeptides regulating appetite, sleep-wake cycle, and cognition functions, which are commonly disrupted in patients with schizophrenia. Patients with schizophrenia show a decreased connectivity between the prefrontal cortex and midline-anterior thalamus, and orexin can directly activate the axon terminal of cells within the prefrontal cortex and selectively depolarize neurons in the midline intralaminar nuclei of the thalamus. To address the relationship between orexin and schizophrenia, this study performed a meta-analysis on the alteration of plasma orexin-A levels in patients with schizophrenia.MethodWe searched eligible studies in PubMed, Embase, Cochrane, and China National Knowledge Infrastructure (CNKI) from 1998 to September 3, 2021. A total of 8 case-control studies were included in the meta-analyses, providing data on 597 patients with schizophrenia and 370 healthy controls. The Stata version 16.0 software was used to calculate the Hedges's adjusted g with 95% confidence intervals (CI).ResultsThe plasma orexin-A levels were not altered in subjects with schizophrenia (n = 597) when compared to healthy controls (n = 370). Subgroup analyses of gender (male and female vs. only male), country (China vs. other countries), medication (medication vs. non-medication), and the measurement of plasma orexin-A (Enzyme-linked immunosorbent assay vs. radioimmunoassay) revealed heterogeneity ranging from 30.15 to 98.15%, but none showed a significant alteration of plasma orexin-A levels in patients with schizophrenia. Heterogeneity was lower in the other countries and radioimmunoassay subgroup, while other subgroups remained to be highly heterogeneous. No significant evidence of publication bias was found either in Begg's test or the Egger's test.ConclusionThe present meta-analysis indicated that patients with schizophrenia did not show abnormal plasma levels of orexin-A.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021283455, identifier: CRD42021283455.

Orexin neurons play an important role in stress‐related mental disorders including post‐traumatic stress disorder (PTSD). Anxiety‐ and depression‐related symptoms commonly occur in combination with PTSD. However, the role of the orexin system in mediating alterations in these affective symptoms remains unclear. The medial prefrontal cortex (mPFC) is implicated in both cognitive and emotional processing. In the present study, we investigated anxiety‐ and depression‐related behavioral changes using the elevated plus maze, the sucrose preference test, and the open field test in male rats with single prolonged stress (SPS) induced‐PTSD. The expression of orexin‐A in the hypothalamus and orexin receptors (OX1R and OX2R) in the mPFC was detected and quantified by immunohistochemistry, western blotting, and real‐time polymerase chain reaction. We found that the SPS rats exhibited enhanced levels of anxiety, reduced exploratory activities, and anhedonia. Furthermore, SPS resulted in reductions in the expression of orexin‐A in the hypothalamus and the increased the expression of OX1R in the mPFC. The intracerebroventricular administration of orexin‐A alleviated behavioral changes in SPS rats and partly restored the increased levels of OX1R in the mPFC. These results suggest that the orexin system plays a role in the anxiety‐ and depression‐related symptoms observed in PTSD. [ABSTRACT FROM AUTHOR]

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Abstract Aims Orexin‐A is known to induce anti‐nociceptive effects in animal models of chronic pain. We have found that orexin‐A inhibits KCl loading‐induced increases in the intracellular calcium ion levels ([Ca2+]i) in C‐fiber‐like neurons of rats showing inflammatory nociceptive behavior. Here, we examined the effects of orexin‐A on the depolarization of C‐fiber‐like neurons derived from a rat model for another type of chronic pain, namely neuropathic pain. Thus, we analyzed the effects of orexin‐A on KCl‐induced increases in [Ca2+]i in C‐fiber‐like neurons of rats with sciatic nerve ligation. Methods Paw withdrawal and threshold force in response to tactile stimuli were evaluated using von Frey filaments. Sham‐operated rats served as controls. [Ca2+]i in neurons were visualized by calcium fluorescent probe. Changes in [Ca2+]i were assessed using relative fluorescence intensity. Results Seven days after sciatic nerve ligation, paw withdrawal and threshold force for tactile stimuli were increased and reduced, respectively. KCl loading to neurons from either sciatic nerve‐ligated or control rats increased relative fluorescence intensity. The KCl‐induced increase in relative fluorescence intensity in sciatic nerve‐ligated, but not that of control, rats was inhibited by orexin‐A. The OX1 and OX2 receptor antagonist MK‐4305 and OX2 receptor antagonist EMPA, but not the OX1 receptor antagonist SB 334867, each counteracted orexin‐A‐induced inhibition of KCl‐provoked increases in relative fluorescence intensity. Conclusion The present findings constitute neuropharmacological evidence that OX2 but not OX1 receptors mediate the inhibitory effects of orexin‐A on KCl‐induced increases in [Ca2+]i in C‐fiber‐like neurons of rats showing hyperalgesia provoked by sciatic nerve ligation.

BACKGROUND AND OBJECTIVE: Due to the proximity of epicardial adipose tissue (EAT) to the myocardial tissue, it is considered that EAT be more pathogenic than subcutaneous adipose tissue. The aim of this study was to evaluate the alterations of PGC-1α andUCP1 gene expression in EAT and orexin-A following aerobic exercise in high-fat diet induced and obese male wistar rats. METHODS: In this study, 32 male wistar rats aged 6-week and weight of 180-200 g, assigned randomly in: 1) Normal fat diet (NFD), 2) High-fat diet induced obesity (HFDO), 3) Normal fat diet after high-fat diet induced obesity group (HFDO-NFD) and Aerobic exercise group with normal fat diet after high-fat diet induced obesity group (HFDO-AEX). After obesity-induced in HFDO group (8-week diet with 60% fat) and 48 hours after eight weeks of aerobic exercise (60% of maximal training capacity, 4 sessions/week) in other groups, fasting levels of OXA, Lee index, lipid profile, and gene expression of PGC-1α and UCP1 in EAT have been measured. FINDINGS: The results revealed that HFD significantly decreased serum OXA, HDL-c, gene expression of PGC1α and UCP1, also caused a significant increase in Lee index, TG, LDL-c, cholesterol and EAT mass (p≤0.001), but aerobic exercise significantly improved the OXA (34.74%), HDL-c (23.65%), gene expression of PGC-1α and UCP1 (61.28% and 82.67%), lipid profile, EAT mass (76.19%) and Lee index (18.34%) to the normal levels (P≤ 0.001). CONCLUSION: Aerobic exercise by affecting OXA and gene expression of PGC-1α and UCP1 in EAT, probably could reduce the risk factors of cardiovascular diseases due to high-fat diet.

Abstract Background Sleep disorders are commonly encountered in clinic. Evidences showed that sleep deprivation may modulate the effectiveness of general anesthetics in rats. However, this phenomenon has not been explored in humans. The study aimed to investigate whether the hypnotic potency of sevoflurane in patients with sleep disorders differ from patients with normal sleep habits. Methods We recruited 44 patients scheduled for elective breast surgery and eventually analyzed 38 patients, including 19 subjects with normal sleep habits and 19 subjects with sleep disorders. According to the Dixon ‘up-and-down’ design, patients received sevoflurane at preselected concentrations starting at 1.0 vol%. After a steady-state period, a verbal command for testing awakening was performed. Based on the negative or positive response to the verbal command, we decreased or increased the concentration of sevoflurane by 0.2 vol% in the next patient accordingly. Plasma orexin-A was also measured before observation. Results The MACawake of sevoflurane was 0.80% [95% confidence interval (CI), 0.683–0.926%] in the sleep disordered group vs 0.60% [95% CI, 0.493–0.689%] in the control group. The relative median potency between groups was 0.750 (95% CI, 0.236–0.969). Patients with sleep disorders had significantly higher orexin-A levels than control (72.17 ± 18.24 vs. 36.16 ± 14.18 pg/mL). A significant, positive relationship was detected between orexin-A level and probability of awakening (OR = 1.081, 95% CI is 1.020–1.146, P = 0.008). Conclusions MACawake of sevoflurane is higher in mild-aged women of breast surgery with sleep disorders compared to those with normal sleep habits. The increased anesthetic requirement may be related to changes of orexin-A levels. These findings suggest that sleep may have a potential impact on clinical anesthesia, including changes of sensitivity to anesthetics or postoperative complications. Further research is needed to confirm this hypothesis. Clinical trial registration Chinese Clinical Trial Registry (ChiCTR1800016022), date of registration 07 May 2018.

Clinical Relevance: Retinopathy is one of the most common microvascular complications of diabetes mellitus and is the leading cause of vision loss in the working middle-aged population., Background: This study aimed to investigate the value of neopterin and orexin-A levels in patients with diabetes mellitus with different stages of diabetic retinopathy and without diabetic retinopathy and to compare those findings with results from healthy individuals without diabetes mellitus., Methods: In total, 65 patients with type 2 diabetes mellitus and 22 healthy individuals without diabetes mellitus were enrolled in this prospective study. The participants were separated into four subgroups. The first subgroup included 25 patients without diabetic retinopathy, the second subgroup included 20 patients non-proliferative diabetic retinopathy, the third subgroup included 20 patients with proliferative diabetic retinopathy, and the fourth subgroup included 22 healthy individuals without diabetes mellitus as controls. Serum neopterin and orexin-A levels were analysed and compared among the groups., Results: The age and gender of the participants between the four subgroups were not statistically significantly different ( p  > 0.05). The mean neopterin levels were significantly higher in patients included in the diabetes mellitus subgroups compared with the controls ( p  < 0.001). Neopterin levels significantly increased as diabetic retinopathy progressed within the diabetes mellitus subgroups. Mean orexin-A levels were significantly lower in the diabetes mellitus subgroups compared with the controls ( p  < 0.001); however, orexin-A levels were not significantly different within the diabetes mellitus subgroups ( p  > 0.05)., Conclusion: Patients with diabetes mellitus have higher serum neopterin and lower serum orexin-A levels compared with healthy individuals without diabetes mellitus. Moreover, serum neopterin levels increase with progression of diabetic retinopathy.

Background: Parkinson's disease (PD) is a progressive neurological condition that affects movement and coordination. Orexin-A (OXA) is an excitatory neuropeptide that is found throughout the central nervous system. There is growing interest in investigating the potential diagnostic and therapeutic utility of OXA in PD. To date, studies have reported a wide range of OXA concentrations in patients with PD. In this review, we discuss the current understanding of the dysregulation of OXA in PD and analyze its levels in the CSF., Methods: We searched six databases (PubMed, Scopus, Web of Science, EMBASE, ProQuest, and EBSCOHost) and preprint servers using a predetermined search strategy through 4th March 4, 2023. The search keywords included "Parkinson's disease", "Orexin-A", "Hypocretin-1", "cerebrospinal fluid", and "CSF". Studies that reported OXA/Hypocretin-1 levels in the CSF of patients with PD were included. Two researchers independently reviewed the records and extracted data., Findings: Eighteen studies involving 244 patients were analyzed. CSF Orexin-A concentrations were lower in patients with Parkinson's disease than in controls, with a mean difference of -59.21 (95 % CI: -89.10 to -29.32). The mean OXA levels were 281.52 (95 % CI: 226.65-336.40)., Conclusion: Our analysis reveals lower concentrations of orexin-A in the cerebrospinal fluid of Parkinson's disease patients compared to controls, but within the normal range. These findings suggest a potential, but not significant, disruption in the orexinergic system associated with the disease., Competing Interests: Declaration of Competing Interest The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Coronavirus disease in 2019 (COVID-19) is a pandemic declared by the World Health Organization after its appearance in the Chinese city of Wuhan in late 2019. It has infected more than 30 million people worldwide and led to the death of nearly one million of them. Orexin-A (OXA), a neuropeptide produced by the lateral hypothalamic area and several peripheral tissues, regulates appetite, reproduction, and other physiological functions. There are many symptoms associated with infection with the coronavirus, such as a cytokine storm, narcolepsy, impaired senses of smell and taste, and loss of appetite, usually are associated with high or low levels of OXA in the infected people. Moreover, some chronic diseases such as cancer, diabetes, and obesity, generally referred to as risk factors for the disease, increase the severity of infection or even lead to death and they are associated with either an increase or a decrease in OXA levels. Moreover, some factors, such as a high testosterone level, facilitate the entry of a virus into the cells, which OXA controls. In this review, we described for the first time the potential impact of high or low levels of OXA on the severity of the symptoms of COVID- 19 or the death due to this disease. [ABSTRACT FROM AUTHOR]

• Orexin-A relieved brain infarct volume and improved neurological function. • Orexin-A alleviated cerebral inflammatory injury in the ischaemic brain. • Orexin-A attenuated stroke-induced immunodepression. Cerebral ischaemia is accompanied by infectious complications due to immunosuppression, known as stroke-induced immunodepression (SIID). Orexin-A (OXA), a neuropeptide produced in the hypothalamus, has been reported to have neuroprotective properties after stroke and is known to modulate inflammatory processes in peripheral tissues. The aim of this study was to determine the effects of orexin-A (OXA) on cerebral ischaemic inflammatory injury and SIID following experimental stroke. Cerebral ischaemia was induced in C57/BL6 mice by middle cerebral artery occlusion (MCAO). A mouse model of pneumonia and poststroke pneumococcal pneumonia was established by intratracheal inoculation with S. pneumoniae in a normal mouse or MCAO mouse model on the third day. We found that OXA postconditioning inhibited cerebral ischaemic inflammatory injury. The mechanism involved downregulation of the NF-κB signalling pathway. In addition, OXA may serve as a potential treatment target for attenuating stroke-induced immunodepression in mice. [ABSTRACT FROM AUTHOR]

Aim: Modified Suanzaoren Decoction (MSZRD) is obtained by improving Suanzaoren Decoction (SZRT), a traditional Chinese herbal prescription that has been used to treat insomnia for more than thousands of years. Our previous study showed that MSZRD can improve the gastrointestinal discomfort related insomnia by regulating Orexin-A. This study is the first study to evaluate the effects and possible mechanisms of MSZRD in mice with insomnia caused by p-chlorophenylalanine (PCPA) combined with multifactor random stimulation. Methods: After 14 days of multifactor stimulation to ICR mice, a PCPA suspension (30 mg/mL) was injected intraperitoneally for two consecutive days to establish an insomnia model. Three different doses of MSZRD (3.6, 7.2, and 14.4 g/kg/day) were given to ICR mice for 24 days. The food intake and back temperature were measured, and behavioral tests and pentobarbital sodium-induced sleep tests were conducted. The levels of Orexin-A, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and adrenocortical hormones (CORT) in the serum and 5-hydroxytryptamine (5-HT), dopamine (DA), and norepinephrine (NE) in hypothalamus were measured using enzyme-linked immunosorbent assay (ELISA) kits. The levels of γ-aminobutyric acid (GABA) and glutamic acid (Glu) were measured by high-performance liquid chromatography (HPLC). The expression of 5HT1A receptor (5-HTRIA) and orexin receptor 2 antibody (OX2R) was measured by Western blot (WB) and immunohistochemical staining (ICH). Hematoxylin and eosin (H&E) staining and Nissl staining were used to assess the histological changes in hypothalamus tissue. Results: Of note, MSZRD can shorten the sleep latency of insomnia mice (P

Hyperactivity of the orexin system within the paraventricular nucleus (PVN) has been shown to contribute to increased sympathetic nerve activity (SNA) and blood pressure (BP) in rodent animals. However, the underlying molecular mechanisms remain unclear. Here, we test the hypothesis that orexin system activation stimulates calcium/calmodulin-dependent kinase II (CaMKII) expression and activation, and stimulation of CaMKII expressing PVN neurons increases SNA and BP. Real-time PCR and/or western blot were carried out to test the effect of orexin-A administration on CaMKII expression in the PVN of normal Sprague Dawley (SD) rats and orexin receptor 1 (OX1R) expressing PC12 cells. Immunostaining was performed to assess OX1R cellular localization in the PVN of SD rats as well as orexin-A treatment on CaMKII activation in cultured hypothalamic neurons. In vivo sympathetic nerve recordings were employed to test the impact of optogenetic stimulation of CaMKII-expressing PVN neurons on the renal SNA (RSNA) and BP. The results showed that intracerebroventricular injection of orexin-A into the SD rat increases mRNA expression of CaMKII subunits in the PVN. In addition, Orexin-A treatment increases CaMKII expression and its phosphorylation in OX1R-expressing PC12 cells. Furthermore, Orexin-A treatment increases CaMKII activation in cultured hypothalamic neurons from neonatal SD rats. Finally, optogenetic excitation of PVN CaMKII-expressing neurons results in robust increases in RSNA and BP in SD rats. Our results suggest that increased orexin system activity activates CaMKII expression in cardiovascular relevant regions, and this may be relevant to the downstream cardiovascular effects of CaMKII.

Background: Orexin as an adipokin hormone plays an important role in appetite regulation, energy metabolism, obesity, diabetes, and cardiovascular disease. The main source of orexin secretion in nonpregnant and pregnant women is adipose tissue and placenta, respectively. This research was conducted to evaluate the association between orexin‐A level and the mode of delivery, anthropometric indices, and sex of the infant. Methods: This prospective cohort study was conducted on 69 normal pregnant women. The samples of umbilical cord blood were obtained at the time of delivery, and maternal blood was taken within 24 h of delivery. Serum orexin‐A levels were measured by using enzyme‐linked immunosorbent assay. Statistical analyses were performed using SPSS and p < 0.05 was considered as significant. Results: We found a significant difference between postpartum maternal and umbilical cord orexin‐A level both with the mode of delivery (p < 0.001). Also, a significant positive correlation was seen between maternal and umbilical cord serum orexin‐A levels (r = −0.61, p < 0.001). There was no relationship between serum orexin‐A levels with anthropometric indices and the sex of the neonate (p > 0.05). Conclusion: Both maternal and umbilical cord serum orexin‐A levels were associated with the mode of delivery. Maternal and cord blood orexin‐A levels in normal vaginal delivery are higher than cesarean section. [ABSTRACT FROM AUTHOR]

Hyperactivity of the orexin system within the paraventricular nucleus (PVN) has been shown to contribute to increased sympathetic nerve activity (SNA) and blood pressure (BP) in rodent animals. However, the underlying molecular mechanisms remain unclear. Here, we test the hypothesis that orexin system activation stimulates calcium/calmodulin-dependent kinase II (CaMKII) expression and activation, and stimulation of CaMKII expressing PVN neurons increases SNA and BP. Real-time PCR and/or western blot were carried out to test the effect of orexin-A administration on CaMKII expression in the PVN of normal Sprague Dawley (SD) rats and orexin receptor 1 (OX1R) expressing PC12 cells. Immunostaining was performed to assess OX1R cellular localization in the PVN of SD rats as well as orexin-A treatment on CaMKII activation in cultured hypothalamic neurons. In vivo sympathetic nerve recordings were employed to test the impact of optogenetic stimulation of CaMKII-expressing PVN neurons on the renal SNA (RSNA) and BP. The results showed that intracerebroventricular injection of orexin-A into the SD rat increases mRNA expression of CaMKII subunits in the PVN. In addition, Orexin-A treatment increases CaMKII expression and its phosphorylation in OX1R-expressing PC12 cells. Furthermore, Orexin-A treatment increases CaMKII activation in cultured hypothalamic neurons from neonatal SD rats. Finally, optogenetic excitation of PVN CaMKII-expressing neurons results in robust increases in RSNA and BP in SD rats. Our results suggest that increased orexin system activity activates CaMKII expression in cardiovascular relevant regions, and this may be relevant to the downstream cardiovascular effects of CaMKII. [ABSTRACT FROM AUTHOR]