Dual orexin receptor antagonists for the treatment of insomnia: systematic review and network meta-analysis / Antagonistas duais do receptor de orexina para o tratamento da insônia: revisão sistemática e metanálise em rede

Abstract Background Several randomized clinical trials (RCTs) have shown that dual orexin receptor antagonists (DORAs) are effective in the treatment of chronic insomnia. However, the superiority of one particular DORA over the others remains unclear. Objective To perform a network meta-analysis to evaluate the efficacy of different DORAs in patients with chronic insomnia. Methods The Medline, Embase, and Cochrane Central databases were searched for RCTs that compared DORA with placebo in patients ≥ 18 years of age with a diagnosis of insomnia disorder. We pooled outcomes for wake time after sleep onset (WASO), latency to persistent sleep (LPS), total sleep time (TST), and adverse events (AEs). Results We included 10 RCTs with 7,806 patients, 4,849 of whom received DORAs as the intervention. Overall, we found that DORAs were associated with the improvement of all analyzed efficacy outcomes. Concerning TST, an apparent dose-dependent pattern was noticed, with higherdoses relating to a longerTST. Lemborexant 10mg provided the largest reduction in WASO (at month 1) in minutes (standardized mean difference [SMD] = −25.40; 95% confidence interval [95%CI] = −40.02- −10.78), followed by suvorexant 20/15mg (SMD = −25.29; 95%CI = −36.42- −14.15), which also appeared to provide the largest decrease in long-term WASO (SMD = −23.70; 95%CI = −35.89- −11.51). The most frequent AEs were somnolence, nasopharyngitis, and headache, with rates of up to 14.8%. Conclusion Our results suggest that DORAs are associated with greater efficacy when compared with placebo in the treatment of insomnia, a complex 24-hour sleep disorder. Additionally, dosing might play an important role in the management of chronic insomnia.

Resumo Antecedentes Inúmeros ensaios clínicos randomizados (ECRs) têm demonstrado que os antagonistas duais do receptor de orexina (dual orexin receptor antagonists, DORAs, em inglês) são eficazes no tratamento da insônia. Contudo, restam dúvidas quanto à superioridade de um DORA com relação aos outros. Objetivo Realizar uma meta-análise em rede para avaliar a eficácia de diferentes DORAs em pacientes com insônia. Métodos Foram feitas buscas nas bases de dados Medline, Embase e Cochrane Central por ECRs que comparassem DORAs e placebo em pacientes ≥ 18 anos de idade com diagnóstico de insônia. Os seguintes desfechos foram selecionados: tempo desperto após o início do sono (wake time after sleep onset, WASO, em inglês), latência para o sono persistente (latency to persistent sleep, LPS, em inglês), tempo total de sono (total sleep time, TST, em inglês), e efeitos adversos (EAs). Resultados Incluímos 10 ensaios clínicos com 7,806 pacientes, 4,849 dos quais receberam DORAs como intervenção. Os DORAs foram associados à melhoria de todos os desfechos de eficácia analisados. Em relação ao TST, um aparente padrão de dependência da dose foi identificado, com doses maiores se associando a um maior TST. Lemborexant 10 mg proporcionou a maior redução em WASO (no primeiro mês) em minutos (diferença padronizada das médias [standardized mean difference, [SMD], em inglês) = −25.40; intervalo de confiança de 95% [IC95%] = −40.02- −10.78), seguido de suvorexant 20/15mg (SMD = −25.29; IC95% = −36.42- −14.15), o qual também proporcionou a maior diminuição em WASO no longo prazo (SMD = −23.70; IC95% = −35.89- −11.51). Os EAs mais frequentes foram sonolência, nasofaringite e cefaleia, com taxas de até 14.8%. Conclusão Nossos resultados sugerem que os DORAs estão associados a uma maior eficácia quando comparados com placebo no tratamento da insónia, um complexo transtorno do sono de 24 horas. Além disso, a dosagem pode desempenhar um papel importante no manejo da insónia crônica.

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 < 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.

Clinical research progress of dual orexin receptor antagonist lemborexant in the treatment of insomnia / 中华神经科杂志

In past two decades, understanding of the role of the orexin system in regulating sleep and wakefulness has increased rapidly. Lemborexant, as a dual orexin receptor antagonist, has been approved in some countries for the treatment of insomnia disorders. Existing studies have shown that its safety and tolerability are significantly superior to traditional hypnotic drugs, and it will be new option for treating insomnia disorders. This article reviews the pharmacology, clinical efficacy and safety of lemborexant.

Effects of orexin A on morphine-induced gastrointestinal dysfunction in mice / 中华麻醉学杂志

Objective:To evaluate the effect of orexin A on morphine-induced gastrointestinal dysfunction in mice.Methods:Forty SPF C57B/6 mice, aged 6-8 weeks, half male and half female, weighing 18-22 g, were divided into 5 groups ( n=8 each) using a random number table method: control group (group C), morphine group (group M) and morphine + different doses of orexin A groups (MOH, MOM and MOL groups). Normal saline 8 ml/kg was subcutaneously injected daily in group C, morphine 6 mg/kg was subcutaneously injected daily in the other four groups, and orexin A 75, 50 and 25 μg/kg were subcutaneously injected daily for 10 days at the same time in MOH, MOM and MOL groups.The fetal water content was calculated and averaged daily.After the last administration, the mice were gavaged with black nutrient paste, and the gastric emptying rate and small intestinal propulsion rate were detected 30 min later.Blood samples were collected from the orbit, and the concentration of serum gastrin (GAS) was detected by enzyme-linked immunosorbent assay.The mice were then sacrificed, and colon tissues were removed for determination of c-kit positive cell area (by immunohistochemistry) and expression of c-kit, substance P (SP) and neural nitric oxide synthase (nNOS) in colon tissues (by Western blot). Results:Compared with group C, the rate of fecal water content, gastric emptying rate, small intestinal propulsion rate and serum GAS concentration were significantly decreased, the area of c-kit positive cells was decreased, and the expression of c-kit and SP was down-regulated, and the expression of nNOS was up-regulated in group M ( P<0.05). Compared with group M, the small intestinal propulsive rate and serum GAS concentration were significantly increased, and the area of c-kit positive cells was increased, and the expression of c-kit was up-regulated in group MOH, the rate of fecal water content, gastric emptying rate, small intestinal propulsion rate and serum GAS concentration were significantly increased, the area of c-kit positive cells was increased, and the expression of c-kit and SP was up-regulated, and the expression of nNOS was down-regulated in group MOM, and the serum GAS concentration and c-kit positive cell area were significantly increased in group MOL ( P<0.05). Conclusions:Orexin A 50 μg/kg can effectively alleviate the gastrointestinal dysfunction induced by morphine in mice, and the mechanism may be related to promotion of GAS secretion, interstitial cells of Cajal growth and SP release and inhibition of NO release.

Research progress of the orexinergic system in migraine attack generation / 中华神经科杂志

Migraine is a complex disorder of brain function. The hypothalamus has been identified to play a crucial role in attack generation and secretes various neuropeptides. The orexinergic system plays a role in energy metabolism, arousal, sleep, stress and pain modulation. These disorders are closely related to clinical symptoms of migraine. Therefore, the study of the mechanism of hypothalamic orexinergic system in migraine may provide a new perspective for treatment. This article discusses the relationship between hypothalamic orexin system and migraine premonitory symptoms, and briefly summarizes the possible role and mechanism of hypothalamic orexin system in migraine.

Narcolepsy: the impact of aging, hypocretin deficiency, and years of formal education in olfactory function and abdominal obesity / Narcolepsia: o impacto da idade, deficiência de hipocretina e anos de estudo na função olfatória e na obesidade central

ABSTRACT Background: Narcolepsy is a disease resulting from the loss of hypocretin-producing cells or other dysfunctions of the hypocretinergic system. In addition to sleep disorders, affected patients may experience increased weight gain, olfactory changes, and poorer quality of life. Methods: This study aimed to investigate the relationship between narcolepsy and weight gain, years of study, sleep parameters, and olfactory dysfunction in patients with narcolepsy type 1 and narcolepsy type 2. Anthropometric, olfactory, socioeducational, and excessive daytime sleepiness evaluations were performed in 77 patients. Results: Greater weight gain and abdominal obesity were observed in patients with type 1 narcolepsy. Patients with higher education level had lower scores of daytime sleepiness, higher scores on the olfactory function test, and lower rates of abdominal obesity. Discussion: Patients with narcolepsy type 1 showed an increased body weight and abdominal obesity when compared to narcolepsy type 2. The patients with a higher schooling level showed a reduction of the daytime sleepiness scores, lower rates of abdominal obesity, and better scores on the olfactory function test. Conclusion: Among all the patients with narcolepsy, the data indicated that aging and hypocretin deficiency are associated with abdominal obesity, while years of study is the variable that mostly influences olfaction function.

RESUMO Antecedentes: A narcolepsia é resultante da perda de células produtoras de hipocretina ou da disfunção do sistema hipocretinérgico. Além dos distúrbios do sono característicos da doença, os pacientes afetados podem apresentar também aumento de peso, alterações olfatórias e pior qualidade de vida. Métodos: O objetivo do estudo é investigar a relação entre a narcolepsia e o ganho de peso, anos de estudo, parâmetros do sono e a disfunção olfatória em pacientes com narcolepsia tipo 1 e narcolepsia tipo 2. Foram realizadas avaliações antropométricas, do olfato, sociais, educacionais e da sonolência excessiva diurna nos 77 indivíduos participantes da pesquisa. Resultados: Foram observados, nos pacientes com narcolepsia tipo 1, maior ganho de peso e maior frequência de obesidade central. Pacientes com ensino superior apresentaram escores mais baixos de sonolência excessiva diurna, escores mais altos no teste de função olfatória e menores taxas de obesidade central. Discussão: Pacientes com narcolepsia tipo 1 apresentaram maior ganho de peso e obesidade central quando comparados aos com narcolepsia tipo 2. Os pacientes com maior escolaridade apresentaram menores escores de sonolência diurna, de obesidade central e melhores escores no teste da função olfatória. Conclusão: Nos indivíduos com narcolepsia tipo 1 e tipo 2, os dados indicaram que o envelhecimento e a deficiência de hipocretina estão associados à obesidade central, enquanto anos de estudo é a variável que mais influencia na função olfatória.

Intervention Effect of Modified Tianwang Buxindan on Glucose and Lipid Metabolism in Mice with Chronic Sleep Deprivation Through Orexin A/OX1R / 中国实验方剂学杂志

Objective:to explore the mechanism of modified Tianwang Buxindan in improving abnormal glucose and lipid metabolism in mice with chronic sleep deprivation from the signal pathway of orexin A/ orexin receptor 1（OX1R）. Method:The 50 6-week-old male C57BL/6 mice were randomly divided into blank group ， model group ， estazolam group and Tianwang Buxindan low and high dose groups ，for ten mice of each group. Except the blank group， rats were deprived of sleep for 8 weeks by the method of multi-platform water environment. In the last 4 weeks， Tianwang Buxindan （8.5，17 g·kg-1）and estazolam solution（9.1 mg·kg-1）were given to the stomach， and the blank group and the model group were fed with pure water of the same volume. The food intake and body weight of mice were measured twice a week， on the 49th day， blood samples were collected from the tail vein for glucose tolerance test （GTT），on the 52nd day for insulin tolerance test（ITT）， was used to detect the expression of total cholesterol （TCH）， triglyceride（TG）and free fatty acid（FFA）in serum， and enzyme-linked immunosorbent assay（ELISA）was used to detect the expression of orexin A in serum and hypothalamus. Real-time fluorescence quantitative polymerase chain reaction（Real-time PCR）and Western blot were used to detect the mRNA and protein expression of OX1R in hypothalamus. Result:After administration， the food intake of mice in each group was different， compared with the blank group， the body weight of model group was significantly reduced（P<0.05）， the glucose tolerance was significantly abnormal， and the TCH， TG， FFA values were significantly increased（P<0.01）. The expression of orexin A in serum and hypothalamus increased significantly（P<0.01）， and the mRNA and protein expression levels of OX1R in hypothalamus increased significantly（P<0.01）. Compared with the model group， the body weight of each group of Tianwang Buxindan was significantly increased（P<0.05）， with better glucose tolerance and insulin sensitivity， TCH， TG， FFA values were significantly reduced（P<0.05，P<0.01）， accompanied by serum and the expression of orexin A in the hypothalamus was significantly decreased（P<0.05，P<0.01）， the mRNA and protein expression levels of OX1R were significantly decreased（P<0.05，P<0.01）. Conclusion:Tianwang Buxindan can protect mice from abnormal glucose and lipid metabolism induced by chronic sleep deprivation， and its mechanism may be related to the down-regulation of orexin A/OX1R signal expression.

The correlation between orexin-A and early postoperative cognitive function in elderly patients undergoing lumbar surgery under general anesthesia / 解放军医学杂志

Objective To analyze the correlation between serum orexin-A (OXA) and early postoperative cognitive function in elderly patients undergoing lumbar spinal surgery under general anesthesia. Methods A total of 76 elderly patients (age ≥65 years) underwent lumbar spine surgery under general anesthesia from December 2018 to December 2019 in the Affiliated Hospital of Inner Mongolia Medical University were collected. All the enrolled patients were evaluated by the same doctor with the Montreal cognitive assessment scale (MoCA) on one day before the surgery and one to three days after the surgery, and venous blood was extracted from the patient on the operation day and one day after the operation, and the serum levels of OXA and S100β were measured by ELISA. According to the results of cognitive function assessment, the patients were divided into postoperative cognitive dysfunction (POCD) group and non-postoperative cognitive dysfunction (NPOCD) group. The differences in serum OXA and S100β protein levels between the two groups and their correlation with MoCA scores were statistically analyzed. Results There was no statistically significant difference in the MoCA score, serum OXA level, and S100β protein level before surgery, and heart rate (HR), mean artery pressure (MAP), bispectral index (BIS) and pulse oxygen saturation (SpO2) levels before anesthesia induction (T0), at the start of surgery (T1), at 1h after the start of surgery (T2), at the withdrawal time (T3), and at 15 minutes after extubation (T4) between the two groups (P>0.05). At the first, second, and third day after operation, the MoCA scores of the POCD group were lower than those before the operation, and they were both lower than those of the NPOCD group, the difference was statistically significant (P<0.001). There was a statistically significant difference in serum OXA levels between the two groups after the operation (P<0.05). The postoperative S100β protein level was higher than that before the operation in the two groups, and the POCD group increased more significantly, the difference between the two groups after the operation was statistically significant (P<0.05). The postoperative OXA level was positively correlated with the MoCA score (r=0.545, 0.531, 0.779) and negatively correlated with the S100β protein level (r=-0.591, -0.362, -0.743) in the two groups, and the difference was statistically significant (P<0.05). Conclusions The level of serum OXA is positively correlated with early postoperative cognitive function in elderly patients undergoing lumbal spine surgery under general anesthesia, suggesting that OXA may be a potential target for reducing the risk of postoperative cognitive dysfunction in such patients, so as to provide new ideas for preventing and improving the postoperative cognitive dysfunction in elderly patients in the future.

Orexin B Enhances the Synaptic Transmission from LGN to Orexin-sensitive Neurons in L6b of Visual Cortex / 中山大学学报(医学科学版)

@#【Objective】To unmask the effect of Orexin B on the synaptic transmission between feed-forward projection from the lateral geniculate nucleus（LGN）to orexin-sensitive neurons in layer 6b（L6b）of visual cortex（VC）.【Methods】C57 mice at P25-P30 were used for micro-injection of CTB555 and ChR2-EGFP into LGN to label the neurons feedback projection to LGN from L6b and the feed-forward projection from LGN to the neurons in L6b of VC respectively. The EPSC in L6b cells was intracellularly recorded from the neurons labeled by CTB555.【Results】The neurons feedback projection to LGN in L6b are mainly pyramidal neurons, and the most of these cells are activated by orexin B，called orexin- sensitive neurons. Orexin B enhanced the NMDAR-mediated postsynaptic current in orexin-sensitive neurons in L6b by electrical or optical stimulation on the LGN projection to VC［electrical stimulation：（125.1 ± 3.7）%，optical stimulation：（123.8 ±3.8）%. In the case of OX2R′s blocker，the effect of Orexin B on EPSC amplitude disappeared with significant statistical significance，P < 0.05］，thus，strengthening the synaptic transmission between LGN and orexin-sensitive neurons in L6b.【Conclusions】Orexin B enhances the synaptic transmission between LGN to pyramidal neurons in L6b of VC.

Effect of Zuoguiwan on mRNA Expression of Orexin and Its Receptors in Hypothalamus of Ovariectomized Rats / 中国实验方剂学杂志

Objective: To observe the mRNA levels of Orexin and its receptors in the hypothalamus of ovariectomized osteoporosis rats, in order to explore the pathogenesis of postmenopausal osteoporosis(PMOP) and the mechanism Zuoguiwan. Method: An osteoporosis model induced by ovariectomy was established in rats. Totally 32 female Sprague-Dawley (SD) rats were randomly divided into sham-operated group, ovariectomized model group, 17β-estradiol treated positive group, and Zuoguiwan group, with 8 rates in each group. After 12 weeks of intragastric administration, the bone mineral density (BMD) and trabecular microstructural changes of femur were detected by micro-CT (μ-CT), and the morphological changes of bone tissue were observed by hematoxylin-eosin staining (HE) staining. The markers of bone turnover in serum osteocalcin (OCN), N-terminal propeptide of type Ⅰ procollagen (PINP), tartrate-resistant acid phosphatase (TRAP) were measured using enzyme-linked immunosorbent assay (ELISA). The mRNA expressions of orexin, orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R) were measured by Real-time PCR. Result: Compared with sham-operated group, the μ-CT showed that BMD, bone volume fraction(BV/TV), trabecular thickness(Tb. Th)and trabecular number(Tb. N)in ovariectomized model group were significantly decreased (PPN-terminal propeptide of type Ⅰ procollagen (PINP) levels decreased, whereas tartrate-resistant acid phosphatase (TRAP) content increased (PPPPPPPPPPConclusion: Decreased mRNA levels of Orexin and its receptors in the hypothalamus may be one of the mechanisms of PMOP. Zuoguiwan may correct the imbalance of bone metabolism, improve the trabecular microstructure and improve bone by up-regulating the mRNA expressions of Orexin and its receptors in the hypothalamus, density, so as to show a therapeutic effect on PMOP.

Phenotypic diversity of hereditary sensory and autonomic neuropathy type IE: a case series and review of the literature

@#Objective: DNA methyltransferase 1 (DNMT1) is crucial to maintaining methylation during DNA replication and DNA repair. DNMT1 mutations have been identified in two neurological syndromes, including hereditary sensory and autonomic neuropathy type IE (HSAN IE) with dementia and hearing loss and autosomal dominant cerebellar ataxia, deafness and narcolepsy. It is likely that DNMT1 mutations lead to various symptoms of the central and peripheral nervous system. The aim of this study was to examine the clinical characteristics, especially the initial symptoms, in the cases of DNMT1 mutations. Methods: We investigated the clinical manifestation and examination findings of four cases of HSAN IE from one family with the DNMT1 mutation c.1531Y>C (p.Try511His). Results: All four cases exhibited sensory neuropathy, cerebellar ataxia, and hearing loss, all of which were demonstrated by the audiograms. The initial symptoms of the four cases included hearing loss (n=1), gait disturbance (n=1), and depressive mood (n=2). Depressive symptoms are reported in some cases with HSAN IE, however, there are currently no published reports that describe them as primary symptoms. The CSF orexin level was measured in three cases, revealing normal values in two cases and intermediate values in one case, in which the patient exhibited rapid eye movement (REM) sleep behavior disorder. Conclusion: Our findings suggest that in cases with HSAN IE or the DNMT1 mutation, psychiatric symptoms should be taken into account as one of the initial manifestations of the disease.

Thalamic paraventricular nucleus mediates orexinergic neurons-induced promotion of emergence from general anesthesia in mice: evaluation using optogenetics method / 中华麻醉学杂志

Objective To evaluate whether the thalamic paraventricular nucleus mediates orexiner-gic ( orexin ) neurons-induced promotion of emergence from general anesthesia by using the optogenetics method in mice. Methods Twenty healthy male Hcrt-cre mice, aged 8-10 weeks, weighing 20-25 g, were divided into 4 groups ( n=5 each) using a random number table method: retrograde labeled viruses channelrhodopsin group ( R group) , anterograde labeled viruses channelrhodopsin group ( A group) , retro-grade labeled viruses control group ( RC group ) , and anterograde labeled viruses control group ( AC group) . The optogenetics technique was used in each group. Anesthesia was induced and maintained through inhaling 1％ isoflurane and pure oxygen 1. 0 L∕min. Electroencephalogram was monitored througout the procedure with the PowerLab monitoring system. The burst suppression ratio ( BSR) was recorded at 1 min before light stimulation and during light stimulation. Results Compared with RC group or the baseline at 1 min before light stimulation, the BSR was significantly decreased during light stimulation in R group ( P<0. 05) . Compared with AC group or the baseline at 1 min before light stimulation, the BSR was signifi-cantly decreased during light stimulation in group A ( P<0. 05) . Conclusion Optogenetics technique ap-plication once again confirms that orexin neurons can promote emergence from general anesthesia through thalamic paraventricular nucleus in mice.

Impacts of the repetitive transcranial acupuncture stimulation on the content of serum orexin A in patients with post-stroke insomnia / 中国针灸

OBJECTIVE@#To compare the effect on post-stroke insomnia between the repetitive transcranial acupuncture stimulation (rTAS) and the conventional western medication in the patients and to explore the mechanism.@*METHODS@#Ninety patients of post-stroke insomnia were randomized into a rTAS group, a medication group and a placebo group, 30 cases in each one. In the rTAS group, patients were intervened by rTAS. The acupoints were Baihui (GV 20), Ningshen (Extra), emotion area, Wangu (GB 12), Taiyang (EX-HN 5), Neiguan (PC 6), Shenmen (HT 7), Sanyinjiao (SP 6), Zhaohai (KI 6), Zusanli (ST 36) and Taichong (LR 3). Fast twist with small amplitude was used at Baihui (GV 20) and emotion area for 2-3 min, 200-300 r/min, once 15 min. Electroacupuncture (EA) was applied at Baihui (GV 20) and Ningshen (Extra), bilateral Wangu (GB 12), Sanyinjiao (SP 6) and Zhaohai (KI 6) on the same side, 10 Hz, 0.5-1 mA. The treatment was given for 40 min in the rTAS group, once a day. Diazepam was prescribed orally in the medication group before sleep, 2.5 mg a day. Starch capsule was used in the placebo group before sleep, once a day. All the treatment was given for continuous 1 month. The level of serum orexin A was observed before and after treatment. The effects were compared. The recurrence rate was recorded 3 months after treatment.@*RESULTS@#The total effective rates in the rTAS group and the medication group were 86.7% (26/30) and 90.0% (27/30) repectively after treatment, which were better than 20.0% (6/30) in the placebo group (both 0.05). The total effective rates in the rTAS group and the medication group were 86.7% (26/30) and 86.7% (26/30) at follow-up repectively, which were better than 16.7% (5/30) in the placebo group (both <0.01).@*CONCLUSION@#The rTAS is safe and effective for post-stroke insomnia, which is similar to oral medication of diazepam. The decreasing serum orexin A may be one of the mechanisms.

Role of orexin-A in doxapram-induced promotion of emergence from general anesthesia / 中华麻醉学杂志

Objective To investigate the role of orexin-A in doxapram-induced promotion of emergence from general anesthesia in patients.Methods Forty-four patients of both sexes,aged 18-60 yr,with body mass index of 21-25 kg/m2,of American Society of Anesthesiology physical status Ⅰ or Ⅱ,scheduled for elective lumbar surgery under general anesthesia,were divided into 2 groups (n =22 each) using a random number table:control group and doxapram group.Anesthesia was induced by intravenously injecting propofol,sufentanil and cisatracurium.The patients were mechanically ventilated after tracheal intubation.Anesthesia was maintained by inhaling sevoflurane and target-controlled infusion of remifentanil.Sevoflurane inhalation and remifentanil infusion were stopped at the end of operation,oxygen flow rate was adjusted to 6 L/min,doxapram 0.5 mg/kg were intravenously injected at the same time in doxapram group,and the equal volume of normal saline was given in control group.The emergence time and extubation time were recorded.On admission to operating room (T0),at 1 h after anesthesia induction (T1) and 5 and 30 min after tracheal extubation (T2,3),arterial blood samples were collected for determination of blood glucose concentrations and plasma orexin-A concentrations (by radioimmunoassay).Results Compared with the baseline at T0,blood glucose concentrations were significantly decreased at T1 and increased at T3,and plasma orexin-A concentrations were increased at T2 in two groups (P ＜ 0.05).Compared with control group,the time to eye opening and extubation time were significantly shortened,plasma orexin-A concentrations were increased at T2 (P＜0.05),and no significant change was found in blood glucose concentrations at each time point in doxapram group (P＞0.05).Conclusion The mechanism by which doxapram promotes emergence from general anesthesia may be related to increasing plasma orexin-A concentrations in patients.

Role of hippocampal PI3K∕Akt signaling pathway in exogenous orexin A-induced improvement of isoflurane anesthesia-caused decline in memory function of mice / 中华麻醉学杂志

Objective To evaluate the role of hippocampal phosphatidylinositol 3-kinase∕serine-threonine kinase (PI3K∕Akt) signaling pathway in exogenous orexin A-induced improvement of isoflurane anesthesia-caused decline in memory function of mice. Methods A total of 100 pathogen-free healthy adult male C57BL∕6 mice, aged 8-12 weeks, weighing 20-25 g, in which the lateral ventricle was catheter-ized, were divided into 5 groups (n = 20 each) using a random number table: control group (group C), isoflurane group (group I), orexin A group (group OA), orexin A plus dimethyl sulfoxide group (group OA+D) and orexin A plus PI3K inhibitor LY294002 group (group OA+LY). Normal saline was administra-ted in group C and group I. Orexin A 1. 5 mmol∕L was given in group OA. Orexin A 1. 5 mmol∕L (dissolved in dimethyl sulfoxide) was given in group OA+D. Orexin A 1. 5 mmol∕L and LY29400210 mmol∕L were given in group OA+LY. Group C only inhaled pure oxygen for 2 h (oxygen flow rate 2 L∕min), all the rest groups inhaled 1. 4％ isoflurane for 2 h, and the corresponding drug 2 μl was injected into the lateral cere-bral ventricle according to the concentration mentioned above at 15 min before the end of anesthesia. Twelve mice were randomly selected from each group and trained for contextual fear conditioning test, and then fear memory retrieval was conducted at 24 h after training. The rest 8 mice in each group were sacrificed at 2 h after the end of anesthesia and their brains were removed for determination of the expression of PI3K, Akt and phosphor-Akt (p-Akt) protein by Western blot. Results Compared with group C, the freezing time was significantly shortened, the expression of PI3K, Akt and p-Akt was down-regulated, and p-Akt∕Akt ratio was decreased in group I (P<0. 05). Compared with group I, the freezing time was significantly pro-longed, the expression of PI3K, Akt and p-Akt was up-regulated, and p-Akt∕Akt ratio was increased in group OA (P<0. 05). There was no significant difference in each parameter mentioned above between group OA and group OA+D (P>0. 05). Compared with group OA+D, the freezing time was significantly short-ened, the expression of PI3K, Akt and p-Akt was down-regulated, and p-Akt∕Akt ratio was decreased in group OA+LY (P<0. 05). Conclusion Hippocampal PI3K∕Akt signaling pathway is involved in exoge-nous orexin A-induced improvement of isoflurane anesthesia-caused decline in memory function of mice.

Effects of orexin-A on firing activity of gastric distension-sensitive neurons in the basomedial amygdala and food intake in diet-induced obese rats / 中华行为医学与脑科学杂志

Objective To investigate the effects of orexin-A on firing activity of gastric distensionsensitive (GD) neurons in the basomedial amygdala (BMA) and food intake in diet-indaced obese rats.Methods Healthy male Wistar rats were selected,and the diet-induced obesity (DIO) rat model and dietinduced resistant (DR) rat model were established by high-fat diet.The effects of orexin-A and an opioid receptor antagonist naloxone on BMA GD neurons were observed by recording the extracellular potentials of single neurons.The effects of orexin-A and naloxone on the food intake of different rats were observed by using BMA catheterization.The mRNA expression and protein expression of orexin-1 receptor (OX-1R) and μ opioid receptor were detected by real-time PCR and Elisa,respectively.Results After microinjection of orexinA into the BMA,the firing frequency of GD-sensitive neurons in the normal rats was significantly increased (GD-E:(78.3±6.9)％,GD-Ⅰ:(55.5±4.7) ％,P＜0.01),and this effect was completely blocked by OX-1R receptor antagonist SB334867,and naloxone partially blocked the discharge-promoting effect of orexin-A;Compared with the normal rats,the firing frequency of GD-sensitive neurons in the DIO (GD-E:(91.6±7.1) ％,GD-Ⅰ:(67.9±8.1) ％) and DR(GD-E:(87.9±6.8) ％,GD-Ⅰ:(69.2±5.8) ％) rats was significantly increased after BMA injection of orexin-A (P＜0.05).After administration of orexin-A into the BMA,food intake of the normal rats,DIO rats and DR rats ((2.38±0.34) g,(3.75 ±0.32) g,(4.01 ±0.38) g,respectively) was significantly increased (P＜0.01),and the food intake of DR and DIO rats were significantly higher than that of normal rats (P＜0.05).After BMA was injected with naloxone,the food intake of rats was inhibited,and the food intake of the DIO rats was significantly lower than that of the DR rats (P＜0.05),food intake of the DR rats was significantly lower than that of the normal rats (P＜0.05).The results of real-time PCR showed that the mRNA levels of OX-1R in DIO and DR rats were(5.85±0.45)and (6.03±0.42)were higher than that of normal rats,and the difference was significant (P＜0.05);and mRNA levels of μ-opioid receptors in DIO and DR rats((4.51±0.42) and (8.31±0.41) times) were higher than those in normal rats (P＜0.05).The results of Elisa showed that the protein levels of OX-1R in DIO ((2.98±0.28) ng/μl)and DR rats ((3.05±0.31) ng/μl) were higher than those in normal rats ((1.53±0.31) ng/μl,P＜0.05).The content of μ-opioid receptor protein in DR rats ((4.21±0.35) ng/μl) was higher than that of DIO rats ((2.77±0.27) ng/μl),and higher than that of normal rats((1.48±0.32) ng/μ),the difference was significant (P＜0.05).Conclusion BMA orexin-A promotes the spontaneous discharge of GD-sensitive neurons and food intake in normal rats,DIO rats and DR rats,μ-opioid receptors may be involved in the regulation of this process.

Orexin-B inhibits cerebral ischemia reperfusion injury in rats / 基础医学与临床

Objective To study the neuroprotective effect of orexin-B on rat model of cerebral ischemia-reperfusion injury and its molecular mechanism. Methods The artery occlusion model of male Wister rats(middle cerebral ar-tery occlusion,MCAO) was established which has been ischemic 2 h and reperfusion 24 h. Rats were randomly di-vided into sham group (control), ischemia-reperfusion group (I/R), ischemia-reperfusion +PBS group (I/R+PBS),and ischemia-reperfusion +orexin-B group (I/R+OXB). The neurological deficit scores were processed to inclusion and exclusion. Infarct size was determined by TTC staining;Using Western blot,the expressions of orexin receptor 2,p-AKT,p-GSK-3β proteins in hippocampus were detected;Jumping test was used to detect learning and memory abilities in rats. Results Orexin-B significantly reduced the volume of cerebral infarction in TTC staining;orexin-B group was significantly increased the expression of orexin receptor 2as well as p-AKT,which decreased p-GSK-3β (P<0.05),compared with the untreated group. Furthmore,the orexin-B treated group can improve the latency period and decline the mistakes in rat Jumping test(P<0.05). Conclusions The neuroprotective effect of orexin-B in cerebral ischemia-reperfusion injury may enhance p-AKT activity and inhibit p-GSK-3β activity,which may increase the proliferation of neurons and improve the cerebral blood glucose concentration.

Recent advances in orexin receptor antagonists for the treatment of insomnia / 药学学报

The orexin system was discovered in 1998 with two G-protein coupled receptors (GPCRs):orexin-1 (OX1R) and orexin-2 (OX2R) receptors that bind the neuropeptides orexin-A (OX-A) and orexin-B (OX-B). The causal link between the orexin system and obesity, anxiety, and sleep/wake disorders as a potential therapeutic target has drawn much attention in the field of pharmaceuticals. The developments of dual antagonism of the receptors by small molecules are clinically efficacious in the treatment of insomnia, where the most advanced molecule suvorexant has been approved by FDA in August, 2014. The small molecule orexin receptor antagonists (ORA) between January 2010 and August 2017 are summarized in this review and we focus on their chemical structures, mechanism and human clinical trials.

Assessment of Switching to Suvorexant versus the Use of Add-on Suvorexant in Combination with Benzodiazepine Receptor Agonists in Insomnia Patients: A Retrospective Study

OBJECTIVE: Suvorexant is a novel hypnotic drug that does not interact with the conventional γ-aminobutyric acid (GABA)-A receptor. We investigated the method by which suvorexant was introduced in insomnia patients who were taking benzodiazepine receptor agonists (BzRA). METHODS: This was a retrospective study. We extracted clinical data for patients who were prescribed suvorexant and were already using BzRA. The patients were assigned to two groups, the switching and add-on groups. We assessed the suvorexant discontinuation rate at one month after the prescription of the drug. RESULTS: One hundred and nineteen patients were assigned to the switching group, and 109 were assigned to the add-on group. The add-on group exhibited a significantly higher all-cause discontinuation rate than the switching group (odds ratio, 2.7; 95% confidence interval, 1.5 to 5.0; adjusted p < 0.001). Intolerability was a significantly stronger risk factor for suvorexant discontinuation in the add-on group (22.0% vs. 7.6%, p < 0.002), and the most common adverse effect was oversedation. CONCLUSION: Our results show that the add-on of suvorexant increases the frequency of oversedation compared with switching in insomnia patients that are taking BzRA. However, this was only a preliminary retrospective study, and further studies will be required to confirm our findings.

Orexin-A inhibits capsaicin-induced changes in cyclooxygenase-2 and brain-derived neurotrophic factor expression in trigeminal nucleus caudalis of rats

BACKGROUND: The trigeminal nucleus caudalis (Vc) is a primary central site for trigeminal transmitting. Noxious stimulation of the trigeminal nociceptors alters the central synaptic releases and neural expression of some inflammatory and trophic agents. Orexin-A and the orexin 1 receptor (OX1R) are expressed in pain pathways including trigeminal pain transmission. However, the the mechanism(s) underling orexin-A effects on trigeminal pain modulation have not been fully clarified. METHODS: Trigeminal pain was induced by subcutaneous injection of capsaicin in the upper lip in rats. The effect of trigeminal pain on cyclooxygenase-2 (COX-2) and brain-derived neurotrophic factor (BDNF) expression in the Vc of animals was determined by immunofluorescence. Subsequently, OX1R agonist (orexin-A) and antagonist (SB-334867-A) was administrated in the Vc to investigate the possible roles of the Vc OX1R on changes in COX-2 and BDNF levels following pain induction. RESULTS: The data indicated an increase in COX-2 and decrease in BDNF immuno-reactivity in the Vc of capsaicin, and capsaicin- pretreated with SB-334867-A (80 nM), groups of rat. However, the effect of capsaicin on COX-2 and BDNF expressions was reversed by a Vc microinjection of orexin-A (100 pM). CONCLUSIONS: Overall, the present data reveals that orexin-A can attenuate capsaicin-induced trigeminal pain through the modulation of pain effects on COX-2 and BDNF expressions in the Vc of rats.