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Objective:To investigate the arousal mechanism after sevoflurane anesthesia using orexinergic modulation in dorsal raphe nucleus(DRN) by optogenetic and chemogenetic techniques in rats.Methods:Forty-five healthy male Hcrt-Cre rats, aged 10-12 weeks, weighing 220-250 g, were divided into 6 groups by the random number table method: optical-excitatory group (CHR2 group, n=5), optical-inhibitory group (eNpHR group, n=5), optical-control group (O-CON group, n=5); chemogenetic-excitatory group (hm3Dq group, n=10), chemogenetic-inhibitory group (hm4Di group, n=10) and chemogenetic-control group (C-CON group, n=10). The optogenetic or chemogenetic techniques were used in each group. Three weeks after injecting the rat virus, anesthesia was induced and maintained with 2.7% sevoflurane anesthesia in 1.5 L/min O 2, and the EEG data were continuously recorded throughout the process. The burst suppression ratio (%BSR) was recorded at 2 min before and of laser stimulation. Combining optogenetic and chemogenetic strategies, it was investigated that whether activation of orexinergic projection to DRN could modulate anesthetic behaviors during sevoflurane anesthesia. Results:Compared with C-CON group, the recovery of righting reflex (RORR) time was significantly shortened after sevoflurane anesthesia in hm3Dq group ( P<0.05), and the RORR time was significantly prolonged after sevoflurane anesthesia in hm4Di group and eNpHR group ( P<0.05). Compared with O-CON group or the baseline at 2 min before light stimulation, the %BSR was significantly decreased during 473nm laser stimulation in CHR2 group ( P<0.05), and no statistically significant change was found in the %BSR during 473nm laser stimulation in eNpHR group ( P>0.05). Compared with O-CON group, the RORR time was significantly shortened after sevoflurane anesthesia in CHR2 group ( P<0.05). Conclusions:Lateral hypothalamic area orexin-DRN neural circuit plays a key role in promoting arousal from general anesthesia in rats.
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RESUMEN: Los biomarcadores más estudiados en la demencia tipo Alzheimer (DA) son los niveles elevados de Aβ42 y de proteína Tau en líquido cefalorraquídeo. Dada la complejidad de la sintomatología cognitiva y síntomas neuropsiquiátricos (SNP) de esta patología, algunos estudios recientes proponen sustancias como las orexinas, como blanco terapéutico de DA y SNP. El presente trabajo tiene como objetivo revisar publicaciones científicas recientes que hayan analizado la asociación entre orexinas, SNP y DA en humanos, algunos modelos animales y que hayan evaluado a las orexinas como posibles biomarcadores tanto para investigación como en el área clínica. En esta revisión también se describen los estudios que sugieren a las orexinas como un posible biomarcador en la DA, dada su relación con el Aβ42 y la proteína Tau, y otros estudios que las asocian con presencia de SNP, especialmente alteración del sueño. Se plantea la hipótesis de que la presencia de SNP en DA se asocia con las orexinas, debido a que este sistema influye en el funcionamiento hipotalámico y de forma indirecta en áreas cerebrales que regulan el comportamiento. Sin embargo, aún falta mayor investigación, principalmente de estudios longitudinales para conocer claramente la influencia de las orexinas en los SNP.
ABSTRACT The most studied biomarkers in Alzheimer's dementia (AD) are elevated levels of Aβ42 and Tau protein in cerebrospinal fluid. Given the complexity of the cognitive symptomatology and neuropsychiatric symptoms (NPS) of this pathology, some recent studies propose substances such as orexins as a therapeutic target for AD and NPS. The present work aims to review recent scientific publications that have analyzed the association between orexins, PNS and AD in humans. There are some animal models that have evaluated orexins as possible biomarkers both for research and in the clinical area. This review also describes studies that suggest orexins as possible biomarkers in AD, given their relationship with Aβ42 and Tau protein, and other studies that associate them with the presence of SNPs, especially sleep disturbance. It is hypothesized that the presence of SNPs in AD is associated with orexins, because this system influences hypothalamic functioning and indirectly in brain areas that regulate behavior. However, further research is still lacking, mainly longitudinal studies to clearly know the influence of orexins on SNPs.
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Humans , Alzheimer Disease/diagnosis , Alzheimer Disease/metabolism , Orexins/metabolism , Sleep Wake Disorders , Biomarkers , Dementia , Alzheimer Disease/physiopathologyABSTRACT
BACKGROUND: Appetite regulation is integral to food intake and is modulated by complex interactions between internal and external stimuli. Hormonal mechanisms which stimulate or inhibit intake have been characterized, but the physiologic effects of serum levels of such hormones in short-term appetite regulation have received little attention. AIM: To evaluate whether fasting levels of orexigenic/anorexigenic hormones were associated with energy intake at breakfast, served soon after drawing a fasting blood sample, in a group of adolescents. MATERIAL AND METHODS: Anthropometry, body composition and fasting blood levels of leptin, insulin, ghrelin, and orexin-A were measured in 655 Chilean adolescents aged 16.8 ± 0.3 years (52% males). Energy intake was measured at a semi-standardized breakfast. Associations between hormone levels and energy intake were studied using multivariate linear models. RESULTS: Thirty nine percent of participants were overweight/ obese. After an overnight fast, median values for leptin, insulin, ghrelin and orexin-A were 7.3 ng/mL, 6.7 IU/dL, 200.8 pg/mL, and 16.1 pg/mL, respectively. Participants ate on average 637 ± 239 calories at breakfast. In multivariable models, insulin levels were inversely and independently associated with caloric intake at breakfast (β = −18.65; p < 0.05), whereas leptin, ghrelin and orexin-A levels were positively and independently associated with intake: β= 5.56, β = 0.34 and β = 8.40, respectively, p < 0.05. CONCLUSIONS: Fasting leptin, ghrelin and orexin-A were positively associated with energy intake during breakfast provided soon after the blood draw. Insulin was negatively associated with energy intake. Modifiable factors influencing levels of appetite regulating hormones could be a potential target for influencing food intake.
ANTECEDENTES: La regulación del apetito es parte integral de la ingesta alimentaria y es modulada por complejas interacciones entre estímulos internos y externos. Se han caracterizado los mecanismos hormonales que estimulan o inhiben la ingesta, pero los efectos fisiológicos de los niveles séricos de tales hormonas en la regulación del apetito a corto plazo han recibido poca atención. OBJETIVO: Evaluar si los niveles en ayunas de hormonas orexigénicas/ anorexigénicas se asocian con la ingesta energética en el desayuno, entregado inmediatamente después de una muestra de sangre en ayunas, en un grupo de adolescentes. MATERIAL Y MÉTODO: Se efectuaron mediciones antropométricas, composición corporal y medición de niveles en ayunas de leptina, insulina, grelina y orexina-A en 655 adolescentes de 16,8 ± 0,26 años. La ingesta energética se midió en un desayuno semiestandarizado. Se estudiaron las asociaciones entre los niveles hormonales y la ingesta energética mediante modelos lineales multivariados. RESULTADOS: Los valores de leptina, insulina, grelina y orexina-A fueron 7,3 ng/mL, 6,7 UI/dL, 200,8 pg/mL y 16,1 pg/mL respectivamente. Los participantes comieron un promedio de 637 ± 239 calorías en el desayuno. Los niveles de insulina se asociaron inversa e independientemente con la ingesta del desayuno (β = −18,65; p < 0,05), mientras que los niveles de leptina, grelina y orexina-A se asociaron positiva e independientemente con la ingesta: β = 5,65; β = 0,34; β = 8,40, (p < 0,05). CONCLUSIONES: La leptina, grelina y orexina-A en ayunas se asociaron positivamente con la ingesta de energía durante el desayuno proporcionado poco después de la muestra de sangre. La insulina se asoció negativamente con la ingesta de energía. Los factores modificables que influyen en las hormonas reguladoras del apetito podrían ser un objetivo potencial para influir en la ingesta de alimentos.
Subject(s)
Humans , Male , Female , Adolescent , Appetite/physiology , Breakfast , Energy Intake/physiology , Chile , Fasting , Leptin , Ghrelin , Orexins , InsulinABSTRACT
Suvorexant, an orexin receptor antagonist used for insomnia, has been shown to have a preventive effect on delirium in a randomized placebo-controlled trial. However, its effectiveness in the management of nocturnal delirium has not yet been determined. Here we report four cases in which elderly patients with moderate to severe Alzheimer's disease who developed nocturnal delirium were treated with suvorexant. In case 1, 15 mg suvorexant was initiated to manage nocturnal delirium refractory to antipsychotics, antidepressants, and a Japanese herbal medicine, resulting in immediate sleep improvement. However, treatment discontinuation led to recurrence of symptoms, which were reversed by recommencing suvorexant. In case 2, as antipsychotics used for the treatment of nocturnal delirium were ineffective, 15 mg suvorexant was administered. The patient achieved rapid improvement in sleep. In case 3, the use of atypical antipsychotics for the treatment of nocturnal delirium was contraindicated, as the patient had diabetes. Therefore, 15 mg suvorexant was administered following good outcomes in cases 1 and 2, resulting in immediate sleep improvement. Finally, in case 4, 15 mg suvorexant was used as an initial medication for nocturnal delirium, and the patient showed sleep improvement immediately. Elevated orexin levels in the cerebrospinal fluid are reportedly linked to sleep deterioration in patients with moderate to severe Alzheimer's disease. The immediate and reproducible action and effectiveness of suvorexant observed in our patients suggest that enhanced cerebral orexin activity might be associated with sleep-wake cycle disturbances due to delirium in elderly patients with Alzheimer's disease.
Subject(s)
Aged , Humans , Alzheimer Disease , Antidepressive Agents , Antipsychotic Agents , Asian People , Cerebrospinal Fluid , Delirium , Herbal Medicine , Orexins , Recurrence , Sleep Initiation and Maintenance DisordersABSTRACT
Diabetes mellitus is a metabolic disease characterized by chronic hyperglycemia. Recently, the number of diabetic patients in the world is rapidly growing, which has brought a heavy burden to the society. At the same time, changes in lifestyle lead to a general decline in the quality of sleep in the population. Epidemiological and clinical studies have shown a close relation between the development of diabetes and sleep disorders, which may form a vicious circle. Sleep disorders promote the occurrence of type 2 diabetes and affect the glycemic control of diabetic patients; on the other hand, diabetic patients, especially in poor glycemic control, often have sleep disorders. This review discusses the relationship between type 2 diabetes and sleep disorders based on related research, and may provide new strategies for future treatment of diabetes.
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ABSTRACT The neuropeptide orexin-A and its receptors are widely distributed in both hippocampal circuitry and pain transmission pathways. Objective: Involvement of the CA1 orexin 1 receptor (OX1R) on the modulation of orofacial pain and pain-induced changes in hippocampal expression of cyclooxygenase-2 (COX-2) and brain-derived neurotrophic factor (BDNF) was investigated. Methods: Orofacial pain was induced by an intra-lip injection of capsaicin (100 μg). Reverse transcription polymerase chain reaction and immunoblot analysis were used to indicate changes in hippocampal BDNF and COX-2 expression, respectively. Results: Capsaicin induces a significant pain response, which is not affected by either orexin-A or SB-334867-A, an OX1R antagonist. However, an increased expression of COX-2 and decreased expression of BDNF was observed in the hippocampus of animals that received capsaicin or SB-334867-A (80 nM) plus capsaicin. Meanwhile, orexin-A (40 pM) attenuated the effects of capsaicin on the expression of COX-2 and BDNF. Conclusions: CA1 OX1R activation moderates capsaicin-induced neuronal inflammation and neurotrophic deficiency.
RESUMO O neuropeptídeo orexina-A e seus receptores estão amplamente distribuídos nos circuitos do hipocampo e nas vias de transmissão da dor. Objetivo: O envolvimento do receptor de orexina 1 CA1 (OX1R) na modulação da dor orofacial e alterações induzidas pela dor na expressão do hipocampo de ciclooxigenase-2 (COX-2) e fator neurotrófico derivado do cérebro (BDNF) foi investigado. Métodos: A dor orofacial foi induzida por injeção intra-labial de capsaicina (100 μg). A reação em cadeia da polimerase de transcrição reversa e a análise de imunotransferência foram utilizadas para indicar alterações na expressão de BDNF e COX-2 no hipocampo, respectivamente. Resultados: A capsaicina induz uma resposta significativa à dor, que não é afetada pela orexina-A ou pelo SB-334867-A, um antagonista do OX1R. No entanto, uma expressão aumentada de COX-2 e uma expressão diminuída de BDNF foi observada no hipocampo de animais que receberam capsaicina ou SB-334867-A (80 nM) mais capsaicina. Enquanto isso, a orexina A (40 pM) atenuou os efeitos da capsaicina na expressão de COX-2 e BDNF. Conclusões: A ativação de CA1 OX1R modera a inflamação neuronal induzida por capsaicina e a deficiência neurotrófica.
Subject(s)
Animals , Male , Rats , Facial Pain/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Cyclooxygenase 2/metabolism , Orexin Receptors/metabolism , Orexins/pharmacology , Hippocampus/metabolism , Urea/analogs & derivatives , Urea/pharmacology , Benzoxazoles/pharmacology , Capsaicin , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction , Disease Models, Animal , Hippocampus/drug effects , Naphthyridines , Neurons/drug effects , Neurons/metabolismABSTRACT
Objective:To investigate the effects of Orexin peptides on feeding and energy metabolism in mice.Methods:The mice were divided into two groups:feeding group and metabolic group.The feeding group were injected with different doses (1,3 and 10 nmol) of orexin-A and orexin-B to observe their effects on feeding and the activity of tyrosine hydroxylase in liver.We used the metabolic cages and observed the changes of respiration rate and respiration rate of mice were under light condition,dark condition and fasting condition.Results:Compared with the control group,1 nmol and 10 nmol orexin-A significantly stimulated mice to feed (P ＜0.05) within 4 hours after injection,and the effect of 3 nmol orexin-A on feeding was not obvious,but increase the activity of tyrosine hydroxylase.Any dose of orexin-B did not show a stimulating effect on mice feeding.(P ＞0.05).In the light cycle,orexin-A could significantly reduce the respiration rate (RQ),the metabolic rate was significantly increased (P ＜0.05);In the dark cycle,orexin-A had no effect on RQ,but the metabolic rate was significantly rised (P ＜0.05);But the injection of orexin-A in fasting mice induced a brief increase in RQ and a significant increase in metabolic rate (P ＜0.05).Conclusion:Orexins may play an important role in regulating feeding and energy metabolism in mice.
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Orexins are a class of important hypothalamic neuropeptides,including type A and B. Orexins are associated w ith numerous physiological functions, including sleep-aw akening, energy balance, endocrine and visceral functions, and they also have certain relations w ith the pathophysiological changes, such as drow siness and drug abuse. In recent years, the pathophysiological role and mechanism, as w el as the clinical significance of orexins in cerebrovascular diseases are causing concern. This article summarizes the roles of orexins and focuses on the roles of orexin A in cerebrovascular diseases.
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Las orexinas o hipocretinas son neuropéptidos recientemente descritos (1998), encontrados en mayor densidad en neuronas de las regiones lateral, posterior y perifornical del hipotála-mo, las cuales se han visto implicadas en procesos de modulación de la ingesta alimenticia y del ciclo sueño-vigilia. El sistema orexinérgico tiene amplias proyecciones a todo lo largo y ancho del SNC especialmente a centros monoaminérgicos, tales como el locus coeruleus, núcleo tuberomamilar, núcleos del rafé y el área tegmental ventral. Inicialmente se pensó en un papel fundamental de las orexinas en la regulación de la función alimenticia, sin embargo estudios recientes han implicado a estos neuropéptidos en la regulación del ciclo sueño-vigilia. Estos hallazgos permiten conocer mejor una región como el hipotálamo, al igual que brinda un mejor entendimiento de la patogenia y fisiopatología relacionadas con los trastornos de la alimentación y el sueño. Este artículo pretende presentar una revisión lo más completa posible de lo que se conoce hasta ahora de estos neuromoduladores y su papel en relación con los trastornos del sueño, especialmente su implicación en la narcolepsia.
Orexins or hypocretins are recently described (1998) neuropeptides found in greater density in hypothalamic neurons, wich have been shown to be important for modulating feeding and sleep-wakefulness cycle. Orexinergic system has broad projections throughout the length and breadth of the CNS specially to monoaminergic centers such as the locus coeruleus, tuberoamilar neclei, raphe nuclei, and ventral tegmental area. Initially it was thought a key role of orexin in feedin behavior regulation, however, recent studies give a leading role to these neuropeptides in regulating the sleep-wakefulness cycle, this discovery opens a door to help better understand the operation of an area so important for the homeostasis of the human body, such as the hypothalamus, and gives some basis for a better understanding of the pathogenesis and pathophysiology in relation to eating disorders and sleep. The aim of this paper is to provide an updated review of the morphological and functional aspects that are known so far in relation to these molecules and their relationship with sleep disorders, especially their involvement in narcolepsy.
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Cataplexy is one of the most pathognomonic symptoms in narcolepsy. This study was designed to investigate the frequency of the HLA-DQB1 allele and cerebrospinal fluid (CSF) hypocretin levels in Korean narcoleptics with cataplexy as compared with those who do not have cataplexy. Seventy-two narcoleptics were selected based on polysomnography and multiple sleep latency test as well as their history and clinical symptoms at Sleep Disorders Clinic. The patients were divided into a narcolepsy with cataplexy group (n=56) and a narcolepsy without cataplexy group (n=16). All patients were subjected to HLA typing to determine the frequency of DQB1 allele and to spinal tapping to measure the level of CSF hypocretin. In cataplexy-positive patients, as compared with cataplexy-negative patients, the frequency of HLA-DQB1*0602 was found to be significantly high (89.3% vs. 50.0%) (p=0.003). On the other hand, the frequency of HLA-DQB1*0601 was found to be significantly low (0% vs. 43.8%) (p<0.001). In 48 of 56 cataplexy-positive patients (85.7 %), hypocretin levels were decreased (< or =110 pg/mL). However, only 6 of 16 cataplexy-negative patients (37.5%) exhibited a decreased hyopcretin level (p<0.001). The high frequency of HLA-DQB1*0602, low frequency of HLA-DQB1*0601 and low hypocretin levels in cataplexy-positive groups suggest that cataplexy-positive narcolepsy might be an etiologically different disease entity from the cataplexy-negative.
Subject(s)
Middle Aged , Male , Humans , Female , Child , Aged , Adult , Adolescent , Sleep, REM , Neuropeptides/cerebrospinal fluid , Narcolepsy/cerebrospinal fluid , Intracellular Signaling Peptides and Proteins/cerebrospinal fluid , HLA-DQ Antigens/genetics , Cataplexy/cerebrospinal fluid , AllelesABSTRACT
Objective: To study the effect of acute hypoxia with simulated high altitude on the expression of orexins in rats hypothalamus. Methods: Rats were exposed to different high altitude(3 000 m,(4 000) m,5 000 m and 6 000 m for 8 h daily) in a hypobaric chamber.The expression of orexins in rat hypothalamus was determined by immunohistochemistry and the pathology changes of rat hypothalamus was observed with transelectricity. Results: The number of orexin-A immunoreactive positive cells in hypothalamus decreased obviously with hypoxia for 1 day(P