المؤلفون: Zegarra Valdivia, Jonathan Adrián

مرشدي الرسالة: Torres Alemán, Ignacio, Nuñez Molina, Ángel

المصدر: TDX (Tesis Doctorals en Xarxa)

مصطلحات موضوعية: Factor de creixement similar a la insulina - I, Factor de crecimiento similar a la insulina tipo I, Insulin-like growth factor-I, Sistema orexin, Sistema orexinérgico, Sistema colinèrgic, Sistema colinérgico, Ciències de la Salut

الوقت: 616.8

الوصف: L’estudi de l’factor de creixement similar a la insulina tipus I (IGF-I) ha adquirit rellevància en els últims anys per la seva activitat pleiotrópica, el seu paper en la patologia cerebral i les seves possibles aplicacions terapèutiques. IGF-I és una hormona circulant produïda principalment pel fetge sota la senyalització de l’hormona de creixement (GH) que pot creuar la barrera hematoencefàlica (BBB) ​​cap al sistema nerviós central (SNC). No obstant això, no es comprèn de l’tot el seu important paper en l’envelliment i la malaltia d’Alzheimer. Alguns estudis suggereixen que l’IGF-I està involucrat en els canvis adaptatius durant l’envelliment, i ha evidència que dóna suport a la noció que la malaltia d’Alzheimer (EA) també s’associa amb una funció metabòlica alterada que afecta la insulina i a l’IGF -I. L’envelliment i la MA estan estretament relacionats amb les alteracions corticals, de el processament de la informació i de la son / vigília, comorbiditats comuns de les malalties metabòliques. A més, l’envelliment sol anar acompanyat d’una disminució de la cognició, i els canvis en la durada de la son van acompanyats de canvis en els nivells d’IGF-I. A més, l’envelliment s’associa amb nivells més baixos d’IGF-I en sèrum que poden contribuir a aquest deteriorament. No obstant això, els processos subjacents que vinculen tots dos encara no estan completament definits. En aquest treball estudiem un grup específic de cèl·lules involucrades en la regulació de la son i l’activitat cortical. El primer grup, les neurones orexinérgicas, és una població de cèl·lules discretes a l’hipotàlem lateral involucrat en el cicle circadià de son / vigília, metabolisme, despesa energètica i arousal. El segon grup, les cèl·lules colinèrgiques de l’prosencèfal basal, tenen un paper essencial en la funció cortical, el processament de la informació i l’estat de son / vigília.

الوصف (مترجم): El estudio del factor de crecimiento similar a la insulina tipo I (IGF-I) ha adquirido relevancia en los últimos años por su actividad pleiotrópica, su papel en la patología cerebral y sus posibles aplicaciones terapéuticas. IGF-I es una hormona circulante producida principalmente por el hígado bajo la señalización de la hormona del crecimiento (GH) que puede cruzar la barrera hematoencefálica (BBB) hacia el sistema nervioso central (SNC). Sin embargo, no se comprende del todo su importante papel en el envejecimiento y la enfermedad de Alzheimer. Algunos estudios sugieren que el IGF-I está involucrado en los cambios adaptativos durante el envejecimiento, y existe evidencia que respalda la noción de que la enfermedad de Alzheimer (EA) también se asocia con una función metabólica alterada que afecta a la insulina y al IGF-I. El envejecimiento y la EA están estrechamente relacionados con las alteraciones corticales, del procesamiento de la información y del sueño/vigilia, comorbilidades comunes de las enfermedades metabólicas. Además, el envejecimiento suele ir acompañado de una disminución de la cognición, y los cambios en la duración del sueño van acompañados de cambios en los niveles de IGF-I. Además, el envejecimiento se asocia con niveles más bajos de IGF-I en suero que pueden contribuir a este deterioro. No obstante, los procesos subyacentes que vinculan a ambos aún no están completamente definidos. En este trabajo estudiamos un grupo específico de células involucradas en la regulación del sueño y la actividad cortical. El primer grupo, las neuronas orexinérgicas, es una población de células discretas en el hipotálamo lateral involucrado en el ciclo circadiano de sueño/vigilia, metabolismo, gasto energético y arousal. El segundo grupo, las células colinérgicas del prosencéfalo basal, desempeñan un papel esencial en la función cortical, el procesamiento de la información y el estado de sueño/vigilia.
The study of insulin-like growth factor-I (IGF-I) has reached relevance in recent years for its pleiotropic activity, role in brain pathology, and potential therapeutic applications. IGF-I is a circulating hormone mainly produced by the liver under growth hormone (GH) signaling that can cross the blood-brain-barrier (BBB) into the central nervous system (CNS). However, its extensive role in aging and Alzheimer’s disease is not entirely understood. Some studies suggest that IGF-I is involved in adaptive changes during aging, and there is some evidence that supports the notion that Alzheimer’s disease (AD) is also associated with perturbed metabolic function affecting insulin and insulin-like growth factor. Aging and AD are closely related to cortical, information processing, and sleep/wakefulness disturbances, common comorbidities of metabolic diseases. Besides, aging is frequently accompanied by a decline in cognition, and changes in sleep duration are paralleled by changes in IGF-I levels. Furthermore, aging is associated with lower serum IGF-I levels that may contribute to this deterioration. Nonetheless, the underlying processes linking both are not yet fully defined. Here, we take advantage of a specific group of cells involved in sleep regulation and cortical activity. The first group, the orexin neurons, is a discrete cell population in the lateral hypothalamus involved in the circadian sleep/wake cycle, metabolic, energy expenditure, and arousal. The second group, cholinergic cells from the basal forebrain, plays an essential role in cortical function, information processing, and sleep/wake status.
Universitat Autònoma de Barcelona. Programa de Doctorat en Neurociències

وصف الملف: application/pdf

الوصول الحر: http://hdl.handle.net/10803/674529Test

المؤلفون: Jing Guo, Zhuo Kong, Sha Yang, Jingjing Da, Liangzhao Chu, Guoqiang Han, Jian Liu, Ying Tan, Jiqin Zhang

المصدر: Journal of Neuroinflammation, Vol 21, Iss 1, Pp 1-19 (2024)

مصطلحات موضوعية: Orexin-A, Sepsis-associated encephalopathy, Inflammation, Cognitive dysfunction, Orexin receptors, Neurology. Diseases of the nervous system, RC346-429

الوصف: 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.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1742-2094Test

الوصول الحر: https://doaj.org/article/36ce309a09554f4aa8a84e0b3f903ddeTest

المؤلفون: García Brito, Soleil

المساهمون: University/Department: Universitat Autònoma de Barcelona. Departament de Psicobiologia i de Metodologia de les Ciències de la Salut

مرشدي الرسالة: Aldavert Vera, Laura, Huguet i Blanco, Gemma, Segura Torres, Pilar

المصدر: TDX (Tesis Doctorals en Xarxa)

مصطلحات موضوعية: Estimulació elèctrica intracranial, Estimulación eléctrica intracraneal, Intracranial self-stimulation, Receptor de orexina-A, Orexin-A receptor, Modulació de la memòria, Modulación de la memoria, Memory modulation, Ciències Humanes

الوقت: 159.9

الوصف: La autoestimulación eléctrica intracraneal (AEIC) es un potente tratamiento para la facilitación de la memoria explícita e implícita. Los posibles mecanismos implicados en el efecto facilitador de la AEIC podrían ser múltiples. Así, la AEIC promueve mecanismos de plasticidad en el cerebro relacionados con los procesos de aprendizaje y memoria, tales como cambios estructurales o en la expresión de genes relacionados, en el hipocampo y otras estructuras de diferentes sistemas de memoria. Además, la AEIC produce un arousal generalizado en el cerebro a través de la activación de sistemas de neurotransmisión excitatorios involucrados en el aprendizaje y la memoria. Sin embargo, la implicación del sistema orexinérgico en el efecto de la AEIC sobre la memoria no ha sido estudiada. Las orexinas son neuropéptidos excitatorios que participan en procesos homeostáticos, de ingesta y de regulación sueño-vigilia. La orexina-A y su receptor selectivo, el OX1R, participan en procesos que también son modulados por la AEIC. Por ejemplo, la orexina-A participa en los procesos de refuerzo a partir de sus interacciones con el sistema dopaminérgico mesolímbico. La orexina-A también regula los estados de arousal probablemente a través de la modulación de vías noradrenérgicas y colinérgicas. La activación de los receptores OX1R en neuronas colinérgicas parece modular procesos atencionales. Además, la participación de las orexinas en la modulación de los procesos de aprendizaje y memoria está ganando relevancia, ya que se ha demostrado que la activación de los receptores OX1R puede facilitar diferentes tipos de memoria. Por último, las neuronas que sintetizan orexinas se encuentran principalmente en el hipotálamo lateral, precisamente el área cerebral donde la conducta de AEIC presenta una mayor tasa de respuesta. Con el objetivo de estudiar la relación entre el sistema orexinérgico y el efecto facilitador de la AEIC sobre el aprendizaje y la memoria, se han llevado a cabo cuatro experimentos orientados a evaluar si el bloqueo de los OX1R, por administración de SB-334867, afecta a la facilitación de la memoria producida por la AEIC en dos tareas distintas de aprendizaje, una explícita y otra implícita. Específicamente, los efectos de la AEIC y del bloqueo de los OX1R fueron estudiados en una versión espacial estándar de tarea espacial en el laberinto Acuático de Morris (LAM), y en una tarea de discriminación visual simultánea (DVS), una versión implícita adaptada para el mismo laberinto. El Estudio I y Estudio II sirvieron de experimentos preliminarios para 1) determinar el efecto de la AEIC sobre una tarea de DVS en LAM, y 2) caracterizar el protocolo de entrenamiento en el que el SB-334867 deteriorara el aprendizaje. Observamos que la AEIC facilita la adquisición y retención de una tarea de DVS en el LAM, mientras que promueve una memoria inflexible de la tarea; y que el SB-334867 deteriora la tarea espacial solo en un protocolo de bajo entrenamiento. En el Estudio III, usamos el protocolo de bajo entrenamiento para evaluar los efectos del bloqueo de OX1R sobre la facilitación de la AEIC en la memoria espacial y sobre la expresión de c-Fos en regiones tálamo-cortico-hipocampales relacionadas con la memoria. En el Estudio IV, evaluamos los efectos del bloqueo del OX1R sobre la facilitación de una tarea de DVS en el LAM por la AEIC, así como sus efectos sobre los niveles de acetilcolinesterasa (AChE) en dos regiones colinérgicas relevantes. En general, la AEIC facilita ambos tipos de memoria, mientras que el bloqueo de OX1R los deteriora. Además, la AEIC tiene un efecto compensador del deterioro ocasionado por el SB-334867. Por otro lado, la AEIC promueve una memoria espacial flexible, y una memoria de DVS más rígida. Las observaciones histológicas muestran que la AEIC aumenta la activación de áreas de memoria, mientras que el bloqueo de OX1R provoca una disminución de la activación de las mismas, además de reducir los niveles de AChE en regiones colinérgicas. Por último, el SB-334867 parece anular parcialmente los efectos facilitadores de la AEIC sobre la memoria espacial, mientras que los anula totalmente para la tarea de DVS. En resumen, esta tesis aporta nuevos datos acerca de la implicación del sistema orexinérgico en la facilitación de la memoria por AEIC. Más específicamente, destaca la participación de la orexina-A y su receptor OX1R en la consolidación, la retención a largo plazo y la flexibilidad cognitiva en dos tareas de memoria, una explícita y otra implícita. Además, dedica una especial atención a la participación diferencial del OX1R en un aprendizaje de reversal, dependiendo de las características de cada tarea en términos de flexibilidad. En general, el presente trabajo sugiere que el bloqueo de los receptores OX1R impide la facilitación de la memoria por AEIC de forma parcial, pero que este efecto depende del tipo y del proceso de memoria que se evalúe.

الوصف (مترجم): Intracranial self-stimulation (ICSS) has been shown to facilitate implicit and explicit memory. In order to explain the facilitating effects of ICSS on learning and memory, several mechanisms have been proposed. Firstly, ICSS promotes structural plasticity and the expression of plasticity-related genes in the hippocampus and other memory-related structures. In addition, ICSS boosts general arousal states through the activation of many excitatory neurotransmission systems involved in learning and memory. However, research exploring the implication of the excitatory orexinergic system in the facilitative effects of ICSS on memory has yet to be carried out. The orexinergic system plays a role in homeostatic regulation, food intake and the regulation of the sleep-wake cycle. Orexin-A and its selective receptor OX1R are involved in processes that overlap with those affected by ICSS. For instance, orexin-A participates in reward processing through interactions with the dopaminergic system in several reward-related regions. Moreover, orexin-A is implicated in the regulation of arousal states through the stimulation of the noradrenergic and cholinergic systems. In addition, OX1R action within the cholinergic system also modulates attentional processing. Finally, orexin-A and OX1R have been gaining relevance with regard to learning and memory processes, in that orexin-A administration facilitates the acquisition of several types of memory. Interestingly, the orexinergic neurons are located in the lateral hypothalamus, which is also where the highest rates of ICSS behavior are recorded. In order to study the relationship between the orexinergic system and the facilitating effect of ICSS on learning and memory, this dissertation presents four studies which set out to explore whether or not blocking OX1R, using SB-334867, affects said facilitating effects on two different memory tasks. Specifically, the effects of ICSS and OX1R blockade were studied in a standard spatial version of the Morris Water Maze (MWM) and an adapted version of a simultaneous visual discrimination (SVD) implicit task using the same apparatus. Study I and Study II served as preparatory experiments to 1) examine the effects of ICSS on a SVD task, and 2) characterize the training protocol in which the SB-334867 would result in impaired spatial learning and memory. We found that ICSS facilitates the acquisition and retention of an SVD task, while promoting an inflexible discrimination memory; and that SB-334867 deteriorates spatial learning only in a weak training condition. In Study III, we used the previously characterized training protocol to assess the effects of OX1R blockade on the facilitating effects of ICSS on a spatial memory task in the MWM. The level of c-Fos expression in memory-related areas of the thalamo-cortico-hippocampal system was also measured. Study IV evaluated the effects of OX1R blockade on the facilitation of an SVD task in the MWM caused by ICSS, as well as the acetycholinesterase (AChE) activity in cholinergic areas. Overall, ICSS was shown to be capable of facilitating both types of memory, while the blockade of OX1R had a detrimental effect. Moreover, ICSS seems to compensate for the impairment caused by SB-334867. Furthermore, ICSS promotes flexible spatial memory, but an inflexible SVD memory. In addition, histological observations revealed that ICSS increased c-Fos expression in memory-related areas, while OX1R blockade decreased activation in most of said areas, as well as AChE levels in cholinergic regions. Finally, SB-334867 administration seemed to partially negate ICSS facilitation of the spatial memory task, while it completely negated the facilitative effect of the treatment for the SVD task in the MWM. This dissertation sheds further light on the implication of the orexinergic system in the facilitation of memory by ICSS. More specifically, it highlights the extensive involvement of orexin-A and its selective receptor OX1R in aspects such as consolidation, long-term retention and cognitive flexibility in both implicit and explicit memory. In addition, it provides insight into the differential participation of OX1R in the reversal of each task, depending on how flexible that type of memory is. Overall, we concluded that blocking OX1R partially impedes the facilitation of memory by ICSS, but that this effect varies depending on the type of memory task and specific aspects of memory.

وصف الملف: application/pdf

الوصول الحر: http://hdl.handle.net/10803/565686Test

المؤلفون: Wu, Ming-Fung, Li, Songlin, Lai, Yuan-Yang, Siegel, Jerome, Thannickal, Thomas, Mcgregor, Ronald

المصدر: Sleep. 46(9)

مصطلحات موضوعية: Xyrem, hypocretin, locus coeruleus, narcolepsy, orexin, sodium oxybate, tyrosine hydroxylase, Humans, Mice, Animals, Dogs, Orexins, Sodium Oxybate, Cataplexy, Locus Coeruleus, Narcolepsy, Neurons, Opiate Alkaloids

الوصف: Long-term use of sodium oxybate (SXB), (also called gamma-hydroxybutyrate [GHB]) attenuates the cataplexy and sleepiness of human narcolepsy. We had previously found that chronic opiate usage in humans and long-term opiate administration to mice significantly increased the number of detected hypocretin/orexin (Hcrt) neurons, decreased their size, and increased Hcrt level in the hypothalamus. We also found that opiates significantly decreased cataplexy in human narcoleptics as well as in narcoleptic mice and that cessation of locus coeruleus neuronal activity preceded and was tightly linked to cataplectic attacks in narcoleptic dogs. We tested the hypothesis that SXB produces changes similar to opiates and now report that chronic SXB administration significantly increased the size of Hcrt neurons, the reverse of what we had seen with opiates in humans and mice. Levels of Hcrt in the hypothalamus were nonsignificantly lower, in contrast to the significant increase in hypothalamic Hcrt level after opiates. SXB decreased tyrosine hydroxylase levels in the locus coeruleus, the major descending projection of the hypocretin system, also the reverse of what we saw with opioids. Therefore despite some similar effects on narcoleptic symptomatology, SXB does not produce anatomical changes similar to those elicited by opiates. Analysis of changes in other links in the cataplexy pathway might further illuminate SXBs mechanism of action on narcolepsy.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1685v0b7Test

المؤلفون: Besterman, Aaron D, Jeste, Shafali S

المصدر: European Child & Adolescent Psychiatry. 32(3)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Psychology, Clinical Trials and Supportive Activities, Pediatric, Brain Disorders, Neurosciences, Intellectual and Developmental Disabilities (IDD), Mental Health, Behavioral and Social Science, Sleep Research, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Child, Humans, Adolescent, Sleep Initiation and Maintenance Disorders, Orexin Receptor Antagonists, Sleep, Neurodevelopmental Disorders, Research, Insomnia, Neurodevelopmental disorders, Dual orexin receptor antagonists, Sleep disorders, Developmental & Child Psychology, Clinical sciences, Applied and developmental psychology, Clinical and health psychology

الوصف: Insomnia is a common, impairing, and difficult-to-treat comorbidity in children with neurodevelopmental disorders (NDDs). Behavioral interventions can be challenging because of developmental and behavioral features that interfere with treatment. Medication management also can be difficult due to a high burden of side effects, a high rate of paradoxical responses, and frequent treatment resistance. Therefore, new treatment options for insomnia in children with NDDs are needed. Dual orexin receptor antagonists (DORAs) are a relatively new class of pharmacotherapeutics that induce sleep by inhibiting the orexin signaling pathway. To date, there is little safety or efficacy data on the use of DORAs in children with NDDs. We present four patients with NDDs and insomnia that we treated with the DORA, suvorexant. We found that patients had a wide range of responses, with one patient displaying a robust improvement in sleep onset and maintenance, while another had significant improvement in insomnia symptoms on combination therapy with trazodone. Our final two patients had mild or no benefit from suvorexant therapy. Further research is necessary to establish the safety and efficacy of DORAs in this population and to identify predictive factors, such as specific neurogenetic diagnoses or clinical features, of a positive treatment response.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8769g7sfTest

المؤلفون: Daniel Hoyer, Laura H. Jacobson

المصدر: Medicine in Drug Discovery, Vol 22, Iss , Pp 100190- (2024)

مصطلحات موضوعية: Human orexin receptors, Orexin receptor antagonists, Suvorexant, Almorexant, Filorexant, Lemborexant, Pharmacy and materia medica, RS1-441

الوصف: Orexin receptor antagonists are on the market or under development for the treatment of insomnia and a number of other neuropsychiatric disorders. Currently, suvorexant, lemborexant and daridorexant, three dual orexin receptor antagonists (DORAs) have received market approval by regulatory authorities in the USA, Australia, Europe and/or Japan for the treatment of insomnia. More DORAs and Selective Orexin Receptor Antagonists (SORAs) in addition to orexin receptor agonists are in various stages of preclinical and clinical development: for instance, 1SORAs (selective orexin 1 receptor antagonists) are being developed for the treatment of anxiety, panic, eating disorders, whereas 2SORAs (selective orexin 2 receptor antagonists) are in late clinical stage for the treatment of insomnia and insomnia-related depression. On the other hand, selective orexin 2 receptor agonists are in clinical trials for the treatment of narcolepsy with (NT1) or without cataplexy (NT2) and other aspects of extreme day time sleepiness.Traditionally, the medium to high throughput screening procedures used to screen / characterize orexin receptor antagonists or agonists (and for that matter ligands acting on a variety of potential drug targets), frequently ignore two aspects of new drugs candidates: possible functional selectivity (biased agonism or antagonism) and intrinsic receptor-ligand kinetic properties (i.e. association and dissociation features at the target level), since most screening protocols are conducted under short incubation time conditions with usually a single functional readout. Here, we report on strategies to characterise orexin receptor ligands (agonists or antagonists) in radioligand binding and calcium mobilization assays (e.g. using the FLIPR ® /Fluorescent Imaging Plate Reader assay) and for a few select DORAs, on ERK activation. We studied clinically effective and/or tool orexin receptor antagonists (almorexant, suvorexant, filorexant, SB-649868, MK1064…), which have been or are being evaluated in clinical trials or are on the market, in these signalling pathways with an emphasis on kinetics. Thus, we investigated calcium mobilization and pERK elevation triggered by orexin A (OXA) in HEK293 cells stably transfected with human OX1R or OX2R. We confirmed that the ligands behave as antagonists in either assay. Most ligands do not show significant functional selectivity between the two pathways, except MK-1064, which inhibits calcium mobilization about 35 times more potently than ERK phosphorylation. We also estimated the kinetic properties of the antagonists in radioligand binding, calcium mobilization and pERK assays. The results of radioligand binding and calcium mobilization assays indicate consistently that several of the tested antagonists bind to/dissociate from either or the two orexin receptors very slowly, with equilibrium reached only after several hours. Thus, SB-649868 is a very slow binder at the OX1R, whereas almorexant is a very slow binder at the OX2R. By contrast, all tested antagonists (except almorexant at OX2R), seem to equilibrate with both orexin receptors relatively rapidly in the pERK assay. The different results drawn from the various test systems may relate to experimental design, with different temperature and buffer conditions: some assays were performed with live cells at 37 °C, while others were carried out at room temperature with either intact cells or cell membranes. Our data suggest that orexin receptor ligands may have entirely different effects in different brain cells / nuclei, if biased signalling was to occur. Independent of biased signalling, the kinetic properties of orexin receptor ligands will influence the actual receptor selectivity and duration of action of the compound, as is strongly suggested for clinically relevant antagonists such as almorexant, SB-649868, filorexant or suvorexant. Thus, this paper stresses the importance of studying orexin receptor ‘antagonists’ in different functional assays and to determine their kinetic properties under conditions that are as physiological as feasible.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2590098624000150Test; https://doaj.org/toc/2590-0986Test

الوصول الحر: https://doaj.org/article/7861400ec1b04952ba2470f63c64ed20Test

المؤلفون: Mogavero, Maria, Silvani, Alessandro, Lanza, Giuseppe, Ferini-Strambi, Luigi, Ferri, Raffaele, DelRosso, Lourdes

مصطلحات موضوعية: dual orexin receptor antagonists, hypocretin, insomnia, orexin, orexin receptor antagonist, selective orexin receptor antagonists

الوصف: After a detailed description of orexins and their roles in sleep and other medical disorders, we discuss here the current clinical evidence on the effects of dual (DORAs) or selective (SORAs) orexin receptor antagonists on insomnia with the aim to provide recommendations for their further assessment in a context of personalized and precision medicine. In the last decade, many trials have been conducted with orexin receptor antagonists, which represent an innovative and valid therapeutic option based on the multiple mechanisms of action of orexins on different biological circuits, both centrally and peripherally, and their role in a wide range of medical conditions which are often associated with insomnia. A very interesting aspect of this new category of drugs is that they have limited abuse liability and their discontinuation does not seem associated with significant rebound effects. Further studies on the efficacy of DORAs are required, especially on children and adolescents and in particular conditions, such as menopause. Which DORA is most suitable for each patient, based on comorbidities and/or concomitant treatments, should be the focus of further careful research. On the contrary, studies on SORAs, some of which seem to be appropriate also in insomnia in patients with psychiatric diseases, are still at an early stage and, therefore, do not allow to draw definite conclusions.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1v0542xbTest

المؤلفون: Mohit Varshney, Supriyo Saha, Prinsa Prinsa, Vikash Jakhmola

المصدر: Majalah Obat Tradisional, Vol 29, Iss 1, Pp 14-36 (2024)

مصطلحات موضوعية: melatonin, natural sources, orexin, sleep disorder, synthetic molecules, Medicine

الوصف: Sleep is the natural cellular repair mechanism to improve and restore central neural mechanism, memory, hormonal imbalance, and finally, cell rejuvenation. Sleep disorder is characterized by insomnia, circadian rhythm disorder (CRD), sleep apnea, narcolepsy, parasomnia, and restless leg syndrome (RLS) or periodic limb movement disorder (PLMD). Both oversleeping and less sleeping are associated with sleep disorders (SD). Anxiety, schizophrenia, weight loss/gain, hypothyroidism, and oxidative stress are the most common outcomes of SD. There is also a genetic explanation behind circadian rhythmicity, circadian disorder, narcolepsy-cataplexy syndrome, fatal familial insomnia, and somnambulism. Excessive work pressure, stress, and consumption of caffeine and alcohol collectively push a person toward sleep deprivation. Anxiety, schizophrenia, weight loss/gain, hypothyroidism, and oxidative stress are the most common outcomes of SD. Adenosine, melatonin, dopamine, serotonin, gamma amino butyric acid (GABA), orexin, and histamine regulate SDs by various pathways. Among natural sources, Centella asiatica, Bacopa monnieri, Acorus calamus, Withania somnifera, Nardostachys jatamansi, Poria cocos is, Valeriana officinalis, Matricaria chamomilla, Lavandula angustifolia, Nelumbo nucifera, Melissa officinalis, Convolvulus pluricaulis, Camellia sinensis, Ziziphus jujube, Datura stramonium, Zhizhipus jujube, Passiflora incarnata, and Moringa oleifera showed remarkable effects on different forms of SDs through GABAA, serotonin, and melatonin receptors. Pramipexole, ropinirole, rotigotine, clonazepam, lorazepam, estazolam, zolpidem, lemborexant, daridorexant, and suvorexant showed its activity in the treatment of SDs as a dopamine agonist, inhibitor of GABAA receptor, dual orexin receptor antagonist, respectively. This article focused on the types of SDs, the effects of SDs on mental health, receptors involved in the sleep cycle, and the impact of natural molecules and synthetic molecules in the management of SDs.

وصف الملف: electronic resource

العلاقة: https://jurnal.ugm.ac.id/TradMedJ/article/view/86645Test; https://doaj.org/toc/1410-5918Test; https://doaj.org/toc/2406-9086Test

الوصول الحر: https://doaj.org/article/85f37427be3b403796b6d4428c795824Test

المؤلفون: Sümeyye Koç, Levent Sarıyıldız, Esma Menevşe

المصدر: Ahi Evran Medical Journal, Vol 8, Iss 1, Pp 111-120 (2024)

مصطلحات موضوعية: ghrelin, irisin, leptin, nesfatin-1, neuropeptide-y, orexin, Medicine

الوصف: Obesity, which develops especially in childhood and adolescence, is an important health problem at all ages. Hormones that stimulate the hypothalamus about the body's energy stores prevent eating and keep body weight within certain physiological limits. Investigating obesity and the hormones associated with obesity is very important in this context. We believe that the functions of obesity-associated hormones that have been identified to date can guide further studies. In this review, obesity-related hormones and their mechanisms of action are discussed.

وصف الملف: electronic resource

العلاقة: https://dergipark.org.tr/tr/download/article-file/2817320Test; https://doaj.org/toc/2619-9203Test

الوصول الحر: https://doaj.org/article/38b315bb1000463eb4916a08e018746dTest

المؤلفون: Maiju K. Rinne, Lauri Urvas, Ilona Mandrika, Dāvids Fridmanis, Darren M. Riddy, Christopher J. Langmead, Jyrki P. Kukkonen, Henri Xhaard

المصدر: Scientific Reports, Vol 14, Iss 1, Pp 1-15 (2024)

مصطلحات موضوعية: Orexin, Hypocretin, Calcium, Receptor binding, Ciona intestinalis, Medicine, Science

الوصف: Abstract Tunicates are evolutionary model organisms bridging the gap between vertebrates and invertebrates. A genomic sequence in Ciona intestinalis (CiOX) shows high similarity to vertebrate orexin receptors and protostome allatotropin receptors (ATR). Here, molecular phylogeny suggested that CiOX is divergent from ATRs and human orexin receptors (hOX1/2). However, CiOX appears closer to hOX1/2 than to ATR both in terms of sequence percent identity and in its modelled binding cavity, as suggested by molecular modelling. CiOX was heterologously expressed in a recombinant HEK293 cell system. Human orexins weakly but concentration-dependently activated its Gq signalling (Ca2+ elevation), and the responses were inhibited by the non-selective orexin receptor antagonists TCS 1102 and almorexant, but only weakly by the OX1-selective antagonist SB-334867. Furthermore, the 5-/6-carboxytetramethylrhodamine (TAMRA)-labelled human orexin-A was able to bind to CiOX. Database mining was used to predict a potential endogenous C. intestinalis orexin peptide (Ci-orexin-A). Ci-orexin-A was able to displace TAMRA-orexin-A, but not to induce any calcium response at the CiOX. Consequently, we suggested that the orexin signalling system is conserved in Ciona intestinalis, although the relevant peptide-receptor interaction was not fully elucidated.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-2322Test

الوصول الحر: https://doaj.org/article/3532f53292dc43e187ca5d3298309620Test