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1.
Fortschr Neurol Psychiatr ; 89(3): 103-113, 2021 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-33339064

RESUMO

Narcolepsy is a hypersomnolence disorder of central origin that presents with a disturbance of the wake-sleep regulation. Lead symptoms consist of excessive daytime sleepiness and cataplexy. Nowadays, two types of narcolepsy are distinguished. Type 1 narcolepsy, formerly known as narcolepsy with cataplexy, is based on hypocretin deficiency. The cause of type 2 narcolepsy, formerly known as narcolepsy without cataplexy, remains mainly unknown. A multimodal approach is necessary for diagnosis. The mean latency between the onset of disease and diagnosis in Europe ranges 14 years. Narcolepsy has a major impact on workability and quality of life. The management of narcolepsy is usually life-long and includes non-pharmacological approaches and a symptomatic pharmacological treatment.


Assuntos
Cataplexia , Distúrbios do Sono por Sonolência Excessiva , Narcolepsia , Adulto , Cataplexia/diagnóstico , Cataplexia/terapia , Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Distúrbios do Sono por Sonolência Excessiva/epidemiologia , Distúrbios do Sono por Sonolência Excessiva/etiologia , Europa (Continente) , Humanos , Narcolepsia/diagnóstico , Narcolepsia/epidemiologia , Narcolepsia/terapia , Orexinas , Qualidade de Vida
2.
Rev. neurol. (Ed. impr.) ; 71(12): 460-466, 16 dic., 2020.
Artigo em Espanhol | IBECS | ID: ibc-199340

RESUMO

INTRODUCCIÓN: Entre los mediadores químicos que modulan el eje intestino-cerebro debe incluirse el sistema orexinérgico, ya que la orexina A (OXA) hipotalámica interviene en la motilidad y en la secreción gastrointestinal. También está presente en las células enteroendocrinas de la mucosa intestinal y en las neuronas aferentes primarias del plexo mientérico, y puede intervenir en la señalización intestino-cerebro. OBJETIVO: No se conoce con exactitud la fuente ni la señal que originan la liberación de OXA periférica, ni tampoco si actúa en los receptores orexinérgicos de los tejidos periféricos ante demandas fisiológicas o patológicas. Esta revisión intenta analizar estas cuestiones a la luz de nuevos datos que indican que la OXA en el eje intestino-cerebro puede tener funciones más allá de su participación en la homeostasis energética. DESARROLLO: La OXA en el sistema entérico protege de la inflamación sistémica y central, y en el hipotálamo orquesta numerosos efectos periféricos para suprimir la respuesta inflamatoria sistémica. Por ello, podría actuar como sustancia inmunomoduladora en inflamaciones crónicas o en enfermedades autoinmunitarias. La OXA también se relaciona con la respuesta de estrés, regulando las respuestas fisiológicas a estímulos emocionales o estresantes. CONCLUSIONES: Aunque la OXA tiene efectos antiinflamatorios y gastroprotectores de la mucosa intestinal, en procesos de inflamación crónica podría incrementar la respuesta a estímulos estresantes, tanto externos como internos, y exacerbar la inflamación gastrointestinal. Por ello, se han propuesto intervenciones farmacológicas sobre el sistema orexinérgico como tratamiento para enfermedades en las que la hipersensibilidad intestinal coexiste con pérdida de apetito, alteraciones del sueño, estrés y ansiedad


INTRODUCTION. The orexinergic system is one of the chemical mediators that modulate the gut-brain axis, given the involvement of hypothalamic orexin A (OXA) in gastrointestinal motility and secretion, and the presence of OXA in enteroendocrine cells of the intestinal mucosa and in primary afferent neurons of the mesenteric plexus, permitting its participation in gut-brain signaling. AIM. The source of OXA and the signal(s) triggering its peripheral release are not fully understood, and it is not known whether it acts on orexigenic receptors in peripheral tissues to meet physiological or pathological demands. The aim of this review is to address these questions in the light of new data indicating that OXA may have functions in the gut-brain axis that go beyond its participation in energy homeostasis. DEVELOPMENT. OXA in the enteric system protects against systemic and central inflammation, and hypothalamic OXA orchestrates numerous peripheral effects to suppress the systemic inflammatory response. For this reason, OXA may act as an immunomodulator in chronic inflammations or autoimmune diseases. OXA is also involved in the stress response, regulating physiological responses to emotional or stressful stimuli. CONCLUSIONS. OXA exerts anti-inflammatory and gastroprotective effects on the intestinal mucosa; however, it may increase the response to external and/or internal stress in individuals with chronic inflammation, exacerbating the gastrointestinal inflammation. Hence, pharmacologic interventions in the orexinergic system have been proposed to treat diseases in which intestinal hypersensitivity is combined with appetite loss, sleep disturbance, stress, and anxiety


Assuntos
Humanos , Orexinas/fisiologia , Trato Gastrointestinal/metabolismo , Sistema Imunitário/metabolismo , Estresse Psicológico/metabolismo , Neurônios/metabolismo , Orexinas/análise
3.
Life Sci ; 257: 118046, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622948

RESUMO

Orexin-A is an endogenous peptide with receptors throughout the brain. According to some recent research, learning and memory are affected by the central administration of orexin; however, no study so far has investigated the long-term inhibition of the orexinergic system. The present study has evaluated the effect of pretraining administration of orexin 1 receptor (OXR1) antagonist, SB-334867, on the acquisition of memory. The Morris water maze (MWM) task was used for training and trial purposes in all groups. Memory performance was analyzed by measuring escape latency, traveled distance, and time spent in the target quadrant. Moreover, the effect of SB-334867 on phospholipase Cß3 (PLCß3) levels in the CA1 region of hippocampus slices was examined. Hippocampus slices were prepared using an immunohistochemistry (IHC) approach. SB-334867 (20 mg/kg) increased escape latency in SB-treated rats compared to SB-vehicle group (P < 0.01). SB-treated rats spent less time in the target quadrant compared to the SB-vehicle group (P < 0.001). Distance traveled in the target quadrant was significantly more in SB-treated rats compared to the SB-vehicle group (P < 0.001). Furthermore, SB-334867 decreased PLCß3 levels in the CA1 of the hippocampus (P < 0.01 and P < 0.05, respectively). Put together, our results suggest that the long-term inhibition of OXR1 plays a prominent role in spatial learning and memory, probably by attenuating PLCß3 in CA1 neurons.


Assuntos
Memória/efeitos dos fármacos , Memória/fisiologia , Fosfolipase C beta/metabolismo , Animais , Benzoxazóis/farmacologia , Hipocampo/metabolismo , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Naftiridinas/farmacologia , Receptores de Orexina/metabolismo , Orexinas/metabolismo , Fosfolipase C beta/fisiologia , Ratos , Ratos Wistar , Ureia/análogos & derivados , Ureia/farmacologia
4.
Nat Commun ; 11(1): 3661, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32694504

RESUMO

The relationship between orexin/hypocretin and rapid eye movement (REM) sleep remains elusive. Here, we find that a proportion of orexin neurons project to the sublaterodorsal tegmental nucleus (SLD) and exhibit REM sleep-related activation. In SLD, orexin directly excites orexin receptor-positive neurons (occupying ~3/4 of total-population) and increases gap junction conductance among neurons. Their interaction spreads the orexin-elicited partial-excitation to activate SLD network globally. Besides, the activated SLD network exhibits increased probability of synchronized firings. This synchronized excitation promotes the correspondence between SLD and its downstream target to enhance SLD output. Using optogenetics and fiber-photometry, we consequently find that orexin-enhanced SLD output prolongs REM sleep episodes through consolidating brain state activation/muscle tone inhibition. After chemogenetic silencing of SLD orexin signaling, a ~17% reduction of REM sleep amounts and disruptions of REM sleep muscle atonia are observed. These findings reveal a stabilization role of orexin in REM sleep.


Assuntos
Tronco Encefálico/fisiologia , Orexinas/metabolismo , Privação do Sono/fisiopatologia , Sono REM/fisiologia , Potenciais de Ação/fisiologia , Animais , Comportamento Animal , Tronco Encefálico/citologia , Modelos Animais de Doenças , Eletrodos Implantados , Eletroencefalografia , Eletromiografia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Tono Muscular/fisiologia , Neurônios/metabolismo , Optogenética , Receptores de Orexina/metabolismo , Orexinas/genética , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Vigília/fisiologia
5.
J Oral Sci ; 62(3): 265-270, 2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32493863

RESUMO

Orexins (Oxs) are multifunctional neuropeptides, secreted from the lateral hypothalamus, that stimulate feeding behavior and energy expenditure. In this study, the direct effects of Oxs on the membrane properties of trigeminal motoneurons (TMNs) were examined, which critically participate in the genesis of rhythmical oral motor activities underlying suckling and mastication. Sprague-Dawley rats (3-6 day-old) were used to obtain whole-cell patch-clamp recordings from TMNs. Bath application of Ox-A depolarized the membrane potential and induced inward current, wherein Na+ and Ca2+ were charge carriers. Transient receptor potential channel activation potentially contributed to current and voltage responses by way of Ox-A. Ox-A increased the peak amplitude and duration at half-amplitude of the medium-duration after hyperpolarization following the action potential. The interspike frequency of steady-state firings during repetitive discharge was increased, along with a shift in the frequency-current relationship occurring toward the left. Extracellular and intracellular Ca2+ were involved in regulating modulatory effects, but a requisite level of intracellular Ca2+ was not essential for Ox-induced upregulation of the interspike frequency. Ox-A also enhanced conditional bursting induced by N-methyl-d-aspartate and 5-HT, suggesting it participates in modulating TMNs' discharge patterns during various oral motor activities.


Assuntos
Neurônios Motores , Potenciais de Ação , Animais , Potenciais da Membrana , Orexinas , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley
6.
Arch Oral Biol ; 116: 104778, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32474210

RESUMO

OBJECTIVES: To explore the role of rostral ventromedial medulla (RVM) orexin 1 receptors (OX1R) on orofacial nociception -induced anxiety and locomotion in rats. DESIGN: Forty two adult male Wistar rats (220-270 gr) were randomly divided into 7 groups (n = 6) as follows: untreated control, capsaicin, capsaicin vehicle-treated group (sham operation), capsaicin groups pretreated by intra-RVM administration orexin 1 receptor (OX1R) agonist (orexin A) or antagonist (SB-334867) and the capsaicin groups treated by drugs vehicles (DMSO or aCSF). Orofacial nociception was induced by intradental application of capsaicin (100 µg) into the incisors of rats. Anxiety level and locomotor activity were measured by the elevated plus maze (EPM) and open field (OF) tests, respectively. Hippocampal levels of phosphorylated extracellular signal regulated Kinase (p-ERK) was also assessed by western blotting. RESULTS: Intradental application of capsaicin significantly increased anxiety and decreased locomotion behaviors. Intra-RVM microinjection of orexin-A significantly prevented capsaicin-induced anxiety-like behavior and increased locomotor activity in the EPM and OF tests. These effects were inhibited by SB-334867. Furthermore, orexin-A significantly increased p-ERK levels in capsaicin-treated rats. This effect was inhibited by pretreatment of the rats with SB-334867. CONCLUSIONS: The results suggest that both OX1R signaling in the RVM and hippocampal p-ERK signaling are involved in orofacial nociception-induced anxiety as well as locomotor activity.


Assuntos
Ansiedade , MAP Quinases Reguladas por Sinal Extracelular , Locomoção , Nociceptividade , Receptores de Orexina , Animais , Polpa Dentária/metabolismo , Hipocampo/metabolismo , Masculino , Receptores de Orexina/metabolismo , Receptores de Orexina/fisiologia , Orexinas , Ratos , Ratos Wistar
7.
Nord J Psychiatry ; 74(7): 525-532, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32363986

RESUMO

Objective: Orexin-A is involved in numerous physiological functions, such as feeding behavior and energy balance. Yet, the associations among the orexin system, weight changes and the clinical symptoms of schizophrenia patients remain uncertain, especially in inpatients with chronic schizophrenia (CS). The purpose of this study was to investigate the relationship between the orexin-A levels, body mass index (BMI) and clinical symptoms of CS inpatients.Methods: Altogether, 324 inpatients were enrolled in our study. The clinical symptoms of all inpatients were measured using a 30-item Positive and Negative Syndrome Scale (PANSS), and then we calculated the BMI of each subject and tested the orexin-A levels by ELISA methods.Results: The orexin-A levels of the CS inpatients in the obesity group (1.24 ± 1.45 ng/ml, n = 52) were significantly higher than those in the non-overweight group (0.85 ± 1.18 ng/ml, n = 176) and the overweight group (0.97 ± 1.15 ng/ml, n = 96). Spearman's correlation analysis showed that higher BMIs were associated with higher plasma orexin-A levels and fewer negative symptoms. Furthermore, the multiple regression analysis indicated that the orexin-A level could be a contributor to BMI (F = 30.21, p < 0.001). However, there was no correlation between plasma orexin-A concentrations and clinical symptoms in our research.Conclusion: A higher plasma orexin-A level may be a factor influencing the BMI of inpatients with CS, and fewer negative symptoms seem to be correlated with higher BMI, but the causality among BMI, orexin-A and clinical symptoms of schizophrenia requires further clinical research.


Assuntos
Esquizofrenia , Índice de Massa Corporal , Humanos , Pacientes Internados , Orexinas , Sobrepeso
8.
Nat Neurosci ; 23(5): 638-650, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32284606

RESUMO

Heightened aggression is characteristic of multiple neuropsychiatric disorders and can have various negative effects on patients, their families and the public. Recent studies in humans and animals have implicated brain reward circuits in aggression and suggest that, in subsets of aggressive individuals, domination of subordinate social targets is reinforcing. In this study, we showed that, in male mice, orexin neurons in the lateral hypothalamus activated a small population of glutamic acid decarboxylase 2 (GAD2)-expressing neurons in the lateral habenula (LHb) via orexin receptor 2 (OxR2) and that activation of these GAD2 neurons promoted male-male aggression and conditioned place preference for aggression-paired contexts. Moreover, LHb GAD2 neurons were inhibitory within the LHb and dampened the activity of the LHb as a whole. These results suggest that the orexin system is important for the regulation of inter-male aggressive behavior and provide the first functional evidence of a local inhibitory circuit within the LHb.


Assuntos
Agressão/fisiologia , Neurônios GABAérgicos/metabolismo , Habenula/metabolismo , Orexinas/metabolismo , Animais , Masculino , Camundongos , Transdução de Sinais/fisiologia
9.
Chemosphere ; 253: 126762, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32302915

RESUMO

17ß-trenbolone (17ß-TBOH) is one of the dominant metabolites of trenbolone acetate, which is widely applied in beef cattle operations around the globe. The effects of environmental concentrations of 17ß-trenbolone on the early development of zebrafish embryos have received very little attention. Melatonin could regulate sleep-wake cycle and plays a protective role in various adverse conditions. Here, environmentally realistic concentrations of 17ß-trenbolone (1 ng/L, 10 ng/L, 50 ng/L) has been exposure to zebrafish embryos at 2 h postfertilization (hpf). The results showed that 10 ng/L and 50 ng/L 17ß-trenbolone disturbed the distribution of caudal primary motoneurons and downregulated expression of motoneuron development related genes along with locomotion decreasing. While melatonin could recover the detrimental effects caused by 17ß-trenbolone. Interestingly, 17ß-trenbolone exposure increased waking activity and decreased rest even in a low dose (1 ng/L). Moreover, it upregulated hypocretin/orexin (Hcrt) signaling which promotes wakefulness. Melatonin restored the insomnia-like alternation induced by 17ß-trenbolone exposure. Collectively, we conclude that 17ß-trenbolone disturbed motoneuron development and altered sleep/wake behavior, while melatonin could alleviate the deleterious influence on motoneuron development and recover the circadian rhythm.


Assuntos
Comportamento Animal/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Melatonina/farmacologia , Atividade Motora/efeitos dos fármacos , Distúrbios do Início e da Manutenção do Sono/prevenção & controle , Acetato de Trembolona/toxicidade , Peixe-Zebra , Animais , Bovinos , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/genética , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/fisiologia , Desenvolvimento Embrionário/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Orexinas/genética , Fenótipo , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente
10.
Neurobiol Aging ; 91: 66-75, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32224066

RESUMO

Cognitive impairments and circadian rhythm disorders are the main clinical manifestations of Alzheimer's disease (AD). Orexin has been reported as abnormally elevated in the cerebrospinal fluid of AD patients, accompanied with cognitive impairments. Our recent research revealed that suvorexant, a dual orexin receptor antagonist, could improve behavioral circadian rhythm disorders in 9-month-old APP/PS1 mice. Here we further observed whether suvorexant could ameliorate the cognitive decline in APP/PS1 mice by using behavioral tests, and investigated the possible mechanisms by in vivo electrophysiological recording, western blot, and immunochemistry. The results showed that suvorexant treatment effectively ameliorated the cognitive impairments, alleviated in vivo hippocampal long-term potentiation suppression, restored the circadian phosphorylated CREB expression in the hippocampus, and reduced amyloid-ß protein deposition in the hippocampus and cortex in APP/PS1 mice. These results indicate that the neuroprotective effects of suvorexant against AD are involved in the reduction of amyloid-ß plaques, improvement of synaptic plasticity, and circadian expression of phosphorylated CREB, suggesting that suvorexant could be beneficial to the prevention and treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Azepinas/farmacologia , Azepinas/uso terapêutico , Transtornos Cronobiológicos/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Neuroprostanos , Antagonistas dos Receptores de Orexina , Triazóis/farmacologia , Triazóis/uso terapêutico , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/complicações , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Transtornos Cronobiológicos/etiologia , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/etiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Potenciação de Longa Duração/efeitos dos fármacos , Camundongos Transgênicos , Plasticidade Neuronal/efeitos dos fármacos , Orexinas/líquido cefalorraquidiano
11.
Sci Rep ; 10(1): 4958, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188934

RESUMO

Happiness is key for both mental and physical well-being. To further understand the brain mechanisms involved, we utilized the cataplexy that occurs in narcoleptic animal models as a quantitative behavioral measure because it is triggered by actions associated with happiness, such as laughter in humans and palatable foods in mice. Here we report that the rostral part of the nucleus accumbens (NAc) shell is strongly activated during the beginning of chocolate-induced cataplexy in orexin neuron-ablated mice. We made a local lesion in the NAc using ibotenic acid and observed the animals' behavior. The number of cataplexy bouts was negatively correlated to the lesion size. We also examined the hedonic response to palatable food by measuring the number of tongue protrusions in response to presentation of honey, which was also found to be negatively correlated to the lesion size. Next, we used clozapine N-oxide to either activate or inactivate the NAc through viral DREADD expression. As expected, the number of cataplexy bouts increased with activation and decreased with inactivation, and saline control injections showed no changes. Hedonic response in the DREADD experiment varied and showed both increases and decreases across mice. These results demonstrated that the rostral part of the NAc plays a crucial role in triggering cataplexy and hedonic orofacial movements. Since the NAc is also implicated in motivated behavior, we propose that the NAc is one of the key brain structures involved in happiness and is a driving force for positive emotion-related behaviors.


Assuntos
Comportamento Animal , Cataplexia/patologia , Chocolate/toxicidade , Narcolepsia/patologia , Neurônios/patologia , Núcleo Accumbens/patologia , Orexinas/fisiologia , Animais , Cataplexia/induzido quimicamente , Masculino , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos
13.
Org Biomol Chem ; 18(13): 2459-2467, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32167123

RESUMO

Internalization of G protein-coupled receptor (GPCRs) represents a nearly universal pathway for receptor downregulation. Imaging this process provides a means for the identification of pharmaceutical agents as well as potential ligands for orphan receptors. However, there is a need for the further development of near-infrared (NIR) probes capable of monitoring internalization in order to enable multiplexing with existing green fluorescent GPCR activity assays. Our laboratory has recently described a series of near-infrared (NIR) fluorophores in which a phosphinate functionality is inserted at the bridging position of the xanthene scaffold. These fluorophores, termed Nebraska Red (NR) dyes, provide attractive reagents for imaging protein localization. Herein, we disclose the development of NR-based HaloTag ligands for imaging membrane proteins on living cells. These new probes are utilized to image membrane pools of the human orexin type 2 receptor, an established target for the treatment of insomnia. We demonstrate the ability of fetal bovine serum (FBS) to noncovalently associate with a spirolactonized NR probe, enabling no-wash imaging with a 45-fold enhancement of fluorescence. Furthermore, we characterize the utility of NR-based HaloTag ligands for real-time monitoring of receptor internalization upon agonist stimulation. These new reagents enable potential multiplexing with existing GPCR activity assays in order to identify new modulators of GPCR activity as well as ligands for orphan receptors.


Assuntos
Corantes Fluorescentes/química , Receptores de Orexina/metabolismo , Animais , Células CHO , Cricetulus , Humanos , Hidrolases/química , Hidrolases/genética , Ligantes , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Mutação , Orexinas/metabolismo
14.
J Med Chem ; 63(4): 1526-1527, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32073265

RESUMO

Orexin receptors are G protein coupled receptors that may be useful targets for sleep disorders, eating disorders, or addictive behavior. Recent work shows that binding of antagonists to these receptors is complex, with strong dependence on hydrophobic hot spots and networks of water-mediated hydrogen bonds. Despite the minimal structural differences between receptor types, selectivity can be achieved in a number of different ways.


Assuntos
Receptores Acoplados a Proteínas-G , Receptores de Orexina , Orexinas
15.
Eur J Pharmacol ; 874: 173029, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32084419

RESUMO

Central post-stroke pain (CPSP) is a type of neuropathic pain for which the mechanism and relevant drug pathways remain unknown. Recently, it was reported that intracerebroventricular (ICV) administration of orexin-A suppresses pain and ischemia. In this study, we tested the role of orexin-A in CPSP induction in mice. Male ddY mice were subjected to 30 min of bilateral carotid artery occlusion (BCAO). CPSP was assessed by von Frey test. Colocalization of orexin 1 receptor (OX1R) with various neuron markers were determined by double-immunofluorescence. The hindpaw withdrawal responses to mechanical stimuli were significantly increased 3 days post-BCAO compared with those of sham groups. ICV injection of orexin-A dose-dependently suppressed BCAO-induced mechanical allodynia. These effects were inhibited by pre-treatment with SB334867 (an OX1R antagonist; ICV injection), yohimbine (a noradrenaline α2 receptor antagonist; intrathecal (IT) injection), and WAY100635 (a serotonin 5-HT1A receptor antagonist; IT injection), but not TCS OX2 29 (an OX2R antagonist; ICV injection). OX1R colocalized with TH (a noradrenergic neuron marker) and TPH (a serotonergic neuron marker) in the locus ceruleus (LC) and the rostral ventromedial medulla (RVM), respectively. The number of c-Fos positive cells in the LC and the RVM of BCAO mice was increased at 90 min after ICV injection of orexin-A compared to saline group. These results indicate that orexin-A/OX1R signaling plays an important role through activation of the descending pain control system in the induction of CPSP in mice.


Assuntos
Isquemia Encefálica/metabolismo , Hiperalgesia/metabolismo , Proteínas Mitocondriais/metabolismo , Neuralgia/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Benzoxazóis/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Isoquinolinas/farmacologia , Masculino , Camundongos , Proteínas Mitocondriais/antagonistas & inibidores , Naftiridinas/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Orexinas/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Antagonistas da Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ureia/análogos & derivados , Ureia/farmacologia , Ioimbina/farmacologia
16.
Epilepsia ; 61(3): 572-588, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32030748

RESUMO

OBJECTIVE: Immediately preceding sudden unexpected death in epilepsy (SUDEP), patients experienced a final generalized tonic-clonic seizure (GTCS), rapid ventilation, apnea, bradycardia, terminal apnea, and asystole. Whether a progressive pathophysiology develops and increases risk of SUDEP remains unknown. Here, we determined (a) heart rate, respiratory rate, and blood oxygen saturation (SaO2 ) in low-risk and high-risk knockout (KO) mice; and (b) whether blocking receptors for orexin, a cardiorespiratory neuromodulator, influences cardiorespiratory function mice or longevity in high-risk KO mice. METHODS: Heart rate and SaO2 were determined noninvasively with ECGenie and pulse oximetry. Respiration was determined with noninvasive airway mechanics technology. The role of orexin was determined within subject following acute treatment with a dual orexin receptor antagonist (DORA, 100 mg/kg). The number of orexin neurons in the lateral hypothalamus was determined with immunohistochemistry. RESULTS: Intermittent bradycardia was more prevalent in high-risk KO mice, an effect that may be the result of increased parasympathetic drive. High-risk KO mice had more orexin neurons in the lateral hypothalamus. Blocking of orexin receptors differentially influenced heart rate in KO, but not wild-type (WT) mice. When DORA administration increased heart rate, it also decreased heart rate variability, breathing frequency, and/or hypopnea-apnea. Blocking orexin receptors prevented the methacholine (MCh)-induced increase in breathing frequency in KO mice and reduced MCh-induced seizures, via a direct or indirect mechanism. DORA improved oxygen saturation in KO mice with intermittent hypoxia. Daily administration of DORA to high-risk KO mice increased longevity. SIGNIFICANCE: High-risk KO mice have a unique cardiorespiratory phenotype that is characterized by progressive changes in five interdependent endpoints. Blocking of orexin receptors attenuates some of these endpoints and increases longevity, supporting the notion that windows of opportunity for intervention exist in this preclinical SUDEP model.


Assuntos
Apneia/genética , Bradicardia/genética , Epilepsia/genética , Hipóxia/genética , Canal de Potássio Kv1.1/genética , Morte Súbita Inesperada na Epilepsia , Animais , Apneia/fisiopatologia , Bradicardia/fisiopatologia , Epilepsia/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Região Hipotalâmica Lateral/metabolismo , Região Hipotalâmica Lateral/patologia , Hipóxia/fisiopatologia , Cloreto de Metacolina/toxicidade , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Neurônios/patologia , Antagonistas dos Receptores de Orexina/farmacologia , Orexinas/metabolismo , Oximetria , Oxigênio , Sistema Nervoso Parassimpático/fisiopatologia , Parassimpatomiméticos/toxicidade , Taxa Respiratória/efeitos dos fármacos , Convulsões/induzido quimicamente
17.
Exp Neurol ; 323: 113110, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31712126

RESUMO

Parkinson's disease (PD) is a progressive and chronic neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and affects multiple neurotransmission systems such as hypocretin/orexin (HO) release and can lead to cognitive and memory deficits. The HO neurons located in lateral hypothalamus/perifornical area (LH/PeF) are involved with consolidation and memory processes. Here we verified the involvement of HO deficit in learning and memory process in an animal model of PD induced by bilateral intra-striatal injections of 6-hydroxydopamine (6-OHDA). The present study performed a working memory test by object recognition task and spatial memory test using the Morris water maze in control and PD-induced animals after depletion of HO neurons. In addition, our results indicate that HO system in degenerative disorders such as PD may modulate the declarative and spatial memory (assessed by object recognition and Morris water maze tests, respectively). A significant reduction of HO neurons in the LH/PeF and HO degeneration process in the hippocampus (CA1 and dentate gyrus areas) were noticed. Our data suggest that the HO system degeneration could be associated to memory dysfunction in PD.


Assuntos
Hipotálamo/fisiopatologia , Transtornos da Memória/fisiopatologia , Neurônios/metabolismo , Orexinas/metabolismo , Transtornos Parkinsonianos/fisiopatologia , Animais , Masculino , Camundongos , Ratos Wistar
18.
Theriogenology ; 143: 179-190, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31733930

RESUMO

Orexin A (OXA) is primarily known for its involvement in the regulation of feeding behaviour, energy metabolism and sleep/wake cycle. Nevertheless, studies indicate its engagement in the regulation of the porcine reproductive system. Therefore, the aim of this study was to investigate OXA effect (1, 10, 100 nM), in the presence or absence of the selective orexin receptor type 1 antagonist (SB-3348667; 1 µM), on the gene expression of key steroidogenic enzymes: steroidogenic acute regulatory protein (StAR), P450 side-chain cleavage enzyme (CYP11A1) and 3ß-hydroxysteroid dehydrogenase (HSD3B1), as well as on progesterone (P4) and androstenedione (A4) secretion. Endometrial and myometrial tissue explants were collected from gilts on days 10 to 11, 12 to 13, 15 to 16 and 27 to 28 of pregnancy, and on days 10 to 11 of the oestrous cycle (n = 5 per studied period of pregnancy or mid-luteal phase of the oestrous cycle). Gene expression was evaluated by real-time PCR. The level of steroid hormones secreted into the culture medium was examined by radioimmunoassay (RIA). In the present study, in the endometrium, OXA significantly stimulated StAR expression on days 12 to 13, CYP11A1 expression on days 27 to 28 and HSD3B1 expression on days 15 to 16 of pregnancy. Further, in this tissue, OXA decreased StAR mRNA level on days 10 to 11, CYP11A1 mRNA level on days 15 to 16, as well as HSD3B1 mRNA level on days 10 to 11 and 12 to 13 of gestation. Regarding the myometrium, OXA stimulated CYP11A1 gene expression on days 15 to 16 of pregnancy. In this tissue, OXA decreased StAR transcript content on days 15 to 16 and CYP11A1 mRNA level on days 27 to 28. We also demonstrated that OXA alone enhanced P4 secretion in the endometrium on days 10 to 11 and 12 to 13 of gestation. OXA alone has no significant effect on endometrial and myometrial A4 secretion, whereas OXA in combination with OX1R antagonist increased this hormone secretion during all studied stages of pregnancy. Therefore, we can conclude that OXA may affect de novo synthesis and secretion of P4 and A4 in the porcine uterus via participating in the regulation of key steroidogenic enzymes gene expression, as well as modulating steroid hormones secretion during early pregnancy and mid-luteal phase of the oestrous cycle in pigs. However, further research is required to explain the exact role of OXA in the porcine uterus.


Assuntos
Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Complexos Multienzimáticos/metabolismo , Orexinas/farmacologia , Progesterona Redutase/metabolismo , Esteroide Isomerases/metabolismo , Suínos/fisiologia , Animais , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Ciclo Estral/fisiologia , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Proteínas de Membrana Transportadoras/genética , Complexos Multienzimáticos/genética , Gravidez , Progesterona Redutase/genética , Esteroide Isomerases/genética , Útero/efeitos dos fármacos , Útero/metabolismo
19.
Gen Comp Endocrinol ; 286: 113304, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31654677

RESUMO

In sheep, differences in orexin A (OXA) gene expression and activity are related to changes in energy demand and seasonal reproduction. However, the mechanism by which and the key place where the OXA signal is integrated with photoperiod, whose main biochemical expression is melatonin (MEL), remain unknown. We examined the effects of cisterna magna injections of OXA (0.3 µg/kg body weight) on nocturnal cerebrospinal fluid (CSF) and plasma MEL concentrations; mRNA and protein expression of two rate-limiting enzymes for MEL biosynthesis, tryptophan 5-hydroxylase-1 (TPH1) and arylalkylamine-N-acetyltransferase (AA-NAT); and OXA receptor (OX1R, OX2R) expression in the pineal gland (PG) obtained from twenty ewes during the short-day (SD) and long-day (LD) seasons. OXA increased (P < 0.001) CSF and plasma MEL concentrations regardless of the season. Plasma MEL was positively correlated (P < 0.001) with CSF MEL in the OXA-treated sheep in both seasons. OXA had no effect (P > 0.05) on TPH1 transcript or protein level but upregulated (P < 0.05) AA-NAT mRNA and protein expression in both seasons. OXA enhanced (P < 0.05) OX1R mRNA level only during the LD season. Our results show that the endocrine activity of the ovine PG is regulated by day length and non-photic signals via hypothalamic OXA. These results are important for understanding the work of the biological clock and recognizing mechanisms responsible for the adaptation of seasonal animals to the changing external environment conditions. OXA and MEL are both involved in the regulation of the sleep-wakefulness system, therefore our results can be used in the study on the circadian rhythm disorders in humans (e.g. jet lag, insomnia, seasonal depression).


Assuntos
Melatonina/metabolismo , Orexinas/sangue , Orexinas/líquido cefalorraquidiano , Animais , Feminino , Ovinos
20.
Sleep ; 43(1)2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31556946

RESUMO

Narcolepsy with cataplexy is a sleep disorder caused by a deficiency in hypocretin neurons in the lateral hypothalamus (LH). Here we performed an epigenome-wide association study (EWAS) of DNA methylation for narcolepsy and replication analyses using DNA samples extracted from two brain regions: LH (Cases: N = 4; Controls: N = 4) and temporal cortex (Cases: N = 7; Controls: N = 7). Seventy-seven differentially methylated regions (DMRs) were identified in the LH analysis, with the top association of a DMR in the myelin basic protein (MBP) region. Only five DMRs were detected in the temporal cortex analysis. Genes annotated to LH DMRs were significantly associated with pathways related to fatty acid response or metabolism. Two additional analyses applying the EWAS data were performed: (1) investigation of methylation profiles shared between narcolepsy and other disorders and (2) an integrative analysis of DNA methylation data and a genome-wide association study for narcolepsy. The results of the two approaches, which included significant overlap of methylated positions associated with narcolepsy and multiple sclerosis, indicated that the two diseases may partly share their pathogenesis. In conclusion, DNA methylation in LH where loss of orexin-producing neurons occurs may play a role in the pathophysiology of the disease.


Assuntos
Cataplexia/genética , Metilação de DNA/genética , Região Hipotalâmica Lateral/metabolismo , Esclerose Múltipla/genética , Narcolepsia/genética , Lobo Temporal/metabolismo , Cataplexia/fisiopatologia , DNA/metabolismo , Epigenoma , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Narcolepsia/fisiopatologia , Neurônios/metabolismo , Orexinas/genética , Orexinas/metabolismo
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