RESUMO
RATIONALE: The nuclear receptor retinoid X receptor (RXR) belongs to a nuclear receptor superfamily that modulates diverse functions via homodimerization with itself or several other nuclear receptors, including PPARα. While the activation of PPARα by natural or synthetic agonists regulates the sleep-wake cycle, the role of RXR in the sleep modulation is unknown. OBJECTIVES: We investigated the effects of bexarotene (Bexa, a RXR agonist) or UVI 3003 (UVI, a RXR antagonist) on sleep, sleep homeostasis, levels of neurochemical related to sleep modulation, and c-Fos and NeuN expression. METHODS: The sleep-wake cycle and sleep homeostasis were analyzed after application of Bexa or UVI. Moreover, we also evaluated whether Bexa or UVI could induce effects on dopamine, serotonin, norepinephrine epinephrine, adenosine, and acetylcholine contents, collected from either the nucleus accumbens or basal forebrain. In addition, c-Fos and NeuN expression in the hypothalamus was determined after Bexa or UVI treatments. RESULTS: Systemic application of Bexa (1 mM, i.p.) attenuated slow-wave sleep and rapid eye movement sleep. In addition, Bexa increased the levels of dopamine, serotonin, norepinephrine epinephrine, adenosine, and acetylcholine sampled from either the nucleus accumbens or basal forebrain. Moreover, Bexa blocked the sleep rebound period after total sleep deprivation, increased in the hypothalamus the expression of c-Fos, and decreased NeuN activity. Remarkably, UVI 3003 (1 mM, i.p.) induced opposite effects in sleep, sleep homeostasis, neurochemicals levels, and c-Fos and NeuN activity. CONCLUSIONS: The administration of RXR agonist or antagonist significantly impaired the sleep-wake cycle and exerted effects on the levels of neurochemicals related to sleep modulation. Moreover, Bexa or UVI administration significantly affected c-Fos and NeuN expression in the hypothalamus. Our findings highlight the neurobiological role of RXR on sleep modulation.
Assuntos
Bexaroteno/farmacologia , Ácidos Cumáricos/farmacologia , Receptores X de Retinoides/metabolismo , Fases do Sono/efeitos dos fármacos , Fases do Sono/fisiologia , Tetra-Hidronaftalenos/farmacologia , Animais , Masculino , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ratos , Ratos Wistar , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores X de Retinoides/agonistas , Receptores X de Retinoides/antagonistas & inibidoresRESUMO
It has been widely described that chronic intake of fructose causes metabolic alterations which can be associated with brain function impairment. In this study, we evaluated the effects of fructose intake on the sleepâ»wake cycle, locomotion, and neurochemical parameters in Wistar rats. The experimental group was fed with 10% fructose in drinking water for five weeks. After treatment, metabolic indicators were quantified in blood. Electroencephalographic recordings were used to evaluate the sleep architecture and the spectral power of frequency bands. Likewise, the locomotor activity and the concentrations of orexin A and monoamines were estimated. Our results show that fructose diet significantly increased the blood levels of glucose, cholesterol, and triglycerides. Fructose modified the sleepâ»wake cycle of rats, increasing the waking duration and conversely decreasing the non-rapid eye movement sleep. Furthermore, these effects were accompanied by increases of the spectral power at different frequency bands. Chronic consumption of fructose caused a slight increase in the locomotor activity as well as an increase of orexin A and dopamine levels in the hypothalamus and brainstem. Specifically, immunoreactivity for orexin A was increased in the ventral tegmental area after the intake of fructose. Our study suggests that fructose induces metabolic changes and stimulates the activity of orexinergic and dopaminergic neurons, which may be responsible for alterations of the sleepâ»wake cycle.
Assuntos
Encéfalo/efeitos dos fármacos , Açúcares da Dieta/farmacologia , Dopamina/metabolismo , Comportamento Alimentar , Frutose/farmacologia , Orexinas/metabolismo , Sono/efeitos dos fármacos , Animais , Glicemia/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Tronco Encefálico/efeitos dos fármacos , Tronco Encefálico/metabolismo , Dieta , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Lipídeos/sangue , Locomoção/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Ratos Wistar , Fases do Sono/efeitos dos fármacos , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo , Vigília/efeitos dos fármacosRESUMO
OBJECTIVE: In this study we analyzed the effects of transcranial magnetic stimulation (TMS) on sleep and on the self-perceived quality of life in epileptic patients. METHODS: A total of 24 male patients diagnosed with focal epilepsy were included in the study. Pharmacological treatment with levetiracetam was standardized at 2 g daily. Before TMS onset, all-night polysomnographic recording (PSG) was performed, and the Quality of Life in Epilepsy Inventory (QOLIE-31) was administered. Thereafter, patients underwent low-frequency repetitive TMS (1000 pulses/1 Hz) daily for 10 days. After the end of the treatment, a second polysomnographic study was performed, and the QOLIE-31 questionnaire was administered again. RESULTS: TMS induced a significant increase in sleep efficiency and in total sleep time, along with a decrease in sleep latency and the number of awakenings. In addition, the number of interictal discharges during sleep decreased significantly. Concerning the QOLIE-31 scale values, the patients showed great improvement in the self-perceived quality of life. CONCLUSION: The present results indicate that TMS may mediate therapeutic effects in the treatment of patients with focal epilepsy, and that TMS treatment is accompanied by improvement of sleep patterns as well as improvement in self-perceived quality of life. However, a study that includes a control group undergoing sham stimulation is needed to confirm these findings.
Assuntos
Epilepsias Parciais/terapia , Qualidade de Vida/psicologia , Estimulação Magnética Transcraniana/métodos , Adulto , Anticonvulsivantes/uso terapêutico , Eletroencefalografia/métodos , Humanos , Levetiracetam , Masculino , Piracetam/análogos & derivados , Piracetam/uso terapêutico , Polissonografia , Fases do Sono/efeitos dos fármacos , Inquéritos e QuestionáriosRESUMO
Preclinical Research The aim of the present study was to evaluate the antinociceptive and sedative activity of an ethanol extract of Justicia spicigera an evergreen used in Mexican traditional medicine for the relief of pain, wounds, fever and inflammation. At 200 mg/kg po, the maximum dose examined, the ethanol extract of J. spicigera (JSE) had analgesic activity in mice in the acetic acid writhing test, the second phase of the formalin test and the tail flick test that was similar in efficacy to the NSAID, naproxen (150 mg/kg po). JSE was inactive in the hot plate test and and the ketamine-induced sleeping time test; it had no sedative effects. These results show that the ethanol extract from the leaves of J. spicigera has antinociceptive effects in mice without inducing sedation. Drug Dev Res 77 : 180-186, 2016. © 2016 Wiley Periodicals, Inc.
Assuntos
Analgésicos/farmacologia , Justicia/química , Dor/tratamento farmacológico , Extratos Vegetais/farmacologia , Analgésicos/isolamento & purificação , Analgésicos/toxicidade , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Modelos Animais de Doenças , Etanol/química , Masculino , Medicina Tradicional , Camundongos , Camundongos Endogâmicos BALB C , Naproxeno/farmacologia , Extratos Vegetais/toxicidade , Folhas de Planta , Fases do Sono/efeitos dos fármacosRESUMO
Sleep disturbances are among the most disabling non-motor symptoms in Parkinson's disease. The pedunculopontine tegmental nucleus and basal ganglia are likely involved in these dysfunctions, as they are affected by neurodegeneration in Parkinson's disease and have a role in sleep regulation. To investigate this, we promoted a lesion in the pedunculopontine tegmental nucleus or substantia nigra pars compacta of male rats, followed by 24 h of REM sleep deprivation. Then, we administrated a dopaminergic D2 receptor agonist, antagonist or vehicle directly in the striatum. After a period of 24 h of sleep-wake recording, we observed that the ibotenic acid infusion in the pedunculopontine tegmental nucleus blocked the so-called sleep rebound effect mediated by REM sleep deprivation, which was reversed by striatal D2 receptors activation. Rotenone infusion in the substantia nigra pars compacta also blocked the sleep rebound, however, striatal D2 receptors activation did not reverse it. In addition, rotenone administration decreased the time spent in NREM sleep, which was corroborated by positive correlations between dopamine levels in both substantia nigra pars compacta and striatum and the time spent in NREM sleep. These findings suggest a new circuitry for sleep regulation in Parkinson's disease, involving the triad composed by pedunculopontine nucleus, substantia nigra pars compacta and striatum, evidencing a potential therapeutic target for the sleep disturbances associated to this pathology.
Assuntos
Corpo Estriado/metabolismo , Rede Nervosa/metabolismo , Doença de Parkinson/metabolismo , Parte Compacta da Substância Negra/metabolismo , Fases do Sono/fisiologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Corpo Estriado/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Masculino , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/metabolismo , Rede Nervosa/efeitos dos fármacos , Parte Compacta da Substância Negra/efeitos dos fármacos , Ratos , Ratos Wistar , Fases do Sono/efeitos dos fármacosRESUMO
STUDY OBJECTIVES: In addition to enhancing sleep onset and maintenance, a desirable insomnia therapeutic agent would preserve healthy sleep's ability to wake and respond to salient situations while maintaining sleep during irrelevant noise. Dual orexin receptor antagonists (DORAs) promote sleep by selectively inhibiting wake-promoting neuropeptide signaling, unlike global inhibition of central nervous system excitation by gamma-aminobutyric acid (GABA)-A receptor (GABAaR) modulators. We evaluated the effect of DORA versus GABAaR modulators on underlying sleep architecture, ability to waken to emotionally relevant stimuli versus neutral auditory cues, and performance on a sleepiness-sensitive cognitive task upon awakening. METHODS: DORA-22 and GABAaR modulators (eszopiclone, diazepam) were evaluated in adult male rhesus monkeys (n = 34) with continuous polysomnography recordings in crossover studies of sleep architecture, arousability to a classically conditioned salient versus neutral acoustical stimulus, and psychomotor vigilance task (PVT) performance if awakened. RESULTS: All compounds decreased wakefulness, but only DORA-22 sleep resembled unmedicated sleep in terms of underlying sleep architecture, preserved ability to awaken to salient-conditioned acoustic stimuli while maintaining sleep during neutral acoustic stimuli, and no congnitive impairment in PVT performance. Although GABAaR modulators induced lighter sleep, monkeys rarely woke to salient stimuli and PVT performance was impaired if monkeys were awakened. CONCLUSIONS: In nonhuman primates, DORAs' targeted mechanism for promoting sleep protects the ability to selectively arouse to salient stimuli and perform attentional tasks unimpaired, suggesting meaningful differentiation between a hypnotic agent that works through antagonizing orexin wake signaling versus the sedative hypnotic effects of the GABAaR modulator mechanism of action.
Assuntos
Macaca mulatta/fisiologia , Antagonistas dos Receptores de Orexina/farmacologia , Orexinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sono/efeitos dos fármacos , Sono/fisiologia , Vigília/efeitos dos fármacos , Vigília/fisiologia , Animais , Nível de Alerta/efeitos dos fármacos , Condicionamento Clássico , Estudos Cross-Over , Diazepam/farmacologia , Zopiclona/farmacologia , GABAérgicos/farmacologia , Hipnóticos e Sedativos/farmacologia , Masculino , Piperidinas/farmacologia , Polissonografia , Fases do Sono/efeitos dos fármacos , Fases do Sono/fisiologia , Triazóis/farmacologiaRESUMO
BACKGROUND AND OBJECTIVES: The first weeks of treatment with antipsychotics are important for the development of their long-term efficacy. The objective of this study was to identify factors related to early clinical effects and quality of life (QoL) improvements with quetiapine extended-release (XR). METHODS: Six hundred and sixty-five patients starting with quetiapine XR were followed up for 8 weeks (schizophrenia = 153, major depression = 200, bipolar depression = 252, other psychiatric conditions = 60). Clinical effects were assessed by the Clinical Global Impression of Change scale (CGI-C), QoL by the visual analog scale (VAS) of the EQ-5D (QoL-VAS), and adherence by the Moriksy scale. Adverse events were explored: movement disorders by the UKU and Simpson-Angus scales, weight gain by calibrated balances, and diurnal somnolence by the Epworth Somnolence Scale (ESS). RESULTS: The mean dose of quetiapine XR during follow-up was 195.6 ± 154.8 mg/day. CGI and QoL-VAS scores improved significantly at week 8 by 2.7 ± 0.1 points and 25.1 ± 0.9 points. Adverse events were observed in 34 and 26 % of patients at weeks 4 and 8, respectively. A significant reduction in ESS score was also observed at week 8. Factors independently associated with change in QoL-VAS ≥20 points (n = 292, 43 %) were female gender, more severe disease at baseline, higher antipsychotic dose during follow-up, and improvements in somnolence. Factors independently associated with clinically significant improvement (CGI-C ≥5, n = 610, 93 %) were greater change in QoL-VAS, less frequent movement disorders at baseline, and lack of adverse events during follow-up, especially somnolence. CONCLUSIONS: Results from this real-setting, large observational study in Central America suggest that disease severity at baseline, gender, antipsychotic dose, and occurrence of adverse reactions has a significant impact on the early clinical effects of quetiapine XR. Clinicaltrials.gov registration number NCT02409823.
Assuntos
Antipsicóticos/administração & dosagem , Antipsicóticos/uso terapêutico , Transtornos Psicóticos/tratamento farmacológico , Fumarato de Quetiapina/administração & dosagem , Fumarato de Quetiapina/uso terapêutico , Adulto , Antipsicóticos/efeitos adversos , Transtorno Bipolar/tratamento farmacológico , Preparações de Ação Retardada , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Estudos Prospectivos , Qualidade de Vida , Fumarato de Quetiapina/efeitos adversos , Esquizofrenia/tratamento farmacológico , Fases do Sono/efeitos dos fármacos , Resultado do Tratamento , Aumento de Peso/efeitos dos fármacosRESUMO
The peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear protein that plays an essential role in diverse neurobiological processes. However, the role of PPARα on the sleep modulation is unknown. Here, rats treated with an intrahypothalamic injection of Wy14643 (10µg/1µL; PPARα agonist) enhanced wakefulness and decreased slow wave sleep and rapid eye movement sleep whereas MK-886 (10µg/1µL; PPARα antagonist) promoted opposite effects. Moreover, Wy14643 increased dopamine, norepinephrine, serotonin, and adenosine contents collected from nucleus accumbens. The levels of these neurochemicals were diminished after MK-886 treatment. The current findings suggest that PPARα may participate in the sleep and neurochemical modulation.
Assuntos
Monoaminas Biogênicas/metabolismo , Núcleo Accumbens/metabolismo , PPAR alfa/metabolismo , Sono/fisiologia , Adenosina/metabolismo , Animais , Dopamina/metabolismo , Indóis/farmacologia , Masculino , Norepinefrina/metabolismo , Núcleo Accumbens/efeitos dos fármacos , PPAR alfa/agonistas , PPAR alfa/antagonistas & inibidores , Pirimidinas/farmacologia , Ratos Wistar , Serotonina/metabolismo , Sono/efeitos dos fármacos , Fases do Sono/efeitos dos fármacos , Fases do Sono/fisiologiaRESUMO
INTRODUCTION: It is a well-known fact that epileptic seizures disrupt sleep, yet little information is available about sleep disorders according to the type of epileptic seizures. MATERIALS AND METHODS: The sleep architecture of rats was evaluated in polysomnography recordings 36 hours after inducing partial and generalised epileptic seizures in them. The epileptic seizures were induced by applying 50-100 IU of sodium G penicillin in the amygdala of the temporal lobe. RESULTS: Partial and generalised seizures triggered an increase in the latency of slow wave sleep (SWS) and rapid eye movement (REM) sleep. The number of episodes of the phases of wakefulness, SWS and REM sleep was reduced and the mean duration of the episodes of wakefulness and SWS increased, while that of REM sleep diminished. The total percentage of REM sleep diminished significantly. During the first period of light the partial and generalised seizures triggered an increase in wakefulness and a reduction in the phases of SWS and REM sleep. In the period of darkness, the SWS increased and wakefulness decreased, while there were no changes in REM sleep. In the second period of light, the percentages of the phases of wakefulness and SWS returned to control values and the percentage of REM sleep continued to be reduced. CONCLUSIONS: Changes in the structuring of sleep depend on the type of epileptic seizure that presents. Generalised epileptic seizures caused greater deterioration in REM sleep.
TITLE: Efecto de las crisis epilepticas parciales y generalizadas sobre la arquitectura del sueño en ratas.Introduccion. La alteracion del sueño producido por las crisis epilepticas se conoce; sin embargo, aun se tiene poca informacion de la alteracion en el sueño por el tipo de crisis epileptica. Materiales y metodos. Se evaluo la arquitectura del sueño de ratas en registros polisomnograficos de 36 horas tras inducirles crisis epilepticas parciales y generalizadas. Para la induccion de las crisis epilepticas se aplicaron in situ 50-100 UI de penicilina G sodica en la amigdala del lobulo temporal. Resultados. Las crisis parciales y generalizadas provocaron el aumento en la latencia del sueño de ondas lentas (SOL) y sueño de movimiento oculares rapidos (MOR). El numero de episodios de las fases de vigilia, SOL y sueño MOR disminuyo y la duracion media de los episodios de la vigilia y del SOL aumento, mientras que la del sueño MOR disminuyo. El porcentaje total del sueño MOR disminuyo significativamente. Durante el primer periodo de luz, las crisis parciales y generalizadas provocaron el incremento de la vigilia y la reduccion de las fases del SOL y sueño MOR. En el periodo de oscuridad, aumento el SOL, disminuyo la vigilia y no hubo cambios en el sueño MOR. En el segundo periodo de luz los porcentajes de las fases de vigilia y SOL regresaron a los valores control y el porcentaje del sueño MOR continuo disminuido. Conclusion. Los cambios en la organizacion del sueño dependen del tipo de crisis epileptica que se presenta. Las crisis epilepticas generalizadas provocaron mayor deterioro en el sueño MOR.
Assuntos
Epilepsias Parciais/fisiopatologia , Epilepsia Generalizada/fisiopatologia , Transtornos Intrínsecos do Sono/fisiopatologia , Animais , Convulsivantes/administração & dosagem , Convulsivantes/toxicidade , Relação Dose-Resposta a Droga , Epilepsias Parciais/induzido quimicamente , Epilepsias Parciais/complicações , Epilepsia Generalizada/complicações , Epilepsia do Lobo Temporal/complicações , Epilepsia do Lobo Temporal/fisiopatologia , Masculino , Penicilinas/administração & dosagem , Penicilinas/toxicidade , Fotoperíodo , Polissonografia , Distribuição Aleatória , Ratos , Ratos Wistar , Transtornos Intrínsecos do Sono/etiologia , Fases do Sono/efeitos dos fármacos , Fases do Sono/fisiologia , VigíliaRESUMO
BACKGROUND: Sedation for electroencephalography in uncooperative patients is a controversial issue because majority of sedatives, hypnotics, and general anesthetics interfere with the brain's electrical activity. Chloral hydrate (CH) is typically used for this sedation, and dexmedetomidine (DEX) was recently tested because preliminary data suggest that this drug does not affect the electroencephalogram (EEG). The aim of the present study was to compare the EEG pattern during DEX or CH sedation to test the hypothesis that both drugs exert similar effects on the EEG. MATERIALS AND METHODS: A total of 17 patients underwent 2 EEGs on 2 separate occasions, one with DEX and the other with CH. The EEG qualitative variables included the phases of sleep and the background activity. The EEG quantitative analysis was performed during the first 2 minutes of the second stage of sleep. The EEG quantitative variables included density, duration, and amplitude of the sleep spindles and absolute spectral power. RESULTS: The results showed that the qualitative analysis, density, duration, and amplitude of sleep spindles did not differ between DEX and CH sedation. The power of the slow-frequency bands (δ and θ) was higher with DEX, but the power of the faster-frequency bands (α and ß) was higher with CH. The total power was lower with DEX than with CH. CONCLUSIONS: The differences of DEX and CH in EEG power did not change the EEG qualitative interpretation, which was similar with the 2 drugs. Other studies comparing natural sleep and sleep induced by these drugs are needed to clarify the clinical relevance of the observed EEG quantitative differences.
Assuntos
Hidrato de Cloral , Sedação Consciente/métodos , Dexmedetomidina , Eletroencefalografia/métodos , Hipnóticos e Sedativos , Adulto , Método Duplo-Cego , Feminino , Humanos , Hipotensão/induzido quimicamente , Masculino , Estudos Prospectivos , Sono/efeitos dos fármacos , Fases do Sono/efeitos dos fármacos , Adulto JovemRESUMO
Since the pioneering work of Gadea-Ciria (Gadea-Ciria M, Stadler H, Lloyd KG, Bartholini G. Acetylcholine release within the cat striatum during the sleep-wakefulness cycle. Nature 1973; 243:518-519) indicating pointing to the involvement of acetylcholine and basal ganglia in sleep regulation; extensive literature has suggested that this brain complex participates in the control of the sleep-waking cycle (SWC). On the other hand, it has been demonstrated that the endocannabinoid system (eCBS) is prominently involved in the regulation of the SWC, mood and its related disorders. Since cannabinoid receptor 1 (CB1R) is highly expressed in basal ganglia, in particular in the entopeduncular nucleus (EP), we believe that it is important to know what the role of the EP CB1R is on SWC, depression, and anxiety. To provide insight into the role of the EP CB1R in the regulation of wakefulness (W), non-rapid eye movement sleep (NREMs) and rapid eye movement sleep (REMs), rats were recorded for 24h immediately after a single intra-EP administration of N-arachidonoylethanolamine (AEA) or 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl)pyrazole-3-carboxamide (AM251; CB1 inverse agonist). Likewise, the effect of these drugs on anxiety and depression was tested by means of the elevated plus maze (EPM) and forced swim test (FST), respectively. Results demonstrate that AEA increases NREMs expression, while AM251 increases W and decreases both NREMs and REMs. In addition, administration of AM251 decreases the time rats spent in the open arms and increases immobility time in the FST. It seems that activation of the CB1R in the EP is important to induce sleep, while its blockade promotes W, as well as anxiety and depression, somewhat resembling insomnia in humans. These results suggest that the EP CB1R is modulating sleep and mood.
Assuntos
Afeto/fisiologia , Endocanabinoides/fisiologia , Núcleo Entopeduncular/fisiologia , Sono/fisiologia , Vigília/fisiologia , Afeto/efeitos dos fármacos , Animais , Ácidos Araquidônicos , Agonistas de Receptores de Canabinoides/administração & dosagem , Agonistas de Receptores de Canabinoides/farmacologia , Endocanabinoides/administração & dosagem , Endocanabinoides/farmacologia , Núcleo Entopeduncular/efeitos dos fármacos , Resposta de Imobilidade Tônica/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Microinjeções , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Ratos , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/fisiologia , Teste de Desempenho do Rota-Rod , Sono/efeitos dos fármacos , Fases do Sono/efeitos dos fármacos , Vigília/efeitos dos fármacosRESUMO
INTRODUCTION/OBJECTIVES: Previous publications have shown beneficial effects of cholinergic medication on obstructive sleep apnea (OSA) in Alzheimer's disease (AD) patients. We hypothesized that cholinergic medication could also improve OSA in non-AD patients. The present study evaluated the effects of donepezil on OSA in non-AD patients. METHODS: A randomized, double-blind, placebo-controlled study was conducted. The final sample consisted of 21 male patients with mild to severe OSA and AHI >10 divided into two groups, a donepezil-treated group (n=11) and a placebo-treated group (n=10). The dosage was one tablet/day (5 mg) for the first two weeks and two tablets/day (10 mg) for the last two weeks. Polysomnography and sleepiness evaluations were performed at baseline and after one month of treatment. Groups were compared using two-way ANOVA for repeated measures with treatment-group and treatment-time as the main factors and time-treatment as an interaction effect. RESULTS: Considering the effect of the interaction with time-treatment, there was a significant improvement in the obstructive apnea/hypopnea index, desaturation index, percentage of time with O(2) saturation ≤3% lower than baseline, lowest oxygen saturation, and the Epworth Sleepiness Scale (ESS) scores with donepezil treatment (p<0.05). Sleep efficiency significantly decreased (p<0.01). CONCLUSIONS: Donepezil treatment improved obstructive sleep apnea index, oxygen saturation, and sleepiness in parallel with a reduction in sleep efficiency. Our findings support the concept that cholinergic transmission may influence breathing regulation in OSA patients.
Assuntos
Inibidores da Colinesterase/administração & dosagem , Indanos/administração & dosagem , Piperidinas/administração & dosagem , Apneia Obstrutiva do Sono/tratamento farmacológico , Fases do Sono/efeitos dos fármacos , Adulto , Idoso , Inibidores da Colinesterase/efeitos adversos , Donepezila , Método Duplo-Cego , Humanos , Indanos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Piperidinas/efeitos adversos , Placebos , Polissonografia , Apneia Obstrutiva do Sono/diagnóstico , Resultado do TratamentoRESUMO
Anatomical and functional studies have shown that the NADPH-diaphorase-positive cholinergic neurons of the pedunculopontine nucleus (PPN) send projections to several areas in the brain. The purpose of this work was to investigate whether bilateral lesions with quinolinic acid, a neurotoxin with greater selectivity for NADPH-diaphorase-positive neurons, aimed at the compact portion of the PPN would affect the performance of adaptive behaviors, such as sleep, locomotion, and spontaneous alternation. Lesioned animals were divided in a low lesion group (LL, <50% neuron loss) and a high lesion group (HL, ≥50% neuron loss). The LL animals did not show any significant changes in sleep patterns, as compared to controls. In contrast, the HL group showed a significant increase in the number of REM sleep periods, and a reduction of REM sleep average duration, but did not differ in the total time spent in REM sleep. HL animals also showed an increase in the number of SWS periods, though wakefulness parameters did not show significant alterations. The duration and number of both REM and SWS sleep episodes were significantly correlated with the number of NADPH-diaphorase-positive neurons in the PPN. The short-term habituation pattern of locomotion, the vertical exploratory activity, as well as the thigmotaxis (an index of emotionality), displayed by LL and HL rats in a novel environment were similar to those of control animals. Likewise, there were no significant differences in spontaneous alternation among the groups. Our results indicate that quinolinic acid lesions of NADPH-diaphorase-positive cholinergic neurons localized in the posterior region of the PPN disrupt normal sleep structure, while motor activity and spontaneous alternation remain unaffected.
Assuntos
Emoções/fisiologia , Comportamento Exploratório/fisiologia , Locomoção/fisiologia , Memória de Curto Prazo/fisiologia , Núcleo Tegmental Pedunculopontino/fisiologia , Ácido Quinolínico/toxicidade , Fases do Sono/fisiologia , Animais , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/fisiologia , Emoções/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Memória de Curto Prazo/efeitos dos fármacos , NADPH Desidrogenase/metabolismo , Núcleo Tegmental Pedunculopontino/efeitos dos fármacos , Ratos , Ratos Wistar , Fases do Sono/efeitos dos fármacosRESUMO
The aim of this work was to analyze the effect of oxcarbazepine (OXC) on sleep patterns, "head and body shakes" and monoamine neurotransmitters level in a model of kainic-induced seizures. Adult Wistar rats were administered kainic acid (KA), OXC or OXC + KA. A polysomnographic study showed that KA induced animals to stay awake for the whole initial 10 h. OXC administration 30 min prior to KA diminished the effect of KA on the sleep parameters. As a measure of the effects of the drug treatments on behavior, head and body shakes were visually recorded for 4 h after administration of KA, OXC + KA or saline. The presence of OXC diminished the shakes frequency. 4 h after drug application, the hippocampus was dissected out, and the content of monoamines was analyzed. The presence of OXC still more increased serotonin, 5-hidroxyindole acetic acid, dopamine, and homovanilic acid, induced by KA.
Assuntos
Carbamazepina/análogos & derivados , Dopamina/metabolismo , Hipocampo/efeitos dos fármacos , Convulsões/tratamento farmacológico , Serotonina/metabolismo , Fases do Sono/efeitos dos fármacos , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/uso terapêutico , Carbamazepina/administração & dosagem , Carbamazepina/uso terapêutico , Modelos Animais de Doenças , Ácido Homovanílico/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Ácido Caínico/efeitos adversos , Masculino , Oxcarbazepina , Ratos , Ratos Wistar , Convulsões/induzido quimicamenteRESUMO
OBJECTIVE: To evaluate the magnitude of effects of sildenafil on respiratory parameters and heart rate variability (HRV) in slow wave sleep (SWS) and REM sleep of patients with severe obstructive sleep apnea (OSA). METHODS: Thirteen male patients with untreated severe OSA (aged 43+/-10 years, body mass index of 26.7+/-1.9 kg/m(2)) were studied on two nights, one with sildenafil 50mg and one with a placebo, in a double-blind, randomized fashion. All-night polysomnography and HRV were simultaneously recorded. Short-term HRV measures were performed in apnea-free intervals. Respiratory parameters were separately assessed in non-REM and REM sleep and compared to total sleep time (TST). Short-term HRV analysis was conducted in samples with regular respiration obtained in SWS and REM sleep. RESULTS: Comparing to placebo, during sildenafil night there was an increase in apnea-hypopnea index (AHI) in TST and also in non-REM and REM sleep. Increase in central AHI occurred in non-REM sleep; increase in obstructive AHI and decrease in oxyhemoglobin saturation occurred in both non-REM and REM sleep. Additionally, an increase in arousal index and in low/high frequency component of HRV ratio (LF/HF) was significant only in REM sleep. Correlation between sleep architecture and respiratory parameters were more frequent in non-REM sleep for placebo and in REM sleep for sildenafil. CONCLUSION: In severe OSA, the use of sildenafil 50mg at bedtime plays a detrimental role on respiratory parameters in both non-REM and REM sleep, fragmentation in REM sleep, and a prolonged increase in LH/HF component of HRV after resumption of ventilation.
Assuntos
Frequência Cardíaca/efeitos dos fármacos , Piperazinas/efeitos adversos , Polissonografia/efeitos dos fármacos , Apneia Obstrutiva do Sono/induzido quimicamente , Fases do Sono/efeitos dos fármacos , Sono REM/efeitos dos fármacos , Sulfonas/efeitos adversos , Vasodilatadores/efeitos adversos , Adulto , Idoso , Nível de Alerta/efeitos dos fármacos , Nível de Alerta/fisiologia , Método Duplo-Cego , Esquema de Medicação , Eletrocardiografia Ambulatorial , Frequência Cardíaca/fisiologia , Humanos , Hipóxia/induzido quimicamente , Hipóxia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Oxiemoglobinas/metabolismo , Piperazinas/administração & dosagem , Purinas/administração & dosagem , Purinas/efeitos adversos , Citrato de Sildenafila , Apneia Obstrutiva do Sono/fisiopatologia , Fases do Sono/fisiologia , Sono REM/fisiologia , Sulfonas/administração & dosagem , Vasodilatadores/administração & dosagemRESUMO
Endogenous cannabinoids or endocannabinoids are lipid molecules that have a variety of biological actions, most notably via activation of the cannabinoid receptors. The family of endocannabinoids includes arachidonoylethanolamide (ANA) which modulates different behaviors, such as sleep. However, it is unknown whether pharmacological elevation of ANA endogenous levels might induce sleep. VDM 11 [(5 Z,8 Z,11 Z,14 Z)-N-(4-hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide] is commonly used as an inhibitor of ANA cellular uptake, and thereby to potentiate its actions. In this study we have examined whether VDM-11 exerts any effect on the sleep-wake cycle and c-Fos expression in brain areas. When assayed alone in rats, VDM-11 (10 or 20 microg/5 microL, i.c.v.) at the beginning of the lights-off period, reduced wakefulness and increased sleep. The CB(1) cannabinoid receptor antagonist, SR141716A, partially reversed the effects of VDM-11 on sleep. Additionally, VDM-11 enhanced c-Fos expression in sleep-related brain areas such as the anterior hypothalamic area, paraventricular thalamic nucleus, and pedunculopontine tegmental nucleus. It is concluded that VDM-11 displays sleep-inducing properties and these effects slightly, albeit significantly, are reversed using SR141716A. Furthermore, c-Fos data suggest a possible underlying neuroanatomical substrate of the sleep-inducing properties of VDM-11. We report evidence suggesting that VDM-11 might be considered for the development of new pharmacological and pharmaceutical approaches to treat sleep disorders such as insomnia.
Assuntos
Ácidos Araquidônicos/farmacologia , Química Encefálica/efeitos dos fármacos , Química Encefálica/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Genes fos/genética , Alcamidas Poli-Insaturadas/farmacologia , Sono/efeitos dos fármacos , Animais , Ácidos Araquidônicos/administração & dosagem , Antagonistas de Receptores de Canabinoides , Eletroencefalografia/efeitos dos fármacos , Endocanabinoides , Imuno-Histoquímica , Injeções Intraventriculares , Masculino , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/efeitos dos fármacos , Rimonabanto , Fases do Sono/efeitos dos fármacosRESUMO
The effects of LP-44, a selective 5-HT7 receptor agonist, and of SB-269970, a selective 5-HT7 receptor antagonist, on spontaneous sleep were studied in adult rats implanted for chronic sleep recordings. The 5-HT7 receptor ligands were microinjected directly into the dorsal raphe nucleus (DRN) during the light period of the 12-h light/12-h dark cycle. Infusion of LP-44 (1.25-5.0 mM) into the DRN induced a significant reduction of rapid-eye-movement sleep (REMS) and of the number of REM periods. Similar effects were observed after the direct administration into the DRN of SB-269970 (0.5-1.0 mM). Pretreatment with a dose of SB-269970 (0.5 mM) that significantly affects sleep variables antagonized the LP-44 (2.5 mM)-induced suppression of REMS and of the number of REM periods. It is proposed that the suppression of REMS after microinjection of LP-44 into the DRN is related, at least in part, to the activation of GABAergic neurons in the DRN that contribute to long projections that reach, among others, the laterodorsal and pedunculopontine tegmental nuclei involved in the promotion of REMS.
Assuntos
Proteínas da Membrana Bacteriana Externa/farmacologia , Lipoproteínas/farmacologia , Núcleos da Rafe/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Sono REM/efeitos dos fármacos , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Lipopeptídeos , Masculino , Fenóis/farmacologia , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Fases do Sono/efeitos dos fármacos , Sulfonamidas/farmacologia , Vigília/efeitos dos fármacosRESUMO
We investigated whether administration of MOD in rats during the lights-on period into wake-promoting areas, such as anterior hypothalamus (AH) or into the pedunculopontine tegmental nucleus (PPTg) would enhance waking. Results showed that microinjections of 1 microL of MOD (10, 20, or 30 microg) into both brain areas increased the total time of alertness and decreased sleep. Additionally, MOD-treated rats showed an enhancement in alpha power spectra but delta power spectra was diminished. Finally, c-Fos expression was found increased into either AH or the PPTg. Collectively, these results suggest that MOD induces waking via the activity of two wake-related brain areas such as AH and the PPTg.
Assuntos
Núcleo Hipotalâmico Anterior/efeitos dos fármacos , Compostos Benzidrílicos/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Núcleo Tegmental Pedunculopontino/efeitos dos fármacos , Vigília/efeitos dos fármacos , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eletroencefalografia/métodos , Masculino , Modafinila , Proteínas Oncogênicas v-fos/metabolismo , Ratos , Ratos Wistar , Fases do Sono/efeitos dos fármacosRESUMO
The effects of the selective 5-HT(3) receptor agonist and antagonist m-chlorophenylbiguanide (m-CPBG) and ondansetron, respectively, were studied in adult male Wistar rats implanted for chronic sleep recordings. Microinjection of m-CPBG (2.0 and 4.0 mM) into the dorsal raphe nucleus (DRN) decreased rapid-eye-movement sleep (REMS) and the number of REM periods during the first, second, and third 2-h recording period. On the other hand, direct infusion of ondansetron (0.5-1.0 mM) into the DRN induced no significant changes in sleep variables over the 6 h of recording. Pretreatment with ondansetron (0.5 mM) antagonized the m-CPBG (2.0 mM)-induced reduction of REMS and of the number of REM periods. The data are consistent with the hypothesis that the 5-HT(3) receptor is involved in the effect of DRN serotonergic neurons on brainstem structures that act to promote and induce REMS. It is suggested that the suppression of REMS after the microinjection of m-CPBG into the DRN is related, at least in part, to the stimulation of glutamatergic interneurons that express 5-HT(3) receptors. Activation of these receptors facilitates the release of glutamate, which, in turn, acts on postsynaptic N-methyl-d-aspartate and non-N-methyl-d-aspartate receptors expressed by serotonergic neurons of the DRN and increases the release of 5-HT at postsynaptic sites.
Assuntos
Núcleos da Rafe/efeitos dos fármacos , Receptores 5-HT3 de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Sono REM/efeitos dos fármacos , Animais , Biguanidas/administração & dosagem , Biguanidas/farmacologia , Depressão Química , Eletroencefalografia , Injeções Intraventriculares , Masculino , Ondansetron/farmacologia , Ratos , Ratos Wistar , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/administração & dosagem , Fases do Sono/efeitos dos fármacosRESUMO
Chloral hydrate and hydroxyzine are a drug combination frequently used by practitioners to sedate pediatric dental patients, but their effectiveness has not been compared to a negative control group in humans. The aim of this crossover, double-blinded study was to evaluate the effect of these drugs compared to a placebo, administered to young children for dental treatment. Thirty-five dental sedation sessions were carried out on 12 uncooperative ASA I children aged less than 5 years old. In each session patients were randomly assigned to groups P (placebo), CH (chloral hydrate 75 mg/kg) and CHH (chloral hydrate 50 mg/kg plus hydroxyzine 2.0 mg/kg). Vital signs and behavioral variables were evaluated every 15 min. Comparisons were statistically analyzed using Friedman and Wilcoxon tests. P, CH and CHH had no differences concerning vital signs, except for breathing rate. All vital signs were in the normal range. CH and CHH promoted more sleep in the first 30 min of treatment. Overall behavior was better in CH and CHH than in P. CH, CHH and P were effective in 62.5%, 61.5% and 11.1% of the cases, respectively. Chloral hydrate was safe and relatively effective, causing more satisfactory behavioral and physiological outcomes than a placebo.