Protective effect of melatonin against oxygen-induced retinopathy: a study based on the HMGB1/NF-κB/NLRP3 axis / 中国当代儿科杂志

OBJECTIVES@#To study the protective effect of melatonin (Mel) against oxygen-induced retinopathy (OIR) in neonatal mice and the role of the HMGB1/NF-κB/NLRP3 axis.@*METHODS@#Neonatal C57BL/6J mice, aged 7 days, were randomly divided into a control group, a model group (OIR group), and a Mel treatment group (OIR+Mel group), with 9 mice in each group. The hyperoxia induction method was used to establish a model of OIR. Hematoxylin and eosin staining and retinal flat-mount preparation were used to observe retinal structure and neovascularization. Immunofluorescent staining was used to measure the expression of proteins and inflammatory factors associated with the HMGB1/NF-κB/NLRP3 axis and lymphocyte antigen 6G. Colorimetry was used to measure the activity of myeloperoxidase.@*RESULTS@#The OIR group had destruction of retinal structure with a large perfusion-free area and neovascularization, while the OIR+Mel group had improvement in destruction of retinal structure with reductions in neovascularization and perfusion-free area. Compared with the control group, the OIR group had significant increases in the expression of proteins and inflammatory factors associated with the HMGB1/NF-κB/NLRP3 axis, the expression of lymphocyte antigen 6G, and the activity of myeloperoxidase (P<0.05). Compared with the OIR group, the OIR+Mel group had significant reductions in the above indices (P<0.05). Compared with the control group, the OIR group had significant reductions in the expression of melatonin receptors in the retina (P<0.05). Compared with the OIR group, the OIR+Mel group had significant increases in the expression of melatonin receptors (P<0.05).@*CONCLUSIONS@#Mel can alleviate OIR-induced retinal damage in neonatal mice by inhibiting the HMGB1/NF-κB/NLRP3 axis and may exert an effect through the melatonin receptor pathway.

Insomnio en tiempos de pandemia / Insomnia in pandemic times

El sueño es una función biológica de importancia para los seres vivos y su alteración más frecuente es el insomnio. Se define como la dificultad para conciliar o mantener el sueño, acompañada de una sensación de descanso no reparadora, a pesar de que las condiciones ambientales para ello son adecuadas, y que suele asociarse a fatiga y somnolencia durante el día. En los tiempos prepandemia ya se sabía que existía una alta prevalencia, pero durante la pandemia las cifras han aumentado y probablemente seguirán aumentando postpandemia, lo que conlleva a un incremento de las consultas en la atención primaria. Las medidas no farmacológicas son esenciales para incrementar la eficacia de las medidas terapéuticas. Las benzodiacepinas y los compuestos Z tienen bastantes efectos adversos y no son la primera opción, especialmente en los adultos mayores. La melatonina es mejor tolerada pero su eficacia no está comprobada.

Sleep is an important biological function for living beings and its most frequent alteration is insomnia. It is defined as difficulty in falling or staying asleep, accompanied by a feeling of non-restorative rest, despite adequate environmental conditions, and is usually associated with fatigue and sleepiness during the day. In pre-pandemic times, it was already known that there was a high prevalence, but during the pandemic, the figures have increased and will probably continue to increase post-pandemic, leading to an increase in consultations in primary care. Non-pharmacological measures are essential to increase the efficacy of therapeutic measures. Benzodiazepines and Z-compounds have quite a few adverse effects and are not the first choice, especially in older adults. Melatonin is better tolerated but its efficacy is not verified.

Regulatory aspects and evidences of melatonin use for sleep disorders and insomnia: an integrative review / Aspectos regulatórios e evidências do uso de melatonina em distúrbio do sono e insônia: uma revisão integrativa

ABSTRACT Background: Insomnia is a sleep disorder characterized by difficulty of falling asleep or maintaining sleep, which affects different age groups. Currently, melatonin is used as a therapeutic treatment in cases of insomnia in children, adults, and elderly people. Objective: To evaluate the effectiveness of melatonin in sleep disorders, its dosage, potential adverse effects, as well as labeling laws and regulations in Brazil. Methods: This integrative review was carried out using the Cochrane Library, Medline (Pubmed), and Science Direct databases. Twenty-five articles and three documents available on the Brazilian Society of Endocrinology and Metabology (SBEM) and National Health Surveillance Agency (ANVISA) websites published between 2015 and 2020 were selected to be evaluated in full. Results: It was found that in most of the selected articles the use of melatonin reduces sleep latency. The effective melatonin doses varied according to each age group, from 0.5 to 3 mg in children, 3 to 5 mg in adolescents, 1 to 5 mg in adults, and 1 to 6 mg in elderly people. Side effects are mild when taking usual doses. In Brazil, no registered drug and current regulation on the use and marketing of melatonin has been identified. Conclusion: The use of melatonin is an alternative therapy that can be used for sleeping disorders. According to the evidences found, it did not demonstrate toxicity or severe side effects, nor dependence even when administered at high doses, suggesting that it is a safe medication to treat patients of different ages suffering from sleeping disorders.

RESUMO Antecedentes: Insônia é um distúrbio do sono caracterizado por dificuldade de iniciar e manter o sono, afetando diferentes faixas etárias. Atualmente, a melatonina é utilizada no tratamento de insônia em crianças, adultos e idosos. Objetivo: Avaliar a eficácia da melatonina nos distúrbios do sono, posologia e potenciais efeitos adversos, bem como a regulamentação vigente no Brasil. Métodos: Trata-se de uma revisão integrativa, os artigos foram identificados nas bases de dados Cochrane Library, Medline (Pubmed) e Science Direct, totalizando 25 artigos, e foram selecionados três materiais disponíveis no site da Sociedade Brasileira de Endocrinologia e Metabologia e Agência Nacional de Vigilância Sanitária, publicados entre 2015 e 2020. Resultados: Verificou-se na maioria dos artigos selecionados que a melatonina reduz a latência do sono. Quanto as dosagens de melatonina identificou-se variação em cada faixa etária, para crianças de 0,5 a 3mg; adolescentes de 3 a 5mg; adultos de 1 a 5mg e idosos 1 mg a 6 mg demostraram serem eficazes. Em doses habituais os efeitos colaterais são leves. No Brasil, não foi identificado medicamento registrado e regulamentação vigente sobre o uso e comercialização de melatonina. Conclusão: A utilização da melatonina é uma alternativa que pode ser utilizada em distúrbios do sono. De acordo com as evidências encontradas, não demonstrou toxicidade ou efeitos colaterais severos, nem dependência mesmo em doses elevadas, sendo, portanto, segura para tratamento de pacientes desde crianças a idosos que sofrem de distúrbios do sono.

Importancia del buen dormir en nuestros pacientes / Importance of good sleep in our patients

El sueño es una necesidad biológica. Regula las funciones inmunitarias. Las funciones inmunológicas dependen de los ritmos circadianos y del sueño regular. Según estudios previos a la pandemia, la corta duración del sueño o privación de sueño, en la semana cercana a la vacunación, se asocia con respuestas más bajas de anticuerpos. La privación de sueño da como resultado una función inmunológica más deficiente (es decir, actividad reducida de las células natural killer, producción de IL-2 suprimida) así como un aumento de los niveles circulantes de marcadores inflamatorios (IL-6, TNF-α [factor de necrosis tumoral] y proteína C reactiva). Los médicos deben ser conscientes de que muchas enfermedades que mencionamos en esta resumida actualización son comórbidas con alteraciones del sueño, y es importante, por ello, enseñar a los pacientes a mejorar su comportamiento con respecto al sueño y fomentar la educación sobre higiene del sueño. Destacamos que, en el interrogatorio de cualquier especialidad médica, deben incorporarse preguntas sobre el "dormir", dado que el sueño de buena calidad es fundamental en la prevención y el tratamiento de diversas enfermedades. (AU)

Sleep is a biological necessity. Regulates immune functions. Immune functions depend on circadian rhythms and regular sleep. According to studies prior to the pandemic, short duration of sleep or sleep deprivation, in the week leading up to vaccination, is associated with lower antibody responses to vaccination. Sleep deprivation results in poorer immune function (i.e., reduced natural killer cell activity, suppressed IL-2 production) as well as increased circulating levels of inflammatory markers (IL-6, factor of tumor necrosis, C-reactive protein). Clinicians should be aware that many illnesses, which we mention in this brief update, are comorbid with sleep disturbances and it is therefore important to teach patients to improve their sleep behavior and should encourage sleep hygiene education . We emphasize that in the questioning of any medical specialty, questions about "sleep" should be incorporated, given that good quality sleep is essential in the prevention and treatment of various diseases. (AU)

Melatonin can be, more effective than N-acetylcysteine, protecting acute lung injury induced by intestinal ischemia-reperfusion in rat model

OBJECTIVES: The current study compared the impact of pretreatment with melatonin and N-acetylcysteine (NAC) on the prevention of rat lung damage following intestinal ischemia-reperfusion (iIR). METHODS: Twenty-eight Wistar rats were subjected to intestinal ischemia induced by a 60 min occlusion of the superior mesenteric artery, followed by reperfusion for 120 min. Animals were divided into the following groups (n=7 per group): sham, only abdominal incision; SS+iIR, pretreated with saline solution and iIR; NAC+iIR, pretreated with NAC (20 mg/kg) and iIR; MEL+iIR, pretreated with melatonin (20 mg/kg) and iIR. Oxidative stress and inflammatory mediators were measured and histological analyses were performed in the lung tissues. RESULTS: Data showed a reduction in malondialdehyde (MDA), myeloperoxidase (MPO), and TNF-alpha in the animals pretreated with NAC or MEL when compared to those treated with SS+iIR (p<0.05). An increase in superoxide dismutase (SOD) levels in the NAC- and MEL-pretreated animals as compared to the SS+iIR group (34±8 U/g of tissue; p<0.05) was also observed. TNF-α levels were lower in the MEL+iIR group (91±5 pg/mL) than in the NAC+iIR group (101±6 pg/mL). Histological analysis demonstrated a higher lung lesion score in the SS+iIR group than in the pretreated groups. CONCLUSION: Both agents individually provided tissue protective effect against intestinal IR-induced lung injury, but melatonin was more effective in ameliorating the parameters analyzed in this study.

Melatonin and the cardiovascular system in animals: systematic review and meta-analysis

Melatonin, a hormone released by the pineal gland, demonstrates several effects on the cardiovascular system. Herein, we performed a systematic review and meta-analysis to verify the effects of melatonin in an experimental model of myocardial infarction. We performed a systematic review according to PRISMA recommendations and reviewed MEDLINE, Embase, and Cochrane databases. Only articles in English were considered. A systematic review of the literature published between November 2008 and June 2019 was performed. The meta-analysis was conducted using the RevMan 5.3 program provided by the Cochrane Collaboration. In total, 858 articles were identified, of which 13 were included in this review. The main results of this study revealed that melatonin benefits the cardiovascular system by reducing infarct size, improving cardiac function according to echocardiographic and hemodynamic analyses, affords antioxidant effects, improves the rate of apoptosis, decreases lactate dehydrogenase activity, enhances biometric analyses, and improves protein levels, as analyzed by western blotting and quantitative PCR. In the meta-analysis, we observed a statistically significant decrease in infarct size (mean difference [MD], -20.37 [-23.56, -17.18]), no statistical difference in systolic pressure (MD, -1.75 [-5.47, 1.97]), a statistically significant decrease in lactate dehydrogenase in animals in the melatonin group (MD, -4.61 [-6.83, -2.40]), and a statistically significant improvement in the cardiac ejection fraction (MD, -8.12 [-9.56, -6.69]). On analyzing potential bias, we observed that most studies presented a low risk of bias; two parameters were not included in the analysis, and one parameter had a high risk of bias. Melatonin exerts several effects on the cardiovascular system and could be a useful therapeutic target to combat various cardiovascular diseases.

Possible role of exogenous melatonin in preventing more serious COVID-19 infection in patients with type 2 diabetes mellitus

SUMMARY COVID-19 infection is more severe in patients with type 2 diabetes mellitus (DM2). The severity of this viral infection is associated with an intense inflammatory activity. DM2 is a disease that also determines a greater degree of systemic inflammation. This is due to hyperglycemia, the higher prevalence of sleep disorders and also the low levels of melatonin, a substance with anti-inflammatory actions, in these patients. In this article, we suggest that exogenous melatonin may have an important anti-inflammatory role in preventing severe forms of COVID -19 in patients with DM2.

La melatonina y su rol en los procesos inflamatorios / Melatonin and its role in inflammatory processes

La melatonina es una hormona neuroendocrina pleiotrópica, producida principalmente por la glándula pineal que regula el ritmo circadiano, es antiinflamatoria, inmunomoduladora, neuroprotectora, antioxidante. Se realizó una revisión sobre el tema empleando artículos de libre acceso en la base de datos Pubmed en el período de enero del 2013 a septiembre del 2018 con el objetivo de describir el rol de esta biomolécula en algunas enfermedades autoinmunes y reumatológicas, así como en otros procesos inflamatorios agudos y crónicos. La melatonina ha demostrado acciones favorables cuando se administra en enfermedades como la esclerosis múltiple, diabetes mellitus tipo l, cáncer. No obstante, puede empeorar las crisis en la artritis reumatoide(AU)

Melatonin is a pleiotropic neuroendocrine hormone, produced mainly by the pineal gland that regulates the circadian rhythm, is anti-inflammatory, immunomodulatory, neuroprotective, antioxidant. A review on the subject was performed using articles of free access in the Pubmed database from January 2013 to September 2018 with the aim of describing the role of this biomolecule in some autoimmune and rheumatological diseases, as well as in other acute and chronic inflammatory processes. Melatonin has shown favorable actions when it is administered in diseases such as multiple sclerosis, diabetes mellitus type I, cancer. However, it can worsen crises in rheumatoid arthritis(AU)

Melatonin may prevent or reverse polycystic ovary syndrome in rats

SUMMARY OBJECTIVE To evaluate the ovarian effects of melatonin (Mel) in a rat model of polycystic-ovary-syndrome (PCOS) before and after permanent estrus induction. METHODS Thirty-two adult-female rats with regular estrous cycle were equally divided into four groups: 1) GCtrl - at estrous phase. 2) GPCOS - at permanent-estrous phase. 3) GMel1 - treated for 60 days with Mel (0.4 mg/Kg) during permanent estrus induction and 4) GMel2 - rats with PCOS and treated for 60 days with Mel. After that, the animals were euthanized, and the ovaries were removed and processed for paraffin embedding. Sections were stained with H.E. for histomorphometry or subjected to immunohistochemistry for Ki-67 and cleaved caspase-3 (Casp-3) detections. RESULTS The GPCOS showed lack of corpus luteum and several ovarian cysts, as well as interstitial-like cells. The presence of corpus luteum and a significant increase in primary and antral follicles were observed in Mel-treated groups, which also showed a decrease in the number of ovarian cysts and in the area occupied by interstitial-like cells. These results were more evident in GMel1. The percentage of Ki-67-positive cells was significantly higher in the Mel-treated groups, mainly in the GMel2, as compared to GPCOS. On the other hand, the percentage of Casp-3-positive cells was significantly lower in granulosa cells of GMel1, whereas it was significantly higher in the interstitial-like cells of GMel2, in comparison to GPCOS. CONCLUSION Melatonin administration prevents the permanent estrus state in the PCOS rat model. This effect is more efficient when melatonin is administered before permanent estrus induction.

RESUMO OBJETIVO Avaliar os efeitos ovarianos da melatonina (Mel) em ratas com síndrome dos ovários policísticos (SOP) antes e após a indução do estro-permanente. MÉTODOS Trinta e duas ratas com ciclos estrais regulares foram igualmente divididas em quatro grupos: 1) GCtrl - fase de estro. 2) GSOP - fase de estro-permanente. 3) GMel1 - tratadas por 60 dias com Mel (0,4 mg/kg) durante a indução do estro-permanente e 4) GMel2 - ratas com SOP e tratadas com Mel. Após eutanásia dos animais, os ovários foram processados para inclusão em parafina. Cortes foram corados com H.E ou submetidos à imuno-histoquímica para detecção de Ki-67 e caspase-3 clivada (Casp-3). RESULTADOS O GSOP mostrou ausência de corpos lúteos e vários cistos ovarianos, além de inúmeras células intersticiais. A presença de corpos lúteos e o aumento significativo dos folículos primários e antrais foram observados nos grupos tratados com Mel, os quais também mostraram diminuição no número de cistos ovarianos e na área ocupada pelas células intersticiais. Esses resultados foram mais evidentes no GMel1 do que no GMel2. A porcentagem de células Ki-67 positivas foi significativamente maior no GMel1 e no GMel2, sendo mais evidente no GMel2, em comparação ao GSOP. Por outro lado, a porcentagem de células positivas à Casp-3 foi menor nas células da granulosa do GMel1 e maior nas células intersticiais do GMel2, em comparação ao GSOP. CONCLUSÃO A administração de melatonina previne o estado de estro-permanente em ratas com SOP. Esse efeito é mais eficiente quando a melatonina é administrada após indução do estado de estro-permanente.

El tratamiento postnatal con melatonina modula la expresión de agentes prostanoides en pulmón de neonatos de oveja con hipertensión pulmonar / Melatonin modulates the expression of pulmonary prostanoids

Background: Living above 2,500 meters in hypobaric conditions induces pulmonary arterial hypertension of the neonate (PAHN), a syndrome whose main features are: pathological remodeling of the pulmonary vessels, abnormal vascular reactivity and increased oxidative stress. Melatonin could have pulmonary antioxidant, anti-remodeling and vasodilating properties for this condition. Aim: To determine the effect of melatonin at the transcript level of prostanoid pathways in the lung of neonatal lambs gestated and born under hypobaric hypoxia. Material and Methods: Vehicle (1.4% of ethanol, n = 6) or melatonin (1 mg * kg1, n = 5) were administered from the postnatal day 4 to 21 to lambs gestated and born at 3,600 meters above sea level. After one week of treatment completion, lung tissue was obtained, the transcript and protein levels of prostanoid synthases and receptors were assessed by RT-PCR and Western Blot. Results: Melatonin induced the expression of prostacyclin synthase transcript and increased protein expression of the prostacyclin receptor. In addition, the treatment decreased the expression of transcript and protein of cyclooxygenase-2, without changes in the expression of the prostanoid vasoconstrictor (thromboxane) pathway. Conclusions: Postnatal treatment with melatonin increases the expression of the prostacyclin-vasodilator pathway without changing the vasoconstrictor thromboxane pathway. Further, the decreased COX-2 induced by melatonin could be an index of lesser oxidative stress and inflammation in the lung.

Prophylaxis with melatonin for primary stabbing headache in pediatrics: a case report / Profilaxis con melatonina para cefalea punzante primaria en pediatría: reporte de caso

Abstract Introduction: Primary stabbing headache (or "ice pick headache") is an alteration characterized by brief jabs (short stabs of pain, lasting ~3 seconds), which appear spontaneously, irregularly, and affecting unilaterally or bilaterally. Indomethacin has traditionally been used as the main therapeutic option. However, this drug is ineffective in a considerable percentage of patients and can generate multiple adverse effects that occur at therapeutic doses. Clinical case: A 7-year-old male patient with primary stabbing headache of mild to moderate intensity, lasting 3 to 4 seconds, without relevant history, with normal neurodevelopment, neurological examination and neuroimaging; no triggers were identified. It was started therapeutic trial with Coenzyme Q10; however, no improvement in the symptoms was identified. Treatment and outcomes: A therapeutic management was carried out with Melatonin, which led to complete remission of the symptoms; without adverse effects in the posterior follow-up months. Clinical and scientific relevance: There is little information regarding effective and safe treatments for primary stabbing headache in children. The present case identifies Melatonin as an innovative, effective and safe therapeutic alternative in the treatment of primary stabbing headache in children. This is a significant advance in the understanding of primary stabbing headache in the pediatric population. Conclusion: Melatonin may be an effective and safe therapeutic option for the treatment of primary stabbing headache in pediatric patients. It is necessary to deepen its research, in order to establish its use in a clinical practice guide.

Resumen Introducción: La cefalea punzante primaria, es una alteración que se caracteriza por punzadas breves (∼3 segundos), que aparecen espontáneamente, de forma irregular y afectación unilateral o bilateral. Tradicionalmente se ha utilizado Indometacina como opción terapéutica principal. Sin embargo, este medicamento es inefectivo en un porcentaje considerable de pacientes y puede generar múltiples efectos adversos que se presentan a dosis terapéuticas. Caso clínico: Paciente masculino de 7 años de edad con cefalea punzante primaria de intensidad leve a moderada con una duración entre 3 y 4 segundos sin antecedentes relevantes, con neurodesarrollo, examen neurológico y de neuroimagen normales; no se identificaron desencadenantes. Se inició prueba terapéutica con Coenzima Q10, sin embargo no se identificó mejoría en los síntomas. Tratamiento y resultados: Se realizó un manejo terapéutico con Melatonina que conllevó a remisión completa de la sintomatología y sin efectos adversos en los meses posteriores de seguimiento. Relevancia clínica y científica: Existe poca información respecto a tratamientos efectivos y seguros para cefalea punzante primaria en niños. El presente caso identifica la Melatonina como una alternativa terapéutica innovadora, efectiva y segura en el tratamiento de la cefalea punzante primaria en niños. Lo anterior constituye un avance significativo en la comprensión de la cefalea punzante primaria en la población pediátrica. Conclusión: La melatonina puede ser una opción terapéutica efectiva y segura para el tratamiento de la cefalea punzante primaria en pacientes pediátricos. Se requiere ahondar en su investigación para establecer su uso en una guía de práctica clínica.

A brief review about melatonin, a pineal hormone

ABSTRACT Melatonin is a ubiquitous molecule in nature, being locally synthesized in several cells and tissues, besides being a hormone that is centrally produced in the pineal gland of vertebrates, particularly in mammals. Its pineal synthesis is timed by the suprachiasmatic nucleus, that is synchronized to the light-dark cycle via the retinohypothalamic tract, placing melatonin synthesis at night, provided its dark. This unique trait turns melatonin into an internal synchronizer that adequately times the organism's physiology to the daily and seasonal demands. Besides being amphiphilic, melatonin presents specific mechanisms and ways of action devoted to its role as a time-giving agent, being widely spread in the organism. The present review aims to focus on melatonin as a pineal hormone with specific mechanisms and ways of action, besides presenting the clinical syndromes related to its synthesis and/or function disruptions.

Protective effects of melatonin on spinal cord injury / Efectos protectores de la melatonina en lesión de la médula espinal

Spinal cord injury causes neuron nerve fiber loss. The aim of this study was to investigate the neuroprotective, inflammatory and angiogenetic effects of melatonin on rat spinal cord injury (SCI). For spinal cord injury, a standard weight reduction method was used that caused moderate severity of injury (100 g / cm force) at T10 Melatonin (10 mg/kg intraperitoneally ) was administered for 10 days after trauma. Each group consisted of 10 animals. of these, six were used for biochemical and four were used for the evaluation of histological analysis. Spinal cord samples were taken for histological examination or determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity. Spinal cord injury and melatonin treated group were compared. Melatonin administration in spinal cord injury increased the activity of glial cells in the radial and funicular cells and ependymal cells and increased the activity of glial cells and also showed a positive effect on inflammation and vascular endothelial cells in synaptic connections in the nerve fibers undergoing spinal injury endothelial degeneration It is thought that it can regulate the degenerative effect which is caused by both the inflammatory effect and the angiogenic effect which will have a positive effect on the neural connection.

La lesión de la médula espinal (SCI) provoca daño en la fibra nerviosa, que puede conducir a alteraciones motoras y sensitivas, incluso la muerte. El objetivo de este estudio fue investigar los efectos neuroprotectores, proinflamatorios y proangiogénicos de la melatonina en un modelo de SCI inducida en rata. Para tal efecto se utilizaron dos grupos: Grupo 1 (n:10) se le indujo una SCI, mediante el método de reducción de peso estándar (100 g/cm fuerza), provocando una lesión de severidad moderada. Grupo 2 (n:10) inducción SCI más aplicación de T10 Melatonina (10 mg / kg v.i.) durante 10 días después del trauma. Muestras de seis animales de cada grupo fueron usados para análisis bioquímicos y los otros cuatro para la evaluación histológica. Se tomaron muestras de médula espinal para el examen histológico y para la determinación de niveles de malondialdehído (MDA) y glutatión (GSH), actividad mieloperoxidasa (MPO) y se comparó la lesión de la médula espinal y el grupo tratado con melatonina. La administración de melatonina en la lesión de la médula espinal aumentó la actividad de las células gliales en las células radiales, funiculares y ependimocitos. Ademas mostró un efecto positivo sobre la inflamación y angiogénesis en las conexiones sinápticas en las fibras nerviosas sometidas a lesión espinal. Pudiendo este participar en la regulación del efecto degenerativo causado, principalmente, por acción de angiogénesis e inflamación local.

Transtornos do sono: atualização (parte2/2) / Sleep disorders: up to date (2/2)

Este artigo (2/2) compõe uma revisão sobre fundamentos do sono e transtornos do sono (TS), sendo aqui considerados: 1-Incapacidade de dormir na hora desejada-atraso de fase, avanço de fase, ''jet lag'', ritmo sono-vigília irregular, sono/vigília de livre curso, transtornos dos trabalhadores em turnos; 2-Movimentos ou comportamentos anormais durante o sono. Este segundo grupo é aqui subdividido em: A1-Parassonias relacionadas ao sono NREM (Non-rapid eye movement) ­ despertar confusional, sonambulismo, terror noturno, síndrome da cabeça explosiva, alucinações relacionadas ao sono, enurese noturna e parassonias causadas por doenças e medicações; A2-Parassonias relacionadas ao sono REM (rapid eye movement) - transtorno comportamental do sono REM, pesadelos, paralisias recorrentes isoladas do sono, promulgação sono ''dream enactment behavior"; B-Transtornos do movimento relacionados ao sono-bruxismo, síndrome das pernas inquietas, movimentos periódicos das pernas, câimbras do sono, movimentos rítmicos relacionados ao sono, mioclonias proprioespinhais do início do sono, movimentos relacionados à medicação, mioclonias em doenças sistêmicas e mioclonias benignas do sono em bebês.(AU)

This is the second part (2/2) of an article that intends to review major topics regarding sleep fundamentals and sleep disorders (SD), now considering: 1-Circadian rhythm disorders-delayed onset sleep phase disorder, advanced onset sleep phase disorder, jet lag, irregular sleep-wake rhythm, free-running type, shift work type; 2-Abnormal movements or behaviours during sleep. This second category is divided in two groups: A1-NREM (Non-rapid eye movement) parasomnias ­ confusional awakening, sleepwalking, night terrors, explosive head syndrome, sleep-related hallucinations, nocturnal enuresis and parasomnias related to diseases or medications; A2-REM (Rapid eye movement) parasomnias-REM sleep behaviour disorder, nightmares, recurrent isolated sleep paralysis, dream enactment behaviour; B-Sleep related movement disorders-bruxism, restless legs syndrome, periodical limb movement disorders, nocturnal leg cramps, sleep related rhythmic movement disorder, propriospinal myoclonus, movements related to medication use, myoclonus related to systemic diseases and benign myoclonus of sleep.(AU)

Combined effects of melatonin and topical hypothermia on renal ischemia-reperfusion injury in rats

Abstract Purpose: To evaluate whether their combination was more effective than either alone in decreasing renal damage due to ischemia/reperfusion (I/R) injury in rats. Methods: Thirty-two Wistar rats were assigned to four groups. Following right nephrectomy, their left kidneys were subjected to warm ischemia (IR), cold ischemia (TH+IR), intraperitoneal injection of 10 mg/kg melatonin (MEL+IR), or injection of 10 mg/kg melatonin followed by cold ischemia (MEL+TH+IR). Eight randomly assigned right kidneys constituted the control group. After 240 min of reperfusion, left nephrectomy was performed for histopathological evaluation, lipid peroxidation, and measurement of antioxidant enzyme activity. Serum was collected to measure urea and creatinine concentrations. Results: Histopathological damage induced by ischemia and reperfusion was more attenuated in the MEL+TH+IR group than in the MEL+IR and TH+IR groups (p<0.037). Superoxide dismutase activity was significantly higher (p<0.029) and creatinine (p<0.001) and urea (p<0.001) concentrations were significantly lower in the MEL+TH+IR group than in the MEL+IR and TH+IR groups. Conclusion: The combination of melatonin (MEL) and topical hypothermia (TH) better protects against renal I/R injury than does MEL or TH alone.

Pharmacological interventions for sleepiness and sleep disturbances caused by shift work

BACKGROUND: Shift work results in sleep-wake disturbances, which cause sleepiness during night shifts and reduce sleep length and quality in daytime sleep after the night shift. In its serious form it is also called shift work sleep disorder. Various pharmacological products are used to ameliorate symptoms of sleepiness or poor sleep length and quality. OBJECTIVES: To evaluate the effects of pharmacological interventions to reduce sleepiness or to improve alertness at work and decrease sleep disturbances whilst of work, or both, in workers undertaking shift work. METHODS: Search methods: We searched CENTRAL, MEDLINE, EMBASE, PubMed and PsycINFO up to 20 September 2013 and ClinicalTrials.gov up to July 2013. We also screened reference lists of included trials and relevant reviews. Selection criteria: We included all eligible randomised controlled trials (RCTs), including cross-over RCTs, of pharmacological products among workers who were engaged in shift work (including night shifts) in their present jobs and who may or may not have had sleep problems. Primary outcomes were sleep length and sleep quality while of work, alertness and sleepiness, or fatigue at work. Data collection and analysis: Two authors independently selected studies, extracted data and assessed risk of bias in included trials. We performed meta-analyses where appropriate. ...

Efeito do tratamento com melatonina sobre a produção de metástases neoplasias / Result of the treatment with melatonin inthe production of neoplasic metastasis

Introdução: Neoplasias são células com proliferação e diferenciação anormais. Quando essas células tornam-se capazes de originar outras células em tecidos e vasos diferentes do inicial são denominadas metástases. A melatonina (N-acetil-5-metoxitripamina) é um hormônio secretado pela glândula pineal e que tem associação com o controle celular tumoral. Objetivo: pretendeu-se avaliar o efeito do tratamento com melatonina sobre a produção e crescimento de metástase linfática do tumor sólido de Ehrlich (TE) em camundongos. Método: foram empregados 14 camundongos distribuídos em 2 grupos: controle (GC, N = 07 / 0,1ml de solução fisiológica, via oral, 1x/dia) e teste (GT, N = 07 / 10mg/kg de melatonina, via oral, 1x/ dia). Todos os animais foram inoculados com 10 6 células tumorais no coxim plantar da pata traseira direita. Resultados e Discussão: D=decorridos 17 dias de tratamento os animais foram eutanasiados, removemos as 02 patas traseiras para avaliar o peso da massa tumoral sendo que o grupo controle apresentou peso maior (GC = 0,62 ± 0,14). Também foi removido o linfonodo poplíteo para mensuração da área, constatando redução significativa no grupo teste (GT = 4,37 ± 1,58). A redução da área do linfonodo pode ser associada a uma redução no número de células tumorais presentes nos linfonodos (GT = 62,8 ± 13,07). Conclusão: Concluímos que o tratamento com melatonina reduziu significativamente o crescimento tumoral e metastático do TE.

Introduction: Neoplasms are cells with unusual proliferation and differentiation. When these cells become able to generate other cells in material and veins different from the beginning one arenamed metastasis. The melatonin (N-acetil-5-methoxytryptamine) is a hormone secreted by the pineal gland and it has association with the tumor cell control. Objective: the general aim was to evaluate the treatment result with melatonin on the metastasis lymphatic production and growth of the Ehrlich Tumor in mice. For this experience, 14 mice were used and shared in 2 groups: control (GC, N = 07 / 0,1ml of sterilizing solution, oral, once a day) and test (GT, N = 07 / 10mg/kg of melatonin, oral, once a day). All the animals were inoculated with 106 tumor cells in the footpad of the right back paw. Results and discussion: after 17 days of treatment the animals were euthanized and 2 back paws were removed to evaluate the tumor bulk weight considering that the control group was heavier (GC = 0,62 ± 0,14). The popliteallymph node was also removed for the area measurement where asmaller area for the test group was observed (GT = 62,8 ± 13,07). Conclusion: we concluded that the treatment with melatonin meaningfully reduced the metastatic growth.

Influence of melatonin treatment on the survival and seizures frequency in pilocarpine-induced epilepsy in rats / Influência do tratamento com melatonina na sobrevivência e frequência das crises epiléticas em ratos induzidas por pilocarpina

Objetivo: verificar se o tratamento com melatonina no período crônico pode alterar a frequência de crises e sobrevida de ratos Wistar submetidos ao modelo de epilepsia induzido por pilocarpina. Métodos: os animais foram divididos em dois grupos: Epi+MEL (n=8), animais tratados com melatonina (10 mg/kg) no período crônico; Epi+VEI (n=5), animais tratados com solução veículo no período crônico. Para analisar a duração e a frequência de crises os animais foram vídeo-monitorados antes do tratamento no 5 o e 7o mês de vida e após o início do tratamento no 9°, 11° e 16° mês de vida. Resultados: os animais tratados com melatonina não apresentaram alterações na duração e frequência de crises. Embora tenhamos observado uma taxa de sobrevida de 87,5% nos animais tratados com melatonina e 40% nos animais tratados com veículo, não observamos diferença estatística. Conclusão: o tratamento com melatonina não foi eficaz no controle da frequência e duração das crises, bem como não alterou a sobrevida dos animais. Contudo, acreditamos que a melatonina tenha forte potencial no aumento da expectativa de vida, porém mais estudos são necessários para uma melhor compreensão da sua ação neuroprotetora, bem como seu papel na expectativa de vida...

Objective: to verify if treatment with melatonin in the chronic period can modify the seizures frequency and survival in Wistar rats submitted to pilocarpine-induced model of epilepsy. Methods: animals were divided in two groups: Epi+MEL (n=8) animals treated with melatonin (10 mg / Kg) in the chronic period; EPI+VEH (n=5) animals treated with vehicle solution in the chronic period. To analyze duration and frequency of seizure, all animals were video-monitored during the 5th and 7th month of life and during the treatments in the 9th, 11th and 16th month of life. Results: the animals treated with melatonin in the chronic phase not presented changes in the duration and frequency of seizures. Although, the animals treated with melatonin have shown a survival rate of 87.5% and the animals treated with vehicle 40%, this finding was not statistically significant. Conclusion: Chronic treatment with melatonin was not effective in the control of frequency and duration of seizures, as well did not modify the survival of the animals. Nevertheless, we believe that melatonin has strong potential to increase life expectancy, however, more studies are needed for a better understanding of its neuroprotective action, as well astheir role in life expectancy...

Effectiveness of melatonin in tardive dyskinesia / Efectividad de la melatonina en la discinesia tardía

Tardive Dyskinesia (TD) is a movement disorder associated with the clinical administration of antipsychotics. It is believed that TD is due, among other factors, to an increase in the oxidative damage produced by free radicals. Antioxidants, like vitamin E, have been used in the treatment of TD but there is no evidence of their effectiveness. Melatonin (MEL) is 6 to 10 times more effective, as an antioxidant, than vitamin E and it has been used with an apparent higher effectiveness in the treatment of TD, although the results have not been conclusive. A randomized, double blind, placebo controlled design was used to determine the effectiveness of MEL (20mg/day) during 12 weeks in 7 patients with TD. Six patients with TD were treated with placebo. The Abnormal Involuntary Movement Scale (AIMS) was chosen to assess the severity of TD initially and after 4, 8 and 12 weeks. The psychiatric evaluation was done following the Brief Psychiatric Rating Scale. In two patients treated with MEL a significant improvement (more than 60%) of the values of AIMS was detected. In the remainder five, as well as in the patients treated with placebo, no difference was observed during the 12 weeks. When compared the AIMS score in all the MEL-treated patients with the values in the placebo-treated patients, no significant differences were detected during the 12 weeks of the study. However, the significant clinical improvement observed in two patients must be considered before reaching a final conclusion on the usefulness of MEL in TD.

La Discinesia Tardía (DT) es un trastorno de los movimientos asociado al uso crónico de antipsicóticos que parece producirse, entre otros factores, por un incremento en los procesos oxidativos. La vitamina E se ha utilizado en su tratamiento, pero no hay evidencia de su efectividad. Como la melatonina (MEL) es 6 a 10 veces más efectiva como antioxidante que la vitamina E, se ha utilizado con una aparente mayor efectividad, aunque los resultados no han sido concluyentes. Se realizó un estudio doble ciego, al azar y controlado con placebo, para determinar la efectividad de la administración de la MEL durante 12 semanas en 7 pacientes con DT. Seis pacientes con DT fueron tratados con placebo. La Escala de Movimientos Involuntarios Anormales (AIMS) se usó para evaluar la evolución de los movimientos al inicio y a las 4, 8 y 12 semanas de tratamiento. La evaluación clínica psiquiátrica se hizo con la Escala Breve de Evaluación Psiquiátrica. En dos pacientes tratados con MEL se observó una mejoría clínica superior al 60% pero en los restantes, así como en los tratados con placebo los valores de la AIMS no variaron significativamente en el transcurso de las 12 semanas. Cuando se compararon los valores de la AIMS de la totalidad de los pacientes tratados con MEL, con los del grupo placebo, no se detectó ninguna diferencia significativa. Sin embargo, la mejoría clínica significativa de dos de los pacientes estudiados debe considerarse para llegar a una conclusión sobre la utilidad de la MEL en la DT.

Normalización de trastornos de sueño y su efecto en pacientes con epilepsia refractaria / Effects of sleep disorders normalization in patients during the use of antiepileptic drugs

Los trastornos del sueño son un problema frecuente y subdiagnosticado en niños con cuadros neurológicos y en particular con epilepsias refractarias. Evaluamos los efectos de normalización rápida de los patrones de sueño sobre la refractariedad de la epilepsia. Pacientes y Método: Se ingresaron al estudio todos los pacientes pediátricos con alteración severa del ciclo sueño-vigilia y epilepsia refractaria en control en el Servicio de Neuropsiquiatría Infantil del Hospital Clínico San Borja-Arriarán y Liga contra la Epilepsia, Santiago, Chile, entre Marzo 2004 y Marzo 2008. Cada paciente fue su propio control. Durante el primer mes se solicitó a los padres completar un registro diario de frecuencia y tipo de crisis epiléptica y del ciclo sueño-vigilia de su hijo (a). A contar del segundo mes se implementó un tratamiento para normalizar el ciclo sueño-vigilia utilizando luminoterapia, hábitos estrictos de sueño y melatonina, 30 min antes de la hora de dormir. La terapia antiepiléptica no se modificó durante los primeros seis meses de tratamiento. Resultados: Los once pacientes ingresados normalizaron el ciclo sueño-vigilia durante el primer mes de tratamiento. Diez de 11 casos mostraron una reducción dramática de la frecuencia de crisis por día, mayor a un 85 por ciento, durante los primeros tres meses de intervención, independientemente del tipo de crisis, que se mantuvo por más de un año de seguimiento (13-43 meses). En cinco pacientes se discontinuó la melatonina después de un año de tratamiento, sin que hubiese deterioro del patrón de sueño o aumento en la frecuencia de crisis. Conclusión: Es frecuente el subdiagnóstico de trastorno de sueño en niños con epilepsias refractarias. La normalización del patrón de ciclo sueño-vigilia puede disminuir dramáticamente la frecuencia de crisis y por lo tanto mejorar la calidad de vida de los pacientes y sus familias...

Sleep disorders are a frequent and underdiagnosed problem in children with neurological problems, specially in children with refractory epilepsies. We evaluated the effects of fast normalization of sleep pattern on epilepsy refractoriness. Patients and methods: We enrolled all pediatric patients from March 2004 to March 2008, with severe alterations of the sleep-wake pattern and refractory epilepsy, attending to the Neuropsychiatry Service, Hospital Clínico San Borja-Arriarán and League against Epilepsy from Santiago, Chile. Each patient was his own control. Parents were asked to complete a diary during the first month after enrollment with frequency, type of seizures and sleep-wake cycle of each patient. After the month, sleep-wake cycle was normalized using morning luminotherapy, strict sleep habits and melatonin, 30 minutes before bedtime. Antiepileptic therapy was not modified during the first six months. Results: All patients normalized the sleep-wake cycle during the first month treatment. Ten of 11 patients showed a dramatic reduction of seizure frequency (over 85 percent of total day seizures) during the first three months of intervention, independently from the seizure type that has maintained for more than a year (13–43 months) follow-up. Melatonin was discontinued in five patients after a year of treatment, with no deterioration of sleep pattern or seizures frequency. Conclusions: Sleep disorders in children with refractory epilepsies are frequently underestimated. The normalization of the sleep-wake pattern can diminish seizures dramatically, improving patients and family quality of life. This point must be always taken into account before considering a patient refractory to antiepileptic drugs and adding new drugs to polytherapy.