Detección del polimorfismo en el gen del receptor de melatonina (MT1) en la oveja criolla Araucana / Detection of MT1 melatonin receptor gene polymorphism (MT1) in the Araucana creole sheep

La melatonina es una hormona que regula los ciclos circadianos y muchos de los aspectos reproductivos de los mamíferos y es secretada por la glándula pineal en las horas de ausencia de luz. Esta hormona posee receptores de alta afinidad acoplados a proteínas de tipo G, denominados MT1. Un polimorfismo de la secuencia que codifica para estos receptores estaría involucrado en el control de la reproducción estacional de los ovinos. El propósito de este estudio busca determinar la presencia del polimorfismo del receptor MT1 en la oveja criolla Araucana, un ovino local en el que se ha registrado un corto anestro reproductivo. Para poder realizar este trabajo se utilizó la técnica denominada reacción en cadena de la polimerasa para polimorfismo en el tamaño de los fragmentos de restricción PCR-RFLP, para lo cual, se obtuvieron muestras de ADN genómico de 50 ovejas Araucanas, las cuales fueron digeridas con la endonucleasa de restricción Mnl1. Se logró identificar la presencia del polimorfismo del receptor MT1 en la oveja Araucana. Los genotipos se hallaron en una frecuencia de 68 por ciento para el genotipo +/+, 28 por ciento para el genotipo +/- y4 por ciento para el genotipo -/-. Este alto porcentaje de animales con genotipo +/+ podría explicar el corto anestro reproductivo que presenta esta raza.

Melatonin is a hormone that regulates circadian rhythms and many of the reproductive aspects of mammals and is secreted by the pineal gland during the hours of absence of light. This hormone has high affinity receptors coupled to G-like proteins, termed MT1. A polymorphism of the sequence coding for these receptors was involved in the control of seasonal reproduction in sheep. The purpose of this study was to determine the presence of MT1 receptor polymorphism in Araucana creole sheep, a local breed with a short reproductive anestrus. To carry out this work, we used a technique called polymerase chain reaction-restriction fragment lengh polymorphism PCR-RFLP, for which samples were obtained from genomic DNA of 50 Araucana sheep, which were digested with Mnl1 restriction endonuclease. It was possible to identify the presence of MT1 receptor polymorphism in Araucana sheep. The genotypes were found in a genotype frequency of 68 percent for genotype + / +, 28 percent for genotype + / - y4 percent for genotype - / -. This high percentage of animals with genotype + / + could explain the short reproductive anestrus featuring this breed.

Novos sedativos hipnóticos / The newer sedative-hypnotics

Nas últimas décadas houve um esforço para o desenvolvimento de hipnóticos mais seguros e eficazes. Zolpidem, zaleplona, zopiclona, eszopiclona (drogas-z) e indiplona são moduladores do receptor GABA-A, os quais agem de forma seletiva na subunidade α1, exibindo, desta forma, mecanismos similares de ação, embora evidências recentes sugiram que a eszopiclona não seja tão seletiva para a subunidade α1 quanto o zolpidem. Ramelteon e tasimelteon são novos agentes crono-hipnóticos seletivos para os receptores de melatonina MT1 e MT2. Por outro lado, nos últimos anos, o consumo de drogas antidepressivas sedativas tem aumentado significativamente no tratamento da insônia. Como droga experimental, a eplivanserina tem sido testada como um potente agonista inverso do subtipo 5-HT2A da serotonina, com um uso potencial na dificuldade da manutenção do sono. Outro agente farmacológico para o tratamento da insônia é o almorexant, o qual apresenta um novo mecanismo de ação envolvendo antagonismo do sistema hipocretinérgico, desta forma levando à indução do sono. Finalmente, também discutiremos o potencial papel de outras drogas gabaérgicas no tratamento da insônia.

There has been a search for more effective and safe hypnotic drugs in the last decades. Zolpidem, zaleplon, zopiclone, eszopiclone (the z-drugs) and indiplon are GABA-A modulators which bind selectively α1 subunits, thus, exhibiting similar mechanisms of action, although recent evidence suggests that eszopiclone is not as selective for α1 subunit as zolpidem is. Ramelteon and tasimelteon are new chrono-hypnotic agents, selective for melatonin MT1 and MT2 receptors. On the other hand, the consumption of sedative antidepressant drugs is significantly increasing for the treatment of insomnia, in the last years. As an experimental drug, eplivanserin is being tested as a potent antagonist of serotonin 2-A receptors (ASTAR) with a potential use in sleep maintenance difficulty. Another recent pharmacological agent for insomnia is almorexant, which new mechanism of action involves antagonism of hypocretinergic system, thus inducing sleep. Finally we also discuss the potential role of other gabaergic drugs for insomnia.

La melatonina reduce la respuesta de cortisol al ACTH en humanos / Melatonin reduces cortisol response to ACTH in humans

Background: Melatonin receptors are widely distributed in human tissues but they have not been reported in human adrenal gland. Aim: To assess if the human adrenal gland expresses melatonin receptors and if melatonin affeets cortisol response to ACTH in dexamethasone suppressed volunteers. Material and methods: Adrenal glands were obtained from 4 patients undergoing unilateral nephrectomy-adrenalectomy for renal cáncer. Expression of mRNA MT1 and MT2 melatonin receptors was measured by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR). The effect of melatonin on the response to intravenous (i.v.) ACTH was tested (randomized cross-over, double-blind, placebo-controlled tríal) in eight young healthy males pretreated with dexamethasone (1 mg) at 23:00 h. On the next day at 08:00 h, an i.v. Une was inserted, at 08:30 h, and after a blood sample, subjeets ingested 6 mg melatonin or placebo. At 09:00 h, 1-24 ACTH (Cortrosyn, 1µg/1.73 m² body surface área) was injected, drawing samples at 0, 15, 30, 45 and 60 minutes after. Melatonin, cortisol, cortisone, progesterone, aldosterone, DHEA-S, testosterone and prolactin were measured by immunoassay. Results: The four adrenal glands expressed only MT1 receptor mRNA. Melatonin ingestión reduced the cortisol response to ACTH from 14.6+1.45µg/dl at 60 min in the placebo group to 10.8+1.2µg/dl in the melatonin group (p <0.01 mixed model test). It did not affect other steroid hormone levels and abolished the morningphysiological decline of prolactin. Conclusions: The expression ofMTl melatonin receptor in the human adrenal, and the melatonin reduction of ACTH-stimulated cortisol production suggest a direct melatonin action on the adrenal gland .

Effect of genetic polymorphism of MTNR1A gene on adolescent idiopathic scoliosis / 中华外科杂志

<p><b>OBJECTIVE</b>To investigate whether the MTNR1A gene promotor polymorphism (rs2119882) are associated with the occurrence or curve severity of adolescent idiopathic scoliosis (AIS).</p><p><b>METHODS</b>226 AIS patients and 277 normal controls were recruited. The maximum Cobb angles were recorded in AIS patients. PCR-RFLP was used for the genotyping.</p><p><b>RESULTS</b>The genotype and allele frequency distribution were comparable between AIS and normal control, the mean maximum Cobb angle of different genotypes of rs2119882 were similar with each other among AIS patients.</p><p><b>CONCLUSION</b>The MTNR1A gene promoter polymorphism was neither associated with the occurrence nor the curve severity of AIS.</p>