Cadmium-Induced Disruption in 24-h Expression of Clock and Redox Enzyme Genes in Rat Medial Basal Hypothalamus: Prevention by Melatonin

In a previous study we reported that a low daily p.o. dose of cadmium (Cd) disrupted the circadian expression of clock and redox enzyme genes in rat medial basal hypothalamus (MBH). To assess whether melatonin could counteract Cd activity, male Wistar rats (45 days of age) received CdCl2 (5 ppm) and melatonin (3 μg/mL) or vehicle (0.015% ethanol) in drinking water. Groups of animals receiving melatonin or vehicle alone were also included. After 1 month, MBH mRNA levels were measured by real-time PCR analysis at six time intervals in a 24-h cycle. In control MBH Bmal1 expression peaked at early scotophase, Per1 expression at late afternoon, and Per2 and Cry2 expression at mid-scotophase, whereas neither Clock nor Cry1 expression showed significant 24-h variations. This pattern was significantly disrupted (Clock, Bmal1) or changed in phase (Per1, Per2, Cry2) by CdCl2 while melatonin counteracted the changes brought about by Cd on Per1 expression only. In animals receiving melatonin alone the 24-h pattern of MBH Per2 and Cry2 expression was disrupted. CdCl2 disrupted the 24-h rhythmicity of Cu/Zn- and Mn-superoxide dismutase (SOD), nitric oxide synthase (NOS)-1, NOS-2, heme oxygenase (HO)-1, and HO-2 gene expression, most of the effects being counteracted by melatonin. In particular, the co-administration of melatonin and CdCl2 increased Cu/Zn-SOD gene expression and decreased that of glutathione peroxidase (GPx), glutathione reductase (GSR), and HO-2. In animals receiving melatonin alone, significant increases in mean Cu/Zn and Mn-SOD gene expression, and decreases in that of GPx, GSR, NOS-1, NOS-2, HO-1, and HO-2, were found. The results indicate that the interfering effect of melatonin on the activity of a low dose of CdCl2 on MBH clock and redox enzyme genes is mainly exerted at the level of redox enzyme gene expression

Effects of bisphenol A administration during critical stages of sexual development

El bisfenol A (BPA) es un compuesto estrogénico utilizado en la fabricación de plásticos policarbonatos, que tiene efectos deletéreos sobre el eje reproductor de los individuos expuestos y el de su descendencia. El BPA actuaría sobre el eje hipotálamo-hipófiso-gonadal de ratas hembra modificando sus procesos de maduración. El objetivo del presente trabajo fue estudiar el efecto del BPA sobre la maduración del eje reproductor de ratas hembra peripúberes expuestas a este compuesto desde el inicio de la gestación y durante la lactancia (Grupo 1, 2,5 mg/kg/día)) y otro grupo (Grupo 2, 6,0 mg/kg/día) expuesto desde los 21 días y hasta los 30 días de edad. Se administró BPA en el agua de bebida o etanol al 0,1% (grupo control), (n=10/grupo). Se determinó LH, FSH (RIA, ng/ml), estradiol (ELISA, pg/ml), se evaluaron peso corporal y pesos relativos de útero y ovario. Se realizó estudio histológico de cortes de ovario y útero. Grupo 1, los niveles de LH y estradiol aumentaron significativamente (Control: 11 ± 1,0 vs. BPA: 40 ± 4,0, p<0,001; Control: 20 ± 0,5 vs. BPA: 40 ± 2,0, p<0,0001), mientras los de FSH mostraron tendencia al aumento pero éste no fue significativo. Los pesos corporales y el peso relativo del ovario no se modificaron con el tratamiento. El estudio histológico mostró mayor número de folículos maduros y desarrollo de células de la teca y epitelio cilíndrico en útero de los animales tratados. Grupo 2, LH y estradiol aumentaron significativamente (Control: 3,3 ± 0,3 vs. BPA: 5,1 ± 0,3, p<0,01; Control: 25,0 ± 0,5 vs. BPA: 27,1 ± 0,7, p<0,05). La FSH, si bien mostró tendencia a aumentar, ésta no fue significativa. Los pesos corporales y los pesos relativos de ovario y útero no se modificaron con este tratamiento. En la histología se observa mayor desarrollo de la teca interna y un mayor número de folículos maduros en los animales tratados. No se encontraron diferencias evidentes en el alto del epitelio uterino. La exposición aguda o crónica a BPA en etapas clave de la maduración sexual modifica la actividad del eje reproductor. Los resultados obtenidos sugieren que el BPA ejercería su efecto estrogénico, actuando sobre los mecanismos de retroalimentación positivos.Bisphenol A (BPA) is an estrogenic compound used in the manufacture of polycarbonate plastic. It has deleterious effects on the reproductive axis in human and wildlife, both in individuals exposed to it and their descendants. Evidence suggests that BPA exerts its influence on the hypothalamic-pituitary-gonadal axis of female rats by interfering with its maturation process. The aim of the present study was to analyse the effect of BPA on maturation of the hypothalamo-pituitary-gonadal axis of peripuberal female rats, exposed to it since the beginning of the gestation and during the lactation period (Group 1, 2.5 mg/kg/day), and from the age of 21 days till the age of 30 (Group 2, 6.0 mg/kg/day). The animals were treated with BPA or 0.1% ethanol (Control Group) in their drinking water (n=10/grupo). LH, FSH (RIA, ng/ml) and estradiol (ELISA, pg/ml) were measured in serum. Ovaries and uterus relative weights were obtained. Histological studies were performed on several sections of uterus and ovaries. Group 1, LH and estradiol serum levels increased significantly (Control: 11 ± 1.0 vs. BPA: 40 ± 4.0, p<0.001; Control: 20 ± 0.5 vs BPA: 40 ± 2.0, p<0.0001). FSH levels showed an increasing trend as well, but this was not statistically significant. Corporal weights and ovaries relative weights were not modified by treatment. Histological studies showed an increase in the total number of mature follicles, and development of the theca cells and ovarian stroma, in animals exposed to BPA. Group 2, LH and estradiol serum levels increased significantly (Control: 3.3 ± 0.3 vs. BPA: 5.1 ± 0.3, p<0.01; Control: 25.0 ± 0.5 vs. BPA: 27.1 ± 0.7, p<0.05). Although FSH levels exhibited an increasing trend, this did not reach statistical significance. Corporal weights and ovaries and uterus relative weights were not modified by treatment. Histological studies revealed major development of the internal theca, and an increase in the number of mature follicles, in those animals under treatment. No significant differences were found in the height of the epithelium of the uterus. Acute or chronic exposure to BPA during critical stages of sexual development modifies the activity of the reproductive axis. The results obtained suggest that BPA may exert its estrogenic effect, acting on the positive feedback mechanism.Fil: Cardoso, Nancy Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; ArgentinaFil: Pandolfi, Matias. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Biodiversidad y Biología Experimental. Laboratorio de Embriología Animal; ArgentinaFil: Ponzo, Osvaldo. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; ArgentinaFil: Carbone, Silvia Elena. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Peñalba, Romina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; ArgentinaFil: Dicugno. Mariana. Universidad de Buenos Aires. Facultad de Medicina. Sede Hospital Britanico Bs.as; ArgentinaFil: Scacchi, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Reynoso, Roxana. Hospital Británico; Argentin

Different effects by sex on hypothalamic-pituitary axis of prepubertal offspring rats produced by in utero and lactational exposure to di-(2-ethylhexyl) phthalate (DEHP)

This study investigated the effect of pre and perinatal exposure to di-(2-ethylhexyl) phthalate (DEHP) on the neuroendocrine parameters that regulate reproduction in prepubertal male and female rats. DEHP at doses of 3 and 30 mg/kg. bw/day was administered orally in the drinking water to dam rats since pregnancy onset until the moment of pups sacrifice at 15 days of age. In these animals gonadotropin serum level and the hypothalamic contents of the amino acids aspartate, glutamate and gamma-aminobutyric acid were determined. No changes in gonadotropin levels and amino acid neurotransmitters were detected at the low dose in both sexes. However, DEHP administered at high dose (30 mg/kg bw/day) to dams produced a significant decrease in the inhibitory neurotransmitter GABA and an increase in the stimulatory neurotransmitter aspartate in prepubertal male offspring rats. These modifications were accompanied by gonadotropin serum levels increase. On the contrary, in treated female rats this chemical increased both, aspartate and GABA, which exert a characteristic stimulatory action on gonadotropin in 15-day-old normal females. This study provides new data about changes produced by DEHP on the hypothalamic amino acid neurotransmitters involved in the neuroendocrine reproductive regulation, in prepubertal male and female rat offspring from dams exposed during gestational and lactational periods. These alterations induced by DEHP exposure could be related to the gonadotropin modifications also described in this work, and with changes in the production of sexual hormones previously reported by other authors.Fil: Carbone, Silvia Elena. Universidad Favaloro; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Samaniego, Yanina A.. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Cutrera, Rodolfo Angel. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Reynoso, R.. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Cardoso, N.. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Scacchi, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires"; ArgentinaFil: Moguilevsky, Jaime Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Favaloro; ArgentinaFil: Ponzo, Osvaldo Juan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentin

Erosión en estribos de puentes aliviadores

[ES] En este trabajo se vuelcan parte de los esfuerzos realizados por investigadores de la Facultad de Ingeniería y Ciencias Hídricas de la Universidad Nacional del Litoral y del Laboratorio de Hidráulica del Instituto Nacional del Agua para estudiar la erosión junto a estribos de puentes aliviadores durante la última década en Argentina. Por una parte, estudios experimentales demostraron que las erosiones locales en estribos de puentes aliviadores, cuando estos son de paredes verticales, dependen tanto de las condiciones iniciales del escurrimiento junto a él, como del proceso de redistribución de caudales que se produce durante su desarrollo. Este último fenómeno pudo ser adecuadamente evaluado mediante la incorporación del ancho del puente como variable fundamental en el análisis, la que caracteriza al proceso en su conjunto como un típico fenómeno en planta Por otro lado, se describieron los procesos de erosión local por efecto de los vórtices de eje horizontal y vertical y de erosión por contracción, en estribos no verticales, de uso frecuente en puentes aliviadores. Mediante estudios en modelos físicos, se analizaron cómo es el flujo líquido y se describe la configuración del lecho tras el pasaje de crecidas, indicando la importancia relativa de los diferentes procesos erosivos.Scacchi, G.; Spalletti, P.; Brea, JD.; Schreider, M.; Fuentes Aguilar, R. (2005). Erosión en estribos de puentes aliviadores. Ingeniería del agua. 12(3):1-16. https://doi.org/10.4995/ia.2005.2565OJS116123BATEMAN, A.; BERTRAM, A.; ROCA, M. (2002). "Estudio Experimental de la Erosión Local en Estribos de Puente". XX Congreso Latinoamericano de Hidráulica - La Habana. Cuba.ETTEMA, R.; NAKATO, T.; MUSTE, M. (2003). "An Overview of Scour Types and Scour-Estimation Difficulties Faced al bridge Abutments". Proceedings of the 2003 Mid-Continent Transportation Research Symposium. Iowa. United States.FEDERAL HIGHWAY ADMINISTRATION (2001). "Evaluating Scour at Bridges". Hydraulic Engineering Circular Nº 18.HOFFMANS, G. J. C. M. AND VERHEIJ, H. J. (1997). "Scour Manual". Editorial Balkema.KANDASAMY, J. K. (1989) "Abutments scour." Report Nº 458, School of Engineering, The University of Auckland, Auckland, New Zealand, 278 p. s, Inc., New York, U.S.A.KOTHYARI, U.C.; RANGA RAJU K.G. (2001). "Scour Around Spur Dikes and Bridge Abutments". Journal of Hydraulic Research, Vol. 39, No. 4.KWAN, T. F. (1988) "A study of abutment scour." Report Nº 451, School of Engineering. The University of Auckland, Auckland, New Zealand, 461 p.LIM, S.Y. (1997). "Equilibrium Clear-Water Scour Around an Abutment". Journal of Hydraulic Engineering, March 1997.LOSCHACOFF, C.S.; BUSQUETS, M.; BREA, J.D. (2001). "Estudio en Modelo Físico del Comportamiento de Diferentes Tipos de Protecciones de Márgenes frente a la Acción de las Corrientes". Informe LHA-INA 208-01-2001.MELVILLE, B.W. (1992). "Local Scour at Bridge Abutments" Paper and Discussion. Journal of Hydraulic Engineering, April 1992.MELVILLE, B.W. (1995). "Bridge Abutments Scour in Compound Channels." Journal of Hydraulic Engineering, A.S.C.E., 121 (12). pp. 863 - 868.MELVILLE, B.W. Y COLEMAN, S.E. (2000) "Bridge Scour." Water Resources Publications, LLC.RICHARDSON E.V. (2002). "United States Practice for Bridge Scour Analysis".SCACCHI, G.; MARTÍN VIDE, J.P. Y SCHREIDER, M. (2002) "Flow depth effect on the discharge distribution at bridge sites." Proceedings of the International Conference on Fluvial hydraulics, River Flow 2002. Vol. 2, pp. 1047 - 1052.SCHREIDER, M.; ZANARDI, L.; SCACCHI, G.; FRANCO, F. (1998) "Erosión por contracción y por estribo en puentes aliviadores en valle de inundación." Revista Ingeniería del agua. Vol. 5. Nº 2. Madrid, España, pp. 23 - 34SCHREIDER, M.; SCACCHI, G.; FRANCO, F. Y ROMANO, C. (2000) "Incidencia del ancho del puente en la interacción entre la erosión por contracción y por estribo." Anales del XIX Congreso Latinoamericano de Hidráulica. Vol. I. Córdoba, Argentina, pp. 359 - 368.SPALLETTI, P.; BREA, J.D. (1998). "Estudio en Modelo Físico de los Estribos de los Puentes de la Conexión Física Rosario-Victoria - Etapa de Calibración y Ensayos a Fondo Móvil". Informes LHA-INA 171-01-98 y 171-02-98.STURM, T.W.; JANJUA, N.S. (1994). "Clear-Water Scour Around Abutments in Floodplains". Journal of Hydraulic Engineering, August 1994

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Síndrome metabólico y melatonina : estudio de dos modelos experimentales en ratas

Resumen: El presente Trabajo de Tesis persiguió analizar y comparar algunas de las secuelas del síndrome metabólico (SM) en dos modelos experimentales en ratas, la ingesta de una dieta hipergrasa y la administración de fructosa en el agua de bebida. La comparación de distintos parámetros del SM en ambos modelos experimentales indicó que comparten secuelas somáticas y bioquímicas relevantes como el aumento de peso corporal y de la PA sistólica, la intolerancia a una sobrecarga de glucosa indicativa de una anormalmente alta resistencia a la insulina y cambios en analitos usados en clínica para el diagnóstico de SM tales como la hipertrigliceridemia, hipercolesterolemia, hiperuricemia y el aumento en colesterol-LDL. Pudo verificarse que tanto en el SM por ingesta de una dieta rica en grasa como en el producido por la administración de fructosa se detecta una inhibición del eje hipófiso-gonadal de origen testicular, indicado por la inhibición de la secreción de testosterona en presencia de niveles anormalmente elevados de LH circulante. Se analizó también la evolución del SM mediante el estudio de las etapas incipiente y establecida del SM por administración de fructosa, verificándose que existe una etapa inicial de mayor tolerancia a una sobrecarga de glucosa (indicativa de menor resistencia a la insulina), que coexiste con un aumento de PA sistólica y un desarrollo parcial de secuelas dislipémicas (hipercolesterolemia).En el SM por dieta rica en grasas se producen alteraciones en los ritmos diarios de adiponectina, leptina, insulina, glucosa, triglicéridos y colesterol plasmáticos, compatibles con un relevante efecto de la dieta en la sincronización del sistema circadiano. En vista de que la melatonina combina propiedades cronobióticas y citoprotectoras que pueden ser de relevancia en la prevención y el tratamiento del SM estudiamos distintos aspectos de la actividad de la melatonina en los dos modelos experimentales citados. La administración concomitante de melatonina en el agua de bebida fue eficaz para revertir los aumentos de peso y de PA sistólica, la anormal resistencia a la insulina, la dislipemia y la hiperuricemia que se producen tanto en el SM por ingesta de una dieta rica en grasa como en el producido por la administración de fructosa. Este efecto correctivo de la melatonina es ya evidente en la etapa inicial de sensibilidad aumentada a la insulina que se observa en el SM incipiente por administración de 5% de fructosa. La melatonina no corrigió la inhibición del eje hipófiso-gonadal de origen testicular en el SM y mostró una actividad inhibitoria de la síntesis de testosterona cuando se administró a ratas con dieta normal. La melatonina fue eficaz para normalizar las alteraciones en los ritmos diarios de adipocitoquinas y señales metabólicas circulantes que se observan en el SM. En conclusión, debido a sus efectos sobre el sistema circadiano y a sus potentes propiedades citoprotectoras la melatonina puede ser de utilidad terapéutica en el SM.Abstract: The objective of this Doctoral Thesis work was to analyze and to compare some of the consequences of metabolic syndrome (MS) in two experimental models, i.e. rats eating a high fat diet and rats drinking a high fructose solution. The comparison of various parameters of the MS in both experimental models indicated that they share relevant biochemical sequelae such as increased body weight and abnormally high systolic blood pressure, impaired glucose overload (indicative of an abnormally high insulin resistance) and changes in analytes used clinically for the diagnosis of MS like hypertriglyceridemia, hypercholesterolemia, hyperuricemia and increased cholesterol-LDL. In both types of MS an inhibition of the pituitary-gonadal at the testicular was detectable, as indicated by the inhibition of the secretion of testosterone in the presence of abnormally high circulating LH. We also analyzed the development of MS by studying the early stage and the established stage of MS brought about by fructose administration, verifying that initially there is a higher tolerance to a glucose load (indicative of lower insulin resistance), which coexists with a increased systolic and partial development of dislipemic sequelae (hypercholesterolemia). In the established SM following a high fat diet, alterations of daily rhythms of circulating adiponectin, leptin, insulin, glucose, triglycerides and cholesterol levels were found, consistent with a significant effect of diet on the circadian timing system. In view that melatonin combines chronobiotic and cytoprotective properties which may be relevant in the prevention and treatment of MS, the activity of melatonin in the two experimental models above cited was examined. The concomitant administration of melatonin in the drinking water was effective in reversing the increase in weight and systolic BP, abnormal insulin resistance, dyslipidemia and hyperuricemia occurring both in MS. The corrective effect of melatonin was already evident at the initial stage of increased insulin sensitivity after the administration of 5% fructose. Melatonin did not correct the inhibition of the pituitary-gonadal axis in MS; rather it showed an inhibitory activity per se on testosterone synthesis in rats fed with a normal diet. Melatonin was effective to normalize the disrupted daily rhythms of circulating adipocytokines and metabolic signals found in MS. In conclusion, the results demonstrate that due to its effects on the circadian system and its potent cytoprotective properties, melatonin could be therapeutically useful in the MS

Melatonin and diet-induced metabolic syndrome in rats. Impact on the hypophysial-testicular axis

Abstract: Combinations of fructose- and fat-rich diets in experimental animals can model the human metabolic syndrome (MS). In rats the increase in blood pressure (BP) after diet manipulation is sex-related and highly dependent on testosterone secretion. However, the extent of diet impact on rodent hypophysial-testicular axis remains undefined. In the present study rats drinking a 10% fructose solution or fed a high fat (35%) diet for 10 weeks had higher plasma levels of luteinizing hormone (LH) and lower plasma levels of testosterone, with absence of significant changes in circulating follicle-stimulating hormone (FSH) or in weight of most reproductive organs. Diet manipulation brought about a significant increase in body weight, systolic BP, area under the curve (AUC) of glycemia after an i.p. glucose tolerance test (IPGTT) and plasma lowdensity lipoprotein-cholesterol, cholesterol, triglycerides and uric acid levels. The concomitant administration of melatonin (25 μg/mL of drinking water) normalized the abnormally high LH levels but did not affect the inhibited testosterone secretion found in fructose- or high fat-fed rats. Rather melatonin per se inhibited testosterone secretion. Melatonin significantly blunted the body weight and systolic BP increase, the increase in the AUC of glycemia after an IPGTT and the changes in circulating lipid profile and uric acid found in both MS models. The results are compatible with a primary inhibition of testicular function in the diet-induced MS in rats and with the partial effectiveness of melatonin to counteract the metabolic but not the testicular sequels of rodent M

Melatonin and mitochondrial dysfunction in the central nervous system

Abstract: Cell death and survival are critical events for neurodegeneration, mitochondria being increasingly seen as important determinants of both. Mitochondrial dysfunction is considered a major causative factor in Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). Increased free radical generation, enhanced mitochondrial inducible nitric oxide (NO) synthase activity and NO production, and disrupted electron transport system and mitochondrial permeability transition, have all been involved in impaired mitochondrial function. Melatonin, the major secretory product of the pineal gland, is an antioxidant and an effective protector of mitochondrial bioenergetic function. Both in vitro and in vivo, melatonin was effective to prevent oxidative stress/nitrosative stress-induced mitochondrial dysfunction seen in experimental models of AD, PD and HD. These effects are seen at doses 2-3 orders of magnitude higher than those required to affect sleep and circadian rhythms, both conspicuous targets of melatonin action. Melatonin is selectively taken up by mitochondria, a function not shared by other antioxidants. A limited number of clinical studies indicate that melatonin can improve sleep and circadian rhythm disruption in PD and AD patients. More recently, attention has been focused on the development of potent melatonin analogs with prolonged effects which were employed in clinical trials in sleep-disturbed or depressed patients in doses considerably higher than those employed for melatonin. In view that the relative potencies of the analogs are higher than that of the natural compound, clinical trials employing melatonin in the range of 50-100 mg/day are needed to assess its therapeutic validity in neurodegenerative disorders

Disrupted chronobiology of sleep and cytoprotection in obesity : possible therapeutic value of melatonin

Abstract: From a physiological perspective the sleep-wake cycle can be envisioned as a sequence of three physiological states (wakefulness, non-rapid eye movement, NREM, sleep and REM sleep) which are defined by a particular neuroendocrine-immune profile regulating the metabolic balance, body weight and inflammatory responses. Sleep deprivation and circadian disruption in contemporary “24/7 Society” lead to the predominance of pro-orexic and proinflammatory mechanisms that contribute to a pandemic metabolic syndrome (MS) including obesity, diabetes and atherosclerotic disease. Thus, a successful management of MS may require a drug that besides antagonizing the trigger factors of MS could also correct a disturbed sleep-wake rhythm. This review deals with the analysis of the therapeutic validity of melatonin in MS. Melatonin is an effective chronobiotic agent changing the phase and amplitude of the sleep/wake rhythm and having cytoprotective and immunomodulatory properties useful to prevent a number of MS sequels. Several studies support that melatonin can prevent hyperadiposity in animal models of obesity. Melatonin at a low dose (2‐5 mg/day) has been used for improving sleep in patients with insomnia and circadian rhythm sleep disorders. More recently, attention has been focused on the development of potent melatonin analogs with prolonged effects (ramelteon, agomelatine, tasimelteon, TK 301). In clinical trials these analogs were employed in doses considerably higher than those usually employed for melatonin. In view that the relative potencies of the analogs are higher than that of the natural compound, clinical trials employing melatonin doses in the range of 50-100 mg/day are needed to assess its therapeutic value in MS

Melatonin may curtail the metabolic syndrome: studies on initial and fully established fructose-induced metabolic syndrome in rats

Abstract: To examine the effect of melatonin given to rats simultaneously with fructose on initial and fully developed metabolic syndrome, male Wistar rats had free access to chow and 5% or 10% fructose drinking solution for 8 weeks. As compared to controls, systolic blood pressure augmented significantly under both treatments whereas excessive body weight was seen in rats receiving the 10% fructose only. Rats drinking 5% fructose showed a greater tolerance to a glucose load while rats having access to a 10% fructose drinking solution exhibited the expected impaired glucose tolerance found in the metabolic syndrome. Circulating triglyceride and low density lipoproteins-cholesterol (LDL-c) concentration augmented significantly in rats showing a fully developed metabolic syndrome only, while high blood cholesterol levels were found at both stages examined. Melatonin (25 μg/mL drinking solution) counteracted the changes in body weight and systolic blood pressure found in rats administered with fructose. Melatonin decreased the abnormal hyperglycemia seen after a glucose load in 10% fructose-treated rats but it did not modify the greater tolerance to glucose observed in animals drinking 5% fructose. Melatonin also counteracted the changes in plasma LDL-c, triglyceride and cholesterol levels and decreased plasma uric acid levels. The results underline a possible therapeutical role of melatonin in the metabolic syndrome, both at initial and established phase