Histone Methylation/Demethylation Inhibition Modulates Sleep

Histone methylation/demethylation plays an important modulatory role in chromatin restructuring, RNA transcription and is essential for controlling a plethora of biological processes. Due to many human diseases have been related to histone methylation/demethylation, several compounds such as 3-deazaneplanocin A (DZNep) or 3-((6-(4,5-Dihydro-1H-benzo[d]azepin-3(2H)-yl)-2-(pyridin-2-yl)pyrimidin-4-yl)amino)propanoic acid; N-[2-(2-pyridinyl)-6-(1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-4-pyrimidinyl]-b-Alanine (GSK-J1), have been designed to inhibit histone methylase or suppress histone demethylase, respectively. In the present study, we investigated the effects on the sleep-wake cycle and sleep-related neurochemical levels after systemic injections of DZNep or GSK-J1 given during the light or dark phase in rats. DZNep dose-dependently (0.1, 1.0, or 10 mg/kg, i.p.) prolonged wakefulness (W) duration while decreased slow wave sleep (SWS) and rapid eye movement sleep (REMS) time spent during the lights-on period with no changes observed in dark phase. In opposite direction, GSK-J1 (0.1, 1.0, or 10 mg/kg, i.p.) injected at the beginning of the lights-on period induced no statistical changes in W, SWS, or REMS whereas if administered at darkness, we found a diminution in W and an enhancement in SWS and REMS. Finally, brain microdialysis experiments in freely moving animals were used to evaluate the effects of DZNep or GSK-J1 treatments on contents of sleep-related neurochemicals. The results showed that DZNep boosted extracellular levels of dopamine, norepinephrine, epinephrine, serotonin, adenosine, and acetylcholine if injected at the beginning of the lights-on period whereas GSK-J1 exerted similar outcomes but when administered at darkness. In summary, DZNep and GSK-J1 may control the sleep-wake cycle and sleep-related neurochemicals through histone methylation/demethylation activity

Relación entre la sobrecarga y el índice depresivo de cuidadores primarios de pacientes con enfermedades neuromusculoesqueléticas

Resumen Introducción: Una enfermedad neuromusculoesquelética no solo afecta a la persona que la padece, sino que también repercute de manera directa en la familia y en particular al cuidador primario informal. Las labores de cuidado incrementan la morbilidad psicológica y el estrés de los cuidadores primarios. El objetivo del presente estudio consistió en identificar la relación entre la sobrecarga y el índice de depresión presente en los cuidadores primarios informales de pacientes con enfermedad neuromusculoesquelética. Material y Métodos: Se realizó un estudio exploratorio que incluyó a 18 cuidadores primarios informales de pacientes con enfermedad neuromusculoesquelética, y que asistieron a consulta en la Unidad Universitaria de Rehabilitación de la Universidad Autónoma de Yucatán. Resultados: Entre las características sociodemográficas predominaron las cuidadoras del sexo femenino (83%) con parentesco familiar con el paciente. Además, predomino entre los cuidadores primarios el estado civil casado y un nivel de estudios de licenciatura. La relación entre la sobrecarga y el índice de depresión fue elevada y significativa (r=0.72, p=0.0007). En conclusión, estos resultados sugieren que, a mayor sobrecarga producida por las labores del cuidado, mayor será el grado de afectación en el estado anímico del cuidador primario informal.  Este estudio ayudará en la elaboración de un programa de intervención para prevenir la sobrecarga en cuidadoras primarias informales. Titulo corto: Relación sobrecarga y depresión Palabras clave: Enfermedad neuromusculoesquelética, sobrecarga, depresión, cuidador primario informal

Role of N-Arachidonoyl-Serotonin (AA-5-HT) in Sleep-Wake Cycle Architecture, Sleep Homeostasis, and Neurotransmitters Regulation

The endocannabinoid system comprises several molecular entities such as endogenous ligands [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)], receptors (CB1 and CB2), enzymes such as [fatty acid amide hydrolase (FAHH) and monoacylglycerol lipase (MAGL)], as well as the anandamide membrane transporter. Although the role of this complex neurobiological system in the sleep–wake cycle modulation has been studied, the contribution of the blocker of FAAH/transient receptor potential cation channel subfamily V member 1 (TRPV1), N-arachidonoyl-serotonin (AA-5-HT) in sleep has not been investigated. Thus, in the present study, varying doses of AA-5-HT (5, 10, or 20 mg/Kg, i.p.) injected at the beginning of the lights-on period of rats, caused no statistical changes in sleep patterns. However, similar pharmacological treatment given to animals at the beginning of the dark period decreased wakefulness (W) and increased slow wave sleep (SWS) as well as rapid eye movement sleep (REMS). Power spectra analysis of states of vigilance showed that injection of AA-5-HT during the lights-off period diminished alpha spectrum across alertness in a dose-dependent fashion. In opposition, delta power spectra was enhanced as well as theta spectrum, during SWS and REMS, respectively. Moreover, the highest dose of AA-5-HT decreased wake-related contents of neurotransmitters such as dopamine (DA), norepinephrine (NE), epinephrine (EP), serotonin (5-HT) whereas the levels of adenosine (AD) were enhanced. In addition, the sleep-inducing properties of AA-5-HT were confirmed since this compound blocked the increase in W caused by stimulants such as cannabidiol (CBD) or modafinil (MOD) during the lights-on period. Additionally, administration of AA-5-HT also prevented the enhancement in contents of DA, NE, EP, 5-HT and AD after CBD of MOD injection. Lastly, the role of AA-5-HT in sleep homeostasis was tested in animals that received either CBD or MOD after total sleep deprivation (TSD). The injection of CBD or MOD increased alertness during sleep rebound period after TSD. However, AA-5-HT blocked this effect by allowing animals to display an enhancement in sleep across sleep rebound period. Overall, our findings provide evidence that AA-5-HT is an important modulator of sleep, sleep homeostasis and neurotransmitter contents

Sleep and Neurochemical Modulation by DZNep and GSK-J1: Potential Link With Histone Methylation Status

Histone methylation/demethylation plays an important modulatory role in chromatin restructuring, RNA transcription and is essential for controlling a plethora of biological processes. Due to many human diseases have been related to histone methylation/demethylation, several compounds such as 3-deazaneplanocin A (DZNep) or 3-((6-(4,5-Dihydro-1H-benzo[d]azepin-3(2H)-yl)-2-(pyridin-2-yl)pyrimidin-4-yl)amino)propanoic acid; N-[2-(2-pyridinyl)-6-(1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-4-pyrimidinyl]-β-Alanine (GSK-J1), have been designed to inhibit histone methylase or suppress histone demethylase, respectively. In the present study, we investigated the effects on the sleep-wake cycle and sleep-related neurochemical levels after systemic injections of DZNep or GSK-J1 given during the light or dark phase in rats. DZNep dose-dependently (0.1, 1.0, or 10 mg/kg, i.p.) prolonged wakefulness (W) duration while decreased slow wave sleep (SWS) and rapid eye movement sleep (REMS) time spent during the lights-on period with no changes observed in dark phase. In opposite direction, GSK-J1 (0.1, 1.0, or 10 mg/kg, i.p.) injected at the beginning of the lights-on period induced no statistical changes in W, SWS, or REMS whereas if administered at darkness, we found a diminution in W and an enhancement in SWS and REMS. Finally, brain microdialysis experiments in freely moving animals were used to evaluate the effects of DZNep or GSK-J1 treatments on contents of sleep-related neurochemicals. The results showed that DZNep boosted extracellular levels of dopamine, norepinephrine, epinephrine, serotonin, adenosine, and acetylcholine if injected at the beginning of the lights-on period whereas GSK-J1 exerted similar outcomes but when administered at darkness. In summary, DZNep and GSK-J1 may control the sleep-wake cycle and sleep-related neurochemicals through histone methylation/demethylation activity

Violencia intrafamiliar como factor de riesgo para trastorno depresivo mayor en mujeres: Estudio de casos y controles

Introduction. Depression is the most frequent cause of disability worldwide. Domestic violence is also a remarkable public health problem, and could be an important risk factor for depression. Objective. To determine whether domestic violence is a risk factor for major depression in women living in southeast México. Materials and methods. A control-case study was designed. The cases were patients attending the Psychiatric consultancy of Hospital General Regional “Ignacio García Téllez” and met the DSMIV criteria for major depression according to the DSM-IV. Controls were women seeking for other medical care that did not meet the DSM-IV criteria for major depression. The National Interview for Dynamics of Relationships in Dwellings (ENDIREH was used to evaluate domestic violence. Data was analysed by Chi2 test as univariate analysis, those variables showing statistical association were included into a logistic regression model. Results. A total of 270 cases and 540 controls were included in the study from whom the age was 41.2 ±12.1 and 40.8±12.1 years old (p=0.62), respectively. Domestic violence was detected in 129 cases (47.8%) and 113 controls (20.9%), and this was associated to major depression (OR= 3.4; CI 95% 2.5-4.7). Other factors identified as associated with major depression were, being married (RM=1.6; IC 95% 1.2-2.2) (p < 0.001); low socioeconomic status (RM=1.5; IC 95% 1.0-2.4) (p< 0.03) and minimal social aid support (RM=1.9; IC 95% 1.40-2.72) (p<0.001) also. Conclusions. Domestic violence is associated to major depression in women, this remarks the need to implement measures for its eradication.Introducción. La depresión mayor ocupa el primer lugar dentro de las causas generadoras de discapacidad en el mundo. La violencia intrafamiliartambién constituye un serio problema de salud pública, pudiendo resultar en un importante factor de riesgo para la depresión. Objetivo. Determinar si la violencia intrafamiliar es un factor de riesgo para el trastorno depresivo mayor en mujeres habitantes del sureste de México. Materiales y Métodos. Se realizó un diseño de casos y controles. Los casos fueron pacientes prevalentes en la consulta de Psiquiatría del Hospital General Regional “Ignacio García Téllez”, que cumplieron con los criterios del DSMIV para trastorno depresivo mayor. Los controles fueron mujeres atendidas en la consulta de otra especialidad, que no cumplieron con los criterios para trastorno depresivo. Se utilizó la Encuesta Nacional sobre la Dinámica de las Relaciones en los Hogares (ENDIREH) para detectar violencia intrafamiliar. Se efectuó un análisis univariado de los resultados mediante la prueba de Chi2 y las variables que mostraron asociación estadística fueron ingresadas a un modelo de regresión logística. Resultados. Se incluyeron 270 casos y 540 controles. El promedio de edad fue de 41.2 ±12.1 y 40.8±12.1 (p=0.62), respectivamente. Se detectó violencia intrafamiliar en 129 casos (47.8%) y 113 controles (20.9%), y ésta se asoció con el trastorno depresivo mayor (RM= 3.4; IC 95% 2.5-4.7). Otros factores, como ser casada (RM=1.6 (1.2- 2.2), p <0.001), tener nivel socioeconómico bajo (RM=1.5 (1.0-2.4), p<0.03) y apoyo social mínimo (RM=1.9 (1.40-2.72), p<0.001) también incrementaron las probabilidades de padecer depresión. Conclusiones. La violencia intrafamiliar se encuentra asociada con el trastorno depresivo mayor, por lo que es urgente tomar medidas para su erradicación

Latencia diagnóstica en la enfermedad de Parkinson y su relación con los síntomas prodrómicos motores y no motores

El diagnóstico de la enfermedad de Parkinson (EP) se basa en la presencia obligatoria de bradicinesia y al menos uno de los siguientes síntomas: rigidez muscular, temblor en reposo, o inestabilidad postural. Se ha estimado que la duración promedio de la fase prodrómica de la EP es de 10 años antes de su diagnóstico. En la fase prodrómica pueden presentarse algunos trastornos motores leves, imposibilitando integrar el diagnóstico en ausencia de otros síntomas. La latencia diagnóstica de la EP es el tiempo transcurrido entre la aparición del primer síntoma motor hasta el diagnóstico realizado por un neurólogo. Latencias diagnósticas prolongadas se han asociado significativamente con: iniciar la sintomatología motora con rigidez, trastorno de la marcha o bradicinesia, sufrir un mayor número de síntomas prodrómicos no motores, sexo masculino, aparición temprana de síntomas motores (<40 años), tener un familiar de primer grado con EP y consultas médicas iniciales con médicos no neurólogos. Durante la fase prodrómica muchos pacientes también pueden padecer uno o varios de los siguientes síntomas no motores: disfunción olfatoria, trastorno conductual del sueño MOR, depresión, estreñimiento, hipotensión ortostática, somnolencia diurna y disfunción urinaria o eréctil, entre los cuales los cuatro primeros se han asociado con un mayor riesgo de desarrollar la EP, especialmente si se padece más de uno. Sin embargo, no todos los pacientes con EP reportan haber experimentado alguno de los síntomas no motores antes del diagnóstico. Estudios futuros permitirán determinar si los síntomas no motores podrían usarse para acortar la latencia diagnóstica de la E

Relación entre la sobrecarga y el índice depresivo de cuidadores primarios de pacientes con enfermedades neuromusculoesqueléticas

Introduction. A neuromusculoskeletal disease not only affects the person who suffers it but also directly affects the family and in particular with the informal primary caregiver. Care work increases the psychological morbidity and stress of primary caregivers. The aim of the present study was to identify the relationship between overload and the rate of depression present in informal primary caregivers of patients with the neuromusculoskeletal disease. Methods. An exploratory study was carried out that included 18 informal primary caregivers of patients with the neuromusculoskeletal disease, and who attended a consultation at the University Rehabilitation Unit of the Autonomous University of Yucatan. Results. Among the sociodemographic characteristics, female caregivers prevailed (83%) with a family relationship with the patient. Also, primary married status and a bachelor’s degree level predominated among primary caregivers. The relationship between overload and depression index was high and significant (r = 0.72, p = 0.0007). In conclusion, these results suggest that the greater the overload produced by the tasks of care, the greater the degree of involvement in the state of the informal primary caregiver. This study will help in the development of an intervention program to prevent overload in informal primary caregivers.Una enfermedad neuromusculoesquelética no solo afecta a la persona que la padece, sino que también repercute de manera directa en la familia y en particular al cuidador primario informal. Las labores de cuidado incrementan la morbilidad psicológica y el estrés de los cuidadores primarios. El objetivo del presente estudio consiste en identificar la relación entre la sobrecarga y el índice de depresión presente en los cuidadores primarios informales de pacientes con enfermedad neuromusculoesquelética. Material y Métodos. Se realizó un estudio exploratorio que incluyó a 18 cuidadores primarios informales de pacientes con enfermedad neuromusculoesquelética, y que asistieron a consulta en la Unidad Universitaria de Rehabilitación de la Universidad Autónoma de Yucatán. Resultados. Entre las características sociodemográficas predominaron las cuidadoras del sexo femenino (83%) con parentesco familiar con el paciente. Además, predomino entre los cuidadores primarios el estado civil casado y un nivel de estudios de licenciatura. La relación entre la sobrecarga y el índice de depresión fue elevada y significativa (r=0.72, p=0.0007). En conclusión, estos resultados sugieren que, a mayor sobrecarga producida por las labores del cuidado, mayor será el grado de afectación en el estado anímico del cuidador primario informal. Este estudio ayudará en la elaboración de un programa de intervención para prevenir la sobrecarga en cuidadoras primarias informales

Clinical and environmental risks factors associated with Parkinson’s disease in Yucatan

Objective: The objective of the study is to identify the risk and protective factors associated with Parkinson’s disease (PD) in inhabitants of Yucatan. Methods: Case control study. A questionnaire with the main risk and protective factors for PD described in the literature was applied to cases and controls. Results: The sample consisted of 85 cases and 124 controls. In the univariate logistic regression analyzes, it was found that the following factors were significantly associated with a higher risk of developing PD: family history of PD (OR = 5.28, p = 0.001), personal history of diabetes (OR = 2.35, p = 0.01), the number of head trauma (OR = 1.35, p = 0.02), number of general anesthesia received (OR = 1.27, p = 0.050), exposure to organic solvents (OR = 2.73, p = 0.02) and the years of exposure to organic solvents (OR = 1.05, p = 0.01): Conclusions: The findings of this research indicate that the inhabitants of the state of Yucatan are exposed to the following risk factors: having a relative with PD, personal history of diabetes, number of head traumas, exposure to organic solvents, years of exposure to organic solvents and number of general anesthesia received

Role of N-arachidonoyl-serotonin (AA-5-HT) in sleep-wake cycle architecture, sleep homeostasis, and neurotransmitters regulation

The endocannabinoid system comprises several molecular entities such as endogenous ligands [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)], receptors (CB1 and CB2), enzymes such as [fatty acid amide hydrolase (FAHH) and monoacylglycerol lipase (MAGL)], as well as the anandamide membrane transporter. Although the role of this complex neurobiological system in the sleep-wake cycle modulation has been studied, the contribution of the blocker of FAAH/transient receptor potential cation channel subfamily V member 1 (TRPV1), N-arachidonoyl-serotonin (AA-5-HT) in sleep has not been investigated. Thus, in the present study, varying doses of AA-5-HT (5, 10, or 20 mg/Kg, i.p.) injected at the beginning of the lights-on period of rats, caused no statistical changes in sleep patterns. However, similar pharmacological treatment given to animals at the beginning of the dark period decreased wakefulness (W) and increased slow wave sleep (SWS) as well as rapid eye movement sleep (REMS). Power spectra analysis of states of vigilance showed that injection of AA-5-HT during the lights-off period diminished alpha spectrum across alertness in a dose-dependent fashion. In opposition, delta power spectra was enhanced as well as theta spectrum, during SWS and REMS, respectively. Moreover, the highest dose of AA-5-HT decreased wake-related contents of neurotransmitters such as dopamine (DA), norepinephrine (NE), epinephrine (EP), serotonin (5-HT) whereas the levels of adenosine (AD) were enhanced. In addition, the sleep-inducing properties of AA-5-HT were confirmed since this compound blocked the increase in W caused by stimulants such as cannabidiol (CBD) or modafinil (MOD) during the lights-on period. Additionally, administration of AA-5-HT also prevented the enhancement in contents of DA, NE, EP, 5-HT and AD after CBD of MOD injection. Lastly, the role of AA-5-HT in sleep homeostasis was tested in animals that received either CBD [...]

Sleep and neurochemical modulation by DZNep and GSK-J1: potential link with histone methylation status

Histone methylation/demethylation plays an important modulatory role in chromatin restructuring, RNA transcription and is essential for controlling a plethora of biological processes. Due to many human diseases have been related to histone methylation/demethylation, several compounds such as 3-deazaneplanocin A (DZNep) or 3-((6-(4,5-Dihydro-1H-benzo[d]azepin-3(2H)-yl)-2-(pyridin-2-yl)pyrimidin-4-yl)amino)propanoic acid; N-[2-(2-pyridinyl)-6-(1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-4-pyrimidinyl]-β-Alanine (GSK-J1), have been designed to inhibit histone methylase or suppress histone demethylase, respectively. In the present study, we investigated the effects on the sleep-wake cycle and sleep-related neurochemical levels after systemic injections of DZNep or GSK-J1 given during the light or dark phase in rats. DZNep dose-dependently (0.1, 1.0, or 10 mg/kg, i.p.) prolonged wakefulness (W) duration while decreased slow wave sleep (SWS) and rapid eye movement sleep (REMS) time spent during the lights-on period with no changes observed in dark phase. In opposite direction, GSK-J1 (0.1, 1.0, or 10 mg/kg, i.p.) injected at the beginning of the lights-on period induced no statistical changes in W, SWS, or REMS whereas if administered at darkness, we found a diminution in W and an enhancement in SWS and REMS. Finally, brain microdialysis experiments in freely moving animals were used to evaluate the effects of DZNep or GSK-J1 treatments on contents of sleep-related neurochemicals. The results showed that DZNep boosted extracellular levels of dopamine, norepinephrine, epinephrine, serotonin, adenosine, and acetylcholine if injected at the beginning of the lights-on period whereas GSK-J1 exerted similar outcomes but when administered at darkness. In summary, DZNep and GSK-J1 may control the sleep-wake cycle and sleep-related neurochemicals through histone methylation/demethylation activity