Efecto del esteroide sintético tibolona sobre la gliosis reactiva

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Farmacología. Fecha de lectura: 02-12-2019Cuando se produce un daño en el sistema nervioso central (SNC), las células gliales, como los astrocitos y la microglía, sufren una transformación adaptativa, denominada gliosis reactiva, que se caracteriza por un aumento en la liberación de factores pro- y antiinflamatorios. Además, los astrocitos y la microglía aumentan su actividad fagocítica tras la lesión, lo que facilita la reparación del tejido dañado. Aunque en principio la gliosis favorece el retorno a la homeostasis del tejido nervioso dañado, en ciertas condiciones puede producirse una respuesta glial incontrolada, por ejemplo en situaciones de neuroinflamación crónica, lo que llega a producir un aumento en el daño tisular. Y por este motivo en ocasiones es necesario controlarla. Los estrógenos son sustancias producidas por nuestro organismo tanto en la periferia como en el SNC. Aunque estas hormonas tienen efectos neuroprotectores, su utilización en clínica está limitada debido al aumento del riesgo de padecer cáncer de mama, endometrio y ovarios. Una alternativa al uso de estrógenos como agentes neuroprotectores son algunos esteroides sintéticos, utilizados actualmente para el tratamiento de los síntomas de la menopausia, como la tibolona. Este esteroide sufre una metabolización específica en cada tejido y sus metabolitos tienen afinidad por los receptores de estrógeno, de progesterona y de andrógenos. Estudios previos in vitro sugieren que la tibolona tiene acciones protectoras en células neurales. En este estudio se ha analizado su acción protectora en un modelo murino de lesión cerebral, con particular énfasis en su acción sobre la gliosis reactiva. Nuestros estudios se han complementado con un análisis in vitro sobre los mecanismos de acción de la tibolona en astrocitos y microglía. Nuestros resultados indican que la tibolona modula la respuesta de astrocitos y microglía y aumenta la supervivencia neuronal en la corteza cerebral lesionada. El análisis de las acciones de la tibolona in vitro sugiere acciones directas sobre las células gliales mediadas por receptores de estrógeno y andrógenos. Además, nuestros resultados indican que este esteroide regula la actividad fagocítica de astrocitos y microglía, lo cual podría contribuir a su acción neuroprotectora in vivo.When damage occurs in the central nervous system (CNS), glial cells, such as astrocytes and microglia, undergo an adaptive transformation, characterized by increased release of pro- and anti-inflammatory factors, referred to as reactive gliosis. In addition, astrocytes and microglia increase their phagocytic activity after injury, facilitating the repair of damaged tissue and the return to homeostasis. However, certain conditions, such as chronic neuroinflammation, lead to uncontrolled glial responses and tissue damage. For this reason, regulation of glial responses in these circumstances is key. Estrogens are naturally produced hormones, both in the periphery and in the CNS. Although they have been reported to have neuroprotective effects, their clinical use is limited due to the increased risk of breast, endometrial and ovarian cancer. An alternative to the use of estrogens as neuroprotective agents are some synthetic steroids, such as tibolone, currently used for the treatment of menopausal symptoms. Tibolone is a tissue-specific steroid and its metabolites have affinity for estrogen, progesterone and androgen receptors. Previous in vitro studies suggest that tibolone has protective actions in neural cells. In this study, its protective action was analyzed in a mouse model of brain injury, with particular emphasis on its action on reactive gliosis. Our studies have been complemented with an in vitro analysis on the mechanisms of action of tibolone in astrocytes and microglia. Our results indicate that tibolone reduces the response of astrocytes and microglia and increases neuron survival in the injured cerebral cortex. Analysis of the actions of tibolone in vitro suggests direct actions on glial cells mediated by estrogen and androgen receptors. In addition, our results indicate that this steroid regulates the phagocytic activity of astrocytes and microglia, which could contribute to its neuroprotective action in viv

High-fat diet alters stress behavior, inflammatory parameters and gut microbiota in Tg APP mice in a sex-specific manner

Long-term high-fat diet (HFD) consumption commonly leads to obesity, a major health concern of western societies and a risk factor for Alzheimer's disease (AD). Both conditions present glial activation and inflammation and show sex differences in their incidence, clinical manifestation, and disease course. HFD intake has an important impact on gut microbiota, the bacteria present in the gut, and microbiota dysbiosis is associated with inflammation and certain mental disorders such as anxiety. In this study, we have analyzed the effects of a prolonged (18 weeks, starting at 7 months of age) HFD on male and female mice, both wild type (WT) and TgAPP mice, a model for AD, investigating the behavioral profile, gut microbiota composition and inflammatory/phagocytosis-related gene expression in hippocampus. In the open-field test, no overt differences in motor activity were observed between male and female or WT and TgAPP mice on a low-fat diet (LFD). However, HFD induced anxiety, as judged by decreased motor activity and increased time in the margins in the open-field, and a trend towards increased immobility time in the tail suspension test, with increased defecation. Intriguingly, female TgAPP mice on HFD showed less immobility and defecation compared to female WT mice on HFD. HFD induced dysbiosis of gut microbiota, resulting in reduced microbiota diversity and abundance compared with LFD fed mice, with some significant differences due to sex and little effect of genotype. Gene expression of pro-inflammatory/phagocytic markers in the hippocampus were not different between male and female WT mice, and in TgAPP mice of both sexes, some cytokines (IL-6 and IFN¿) were higher than in WT mice on LFD, more so in female TgAPP (IL-6). HFD induced few alterations in mRNA expression of inflammatory/phagocytosis-related genes in male mice, whether WT (IL-1ß, MHCII), or TgAPP (IL-6). However, in female TgAPP, altered gene expression returned towards control levels following prolonged HFD (IL-6, IL-12ß, TNF¿, CD36, IRAK4, PYRY6). In summary, we demonstrate that HFD induces anxiogenic symptoms, marked alterations in gut microbiota, and increased expression of inflammatory genes, except for female TgAPP that appear to be resistant to the diet effects. Lifestyle interventions should be introduced to prevent AD onset or exacerbation by reducing inflammation and its associated symptoms; however, our results suggest that the eventual goal of developing prevention and treatment strategies should take sex into consideration.This work was supported by Ministerio de Economía, Industria y Competitividad (MINECO), Grant Numbers BFU2014-51836-C2-1-R to LMGS and MAA, BFU2014-51836-C2-2-R and BFU2017-82565-C21-R2 to JAC; Madrid Council S2010/BMD-2349 to MLC; Centre for Biomedical Network Research for Physiopathology of Obesity and Nutrition (CIBEROBN) to JAC, Centre for Biomedical Network Research for Frailty and Healthy Ageing (CIBERFES) to LMGS and MAA, and Centre for Biomedical Network Research for Neurodegenerative Diseases (CIBERNED) to MLC. AC-C was granted with a FPI fellowship by the MINECO (BES-2015-072980)

El correo electrónico en la consulta de Parkinson: ¿soluciones a un clic? // Use of e-mail for Parkinson's disease consultations: Are answers just a clic away?

INTRODUCCION: La problemática de los trastornos del movimiento (TM) es compleja y la duración y frecuencia de las consultas presenciales puede estar limitada por problemas de espacio y tiempo. Analizamos el funcionamiento de un servicio de atención por correo electrónico institucional para médicos de Atención Primaria (MAP) y pacientes en la Unidad de Trastornos del Movimiento (UTM). METODOS: Se revisaron retrospectivamente los correos electrónicos enviados y recibidos en un periodo de 4 meses, un año tras su implantación. La dirección se proporcionaba en consulta y mediante sesiones informativas a los MAP del área. Se analizaron datos clínicos y demográficos de los pacientes, tipo de interlocutor, número de consultas, motivo y actuaciones derivadas de ellas. RESULTADOS: Del 1 de enero al 30 de abril de 2015 se recibieron 137 correos de 63 pacientes (43% varones; edad 71 ± 10,5 años) diagnosticados de enfermedad de Parkinson (76%), parkinsonismos atípicos (10%) y otros (14%), y se enviaron 116 respuestas. En 20 casos (32%) fueron redactados por el paciente, en 38 (60%) por sus familiares y en 5 (8%) por MAP. Los motivos de consulta fueron clínicos en 50 casos (80%): deterioro clínico (16; 32%), nuevos síntomas (14; 28%), efectos secundarios o dudas sobre medicación (20; 40%). Como consecuencia, se adelantó una cita programada en 9 casos (14%), mientras que el resto se solucionaron por correo electrónico. En 13 (20%), el motivo de consulta fue burocrático: relacionado con citas (11, 85%) y solicitud de informe (2, 15%). La satisfacción fue generalizada, sin constituir una sobrecarga asistencial excesiva para los facultativos responsables. CONCLUSIONES: La implantación de una consulta por correo electrónico es factible en UTM, facilita la comunicación médico-paciente y la continuidad asistencial con Atención Primaria. // INTRODUCTION: The clinical problems of patients with movement disorders (MD) are complex, and the duration and frequency of face-to-face consultations may be insufficient to meet their needs. We analysed the implementation of an e-mail-based query service for our MD unit's patients and their primary care physicians (PCPs). METHODS: We retrospectively reviewed all consecutive emails sent and received over a period of 4 months, one year after implementation of the e-mail inquiry system. All patients received the during consultations, and PCPs, during scheduled informative meetings. We recorded and later analysed the profile of the questioner, patients’ demographic and clinical data, number of queries, reason for consultation, and actions taken. RESULTS: From 1 January 2015 to 30 April 2015, the service received 137 emails from 63 patients (43% male, mean age 71 ± 10.5) diagnosed with Parkinson's disease (76%), atypical parkinsonism (10%), and others (14%); 116 responses were sent. Twenty (32%) emails were written by patients, 38 (60%) by their caregivers, and 5 (8%) by their PCPs. The reasons for consultation were clinical in 50 cases (80%): 16 (32%) described clinical deterioration, 14 (28%) onset of new symptoms, and 20 (40%) side effects or concerns about medications. In 13 cases (20%), the query was bureaucratic: 11 were related to appointments (85%) and 2 were requests for clinical reports (15%). In response, new appointments were scheduled in 9 cases (14%), while the rest of the questions were answered by email. Patients were satisfied overall and the additional care burden on specialists was not excessive. CONCLUSIONS: Implementing an e-mail-based consultation system is feasible in MD units. It facilitates both communication between neurologists and patients and continued care in the primary care setting

Recensiones

Óscar Alzaga Villaamil. La conquista de la transición (1960-1978). Memorias documentadas (María Garrote de Marcos) Artemi Rallo Lombarte. Investiduras fallidas y Constitución ignota (Nieves Alonso García) Juan Francisco Sánchez Barrilao. Pluralismo ordinamental y Derecho constitucional: El Derecho como relaciones entre ordenamientos jurídicos (Patricia García Majado) María Salvador Martínez. Partidos políticos. El estatuto constitucional en los partidos y su desarrollo legal (Eva Sáenz Royo) María Garrote De Marcos. El sistema electoral español: memoria, balance y cambio (Carlos Fernández Esquer) María Isabel González Pascual. La salvaguarda de la autonomía política ante las crisis (Andrés Dueñas Castrillo) Ángel Sánchez Navarro y Rosa Fernández Riveira (Dirs.). Reflexiones para una democracia de calidad en una era tecnológica y Jordi Barrat i Esteve y Miguel Pérez Moneo (Eds.). La digitalización de los partidos políticos y el uso del voto electrónico (José Luis Mateos Crespo

El Historiador del Arte en la sociedad actual: profesionalización en los Museos y la Curaduría de Exposiciones

Accésit 2018[ES] Impacto de su desarrollo y resultados con la mejora de la calidad de la educación superior en cuanto a su aplicación práctica, generalización a otros centros, disciplinas, coordinación entre docentes, coordinación entre titulaciones e implicación de la comunidad universitaria

Non-motor symptom burden in patients with Parkinson's disease with impulse control disorders and compulsive behaviours : results from the COPPADIS cohort

The study was aimed at analysing the frequency of impulse control disorders (ICDs) and compulsive behaviours (CBs) in patients with Parkinson's disease (PD) and in control subjects (CS) as well as the relationship between ICDs/CBs and motor, nonmotor features and dopaminergic treatment in PD patients. Data came from COPPADIS-2015, an observational, descriptive, nationwide (Spain) study. We used the validated Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) for ICD/CB screening. The association between demographic data and ICDs/CBs was analyzed in both groups. In PD, this relationship was evaluated using clinical features and treatment-related data. As result, 613 PD patients (mean age 62.47 ± 9.09 years, 59.87% men) and 179 CS (mean age 60.84 ± 8.33 years, 47.48% men) were included. ICDs and CBs were more frequent in PD (ICDs 12.7% vs. 1.6%, p < 0.001; CBs 7.18% vs. 1.67%, p = 0.01). PD patients had more frequent previous ICDs history, premorbid impulsive personality and antidepressant treatment (p < 0.05) compared with CS. In PD, patients with ICDs/CBs presented younger age at disease onset, more frequent history of previous ICDs and premorbid personality (p < 0.05), as well as higher comorbidity with nonmotor symptoms, including depression and poor quality of life. Treatment with dopamine agonists increased the risk of ICDs/CBs, being dose dependent (p < 0.05). As conclusions, ICDs and CBs were more frequent in patients with PD than in CS. More nonmotor symptoms were present in patients with PD who had ICDs/CBs compared with those without. Dopamine agonists have a prominent effect on ICDs/CBs, which could be influenced by dose

Universidad, género, docencia e igualdad

La Red de investigación en docencia universitaria “Universidad, docencia, genero e igualdad” persigue avanzar en la calidad e innovación de las enseñanzas universitarias a partir de la inclusión de la perspectiva de género. Se busca dar cumplimiento a las directrices generales de los nuevos planes de estudio respecto del principio de igualdad de oportunidades entre hombres y mujeres en la formación universitaria (Real Decreto 1393/2007. BOE nº 260, 30 de octubre de 2007). En la cuarta edición de la Red, y dada su composición multidisciplinar, se desarrollaron tres líneas de investigación: 1) mantenimiento del “Portal web con recursos docentes con perspectiva de género”, proyecto financiado por el Instituto de la Mujer (PACUI, 2012) e iniciado en el curso 2012-2013; 2) desarrollo (primera versión) de “iLengUA”, una herramienta informática para un discurso inclusivo e igualitario; y 3) diseño de la Guía para una orientación universitaria inclusiva

Microglial and Astrocytic Function in Physiological and Pathological Conditions: Estrogenic Modulation

© 2020 by the authors.There are sexual differences in the onset, prevalence, and outcome of numerous neurological diseases. Thus, in Alzheimer’s disease, multiple sclerosis, and major depression disorder, the incidence in women is higher than in men. In contrast, men are more likely to present other pathologies, such as amyotrophic lateral sclerosis, Parkinson’s disease, and autism spectrum. Although the neurological contribution to these diseases has classically always been studied, the truth is that neurons are not the only cells to be affected, and there are other cells, such as glial cells, that are also involved and could be key to understanding the development of these pathologies. Sexual differences exist not only in pathology but also in physiological processes, which shows how cells are differentially regulated in males and females. One of the reasons these sexual differences may occur could be due to the different action of sex hormones. Many studies have shown an increase in aromatase levels in the brain, which could indicate the main role of estrogens in modulating proinflammatory processes. This review will highlight data about sex differences in glial physiology and how estrogenic compounds, such as estradiol and tibolone, could be used as treatment in neurological diseases due to their anti-inflammatory effects and the ability to modulate glial cell functions.This research was funded by Agencia Estatal de Investigación (AEI), co-funded by Fondo Europeo de Desarrollo Regional (FEDER), grant number BFU2017-82754-R, and by Centro de Investigación Biomédica en red (CIBERFES).Peer reviewe

Aging and sex: Impact on microglia phagocytosis

Microglia dysfunction and activation are important hallmarks of the aging brain and are concomitant with age-related neurodegeneration and cognitive decline. Age-associated changes in microglia migration and phagocytic capacity result in maladaptive responses, chronic neuroinflammation, and worsened outcomes in neurodegenerative disorders. Given the sex bias in the incidence, prevalence, and therapy response of most neurological disorders, we have here examined whether the phagocytic activity of aged microglia is different in males and females. With this aim, the phagocytosis activity of male and female cells was compared in an in vitro aged microglia model and in microglia isolated from adult (5-month-old) or aged (18-month-old) mice. In both models, the phagocytosis of neural debris increased with aging in male and female cells and was higher in aged female microglia than in aged male cells. However, female aged microglia lost its ability to adapt its phagocytic activity to inflammatory conditions. These findings suggest that microglia phagocytosis of neural debris may represent a previously unexplored neuroprotective characteristic of aged microglia that may contribute to the generation of sex differences in the manifestation of neurodegenerative diseases.The study was supported by a grant from Agencia Estatal de Investigación (AEI), co-funded by Fondo Europeo de Desarrollo Regional (FEDER): BFU2017-82754-R and by CIBERFES