Efecto protector de la tibolona en un modelo inflamatorio de microglía estimulado por palmitato

La microglía tiene un rol crítico en la homeostasis del sistema nervioso central (SNC). Ante una injuria de tipo traumático o metabólico, se caracteriza por alteraciones morfológicas y bioquímicas. Estos mecanismos se dan como respuesta a estímulos inflamatorios y conducen a la secreción de mediadores inflamatorios (citoquinas) que pueden afectar directamente la viabilidad y el funcionamiento celular. En este contexto, la modulación de la activación de microglial puede ser considerada como una potencial estrategia terapéutica protectora frente a injurias cerebrales o y procesos neurodegenerativos. Reciente evidencia demuestra que el uso de compuestos estrogénicos (esferoides neuroactivos) puede proporcionar un efecto protector que contrarresta el daño cerebral, regulando los procesos de activación glial. Se estudió el efecto de la tibolona en un modelo microglial simulando un ambiente inflamatorio metabólico con ácido palmítico. Para suministrar evidencia sobre el efecto protector de la tibolona, se determinó su acción sobre un mejoramiento en la viabilidad celular, el estrés oxidativo y la función mitocondrial. El mecanismo protector de la tibolona se demostró asociado preferencialmente al receptor de estrógeno beta, lo cual se evidenció mediante el bloqueo y activación farmacológica de los receptores de estrogeno. Adicionalmente, se demostró que la tibolona disminuye el estrés oxidativo mediante la modulación de la expresión de enzimas y proteínas responsables de la regulación antioxidante, y de igual manera la tibolona incrementa la expresión de neuroglobina, una proteína que ha sido ampliamente reportada en neuronas por sus efectos protectores. Al mismo tiempo, la tibolona ejerce un efecto protector regulando la expresión de citoquinas pro-inflamatorias y antiinflamatorias, como también la translocación de la subunidad p65 del factor de transcripción NF-kB regulando el proceso inflamatorio.Microglia plays a critical role in central nervous system (CNS) homeostasis. Before a traumatic or metabolic injury, is characterized by morphological and biochemical alterations. These mechanisms are given in response to inflammatory stimuli and lead to the secretion of inflammatory mediators (cytokines) that can directly affect cell viability and functioning. In this context, the modulation of microglial activation can be considered as a potential therapeutic strategy to protect against brain injuries or neurodegenerative processes. Recent evidence shows that the use of estrogenic compounds (neuroactive steroids) can provide a protective effect that counteracts brain damage by regulating glial activation processes. We studied the effect of tibolone in a microglial model simulating a metabolic inflammatory environment with palmitic acid. To provide evidence on the protective effect of tibolone, its action on an improvement in cell viability, oxidative stress and mitochondrial function was determined. The protective mechanism of tibolone was shown to be preferentially associated with estrogen receptor beta, which was evidenced by blocking and pharmacological activation of estrogen receptors. Additionally, it was demonstrated that tibolone decreases oxidative stress by modulating the expression of enzymes and proteins responsible for antioxidant regulation, and likewise tibolone increases the expression of neuroglobin, a protein that has been widely reported in neurons by their Protective effects. At the same time, tibolone exerts a protective effect by regulating the expression of pro-inflammatory and antiinflammatory cytokines, as well as the translocation of the p65 subunit of the transcription factor NF-kB regulating the inflammatory process.Magíster en Ciencias BiológicasMaestrí

Tibolone as Hormonal Therapy and Neuroprotective Agent

Tibolone (TIB), a selective tissue estrogenic activity regulator (STEAR) in clinical use by postmenopausal women, activates hormonal receptors in a tissue-specific manner. Estrogenic activity is present mostly in the brain, vagina, and bone, while the inactive forms predominate in the endometrium and breast. Conflicting literature on TIB's actions has been observed. While it has benefits for vasomotor symptoms, bone demineralization, and sexual health, a higher relative risk of hormone-sensitive cancer has been reported. In the brain, TIB can improve mood and cognition, neuroinflammation, and reactive gliosis. This review aims to discuss the systemic effects of TIB on peri- and post-menopausal women and its role in the brain. We suggest that TIB is a hormonal therapy with promising neuroprotective properties

Molecular mechanisms involved in the protective actions of Selective Estrogen Receptor Modulators in brain cells

Synthetic selective modulators of the estrogen receptors (SERMs) have shown to protect neurons and glial cells against toxic insults. Among the most relevant beneficial effects attributed to these compounds are the regulation of inflammation, attenuation of astrogliosis and microglial activation, prevention of excitotoxicity and as a consequence the reduction of neuronal cell death. Under pathological conditions, the mechanism of action of the SERMs involves the activation of estrogen receptors (ERs) and G protein-coupled receptor for estrogens (GRP30). These receptors trigger neuroprotective responses such as increasing the expression of antioxidants and the activation of kinase-mediated survival signaling pathways. Despite the advances in the knowledge of the pathways activated by the SERMs, their mechanism of action is still not entirely clear, and there are several controversies. In this review, we focused on the molecular pathways activated by SERMs in brain cells, mainly astrocytes, as a response to treatment with raloxifene and tamoxifen.This work is supported in part by grants from Pontificia Universidad Javeriana

Neuroactive steroids, neurosteroidogenesis and sex

The nervous system is a target and a source of steroids. Neuroactive steroids are steroids that target neurons and glial cells. They include hormonal steroids originated in the peripheral glands, steroids locally synthesized by the neurons and glial cells (neurosteroids) and synthetic steroids, some of them used in clinical practice. Here we review the mechanisms of synthesis, metabolism and action of neuroactive steroids, including the role of epigenetic modifications and the mitochondria in their sex specific actions. We examine sex differences in neuroactive steroid levels under physiological conditions and their role in the establishment of sex dimorphic structures in the nervous system and sex differences in its function. In addition, particular attention is paid to neuroactive steroids under pathological conditions, analyzing how pathology alters their levels and their role as neuroprotective factors, considering the influence of sex in both cases.This research was supported by grants from MIUR Progetto Eccellenza. We also acknowledge support from Fondazione CARIPLO (Rif.2012-0547), Colciencias (Convocatoria 777-2017, Contract #120377757021), Ministerio de Economía, Industria y Competitividad (MINECO), Spain (grant numbers BFU2014–51836-C2-1-R and BFU2017-82754-R), CIBER de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain and Fondos Feder