Inhibition of 11β-HSD1, a key enzyme in the stress management, improves cognition by RL-118 drug treatment

In recent years, stress and stress-coping mechanisms constitute a growing public healthcare issue concerning modern society. Experiencing stress engenders a great complex mechanism named stress response, which consists of a rapid release of catecholamines by the sympathetic nervous system, followed by a slower response in which hormones, mainly glucocorticoids (GCs), are synthesized and released to the bloodstream. Once the stressful stimulus is perceived, the hypothalamus secretes the corticotropin-releasing hormone (CRH), which acts on the pituitary gland, activating the release of adrenocorticotropic hormone (ACTH) that binds to the adrenal glands, promoting GC secretion and conforming the hypothalamus-hypophysis-adrenal (HPA) axis. Under normal conditions, GC secretion follows a robust circadian oscillation with a peak around the onset of the active period of the day, i.e., about 1 hour before arising [1]. This basal level of GC secretion is important in exerting tonic effects upon metabolic, immune and neuronal pathways, involving gluconeogenesis stimulation, protein degradation and lipolysis increase, priming of neural regions involved in sensory processing, attention and adaptive responding, as well as accounting for immunosuppressive and anti-inflammatory actions [2]. However, when stressful exposure is prolonged, the HPA axis deregulates and GC secretion is exacerbated. This excessive GC concentration leads to several metabolic, neurological and behavioral alterations, notably cognitive impairment and affective dysfunctions. GC activity is regulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme, which inhibition has been proved to restore metabolic and behavioral alterations, as well as enhance cognitive abilities. In fact, cortisol, the main active GC in humans, has been postulated as a potential biomarker for neurodegenerative disorders [3], like Alzheimer's disease (AD) in which aging is the major risk factor. Although it is completely assumed that stress directly influences the frailty phenotype in aged people, there are strikingly few measures to restrain stressful lifestyles in order to reduce the progression of pathological towards successful aging. Therefore, the study of stress effects on cognition and its relationship with aging is of the utmost importance to unveil what challenged we might have to cope with as a society in a not so far future

Chronic Mild Stress Modified Epigenetic Mechanisms Leading to Accelerated Senescence and Impaired Cognitive Performance in Mice

Cognitive and behavioural disturbances are a growing public healthcare issue for the modern society, as stressful lifestyle is becoming more and more common. Besides, several pieces of evidence state that environment is crucial in the development of several diseases as well as compromising healthy aging. Therefore, it is important to study the effects of stress on cognition and its relationship with aging. To address these queries, Chronic Mild Stress (CMS) paradigm was used in the senescence-accelerated mouse prone 8 (SAMP8) and resistant 1 (SAMR1). On one hand, we determined the changes produced in the three main epigenetic marks after 4 weeks of CMS treatment, such as a reduction in histone posttranslational modifications and DNA methylation, and up-regulation or down-regulation of several miRNA involved in different cellular processes in mice. In addition, CMS treatment induced reactive oxygen species (ROS) damage accumulation and loss of antioxidant defence mechanisms, as well as inflammatory signalling activation through NF-kappa B pathway and astrogliosis markers, like Gfap. Remarkably, CMS altered mTORC1 signalling in both strains, decreasing autophagy only in SAMR1 mice. We found a decrease in glycogen synthase kinase 3 beta (GSK-3beta) inactivation, hyperphosphorylation of Tau and an increase in sAPPbeta protein levels in mice under CMS. Moreover, reduction in the non-amyloidogenic secretase ADAM10 protein levels was found in SAMR1 CMS group. Consequently, detrimental effects on behaviour and cognitive performance were detected in CMS treated mice, affecting mainly SAMR1 mice, promoting a turning to SAMP8 phenotype. In conclusion, CMS is a feasible intervention to understand the influence of stress on epigenetic mechanisms underlying cognition and accelerating senescence

11β-HSD1 Inhibition Rescues SAMP8 Cognitive Impairment Induced by Metabolic Stress

Ageing and obesity have been shown to increase the risk of cognitive decline and Alzheimer's disease (AD). Besides, elevated glucocorticoid (GCs) levels cause metabolic stress and have been associated with the neurodegenerative process. Direct pieces of evidence link the reduction of GCs caused by the inhibition of 11β-HSD type 1 (11β-HSD1) with cognitive improvement. In the present study, we investigated the beneficial effects of 11β-HSD1 inhibitor (i) RL-118 after high-fat diet (HFD) treatment in the senescence-accelerated mouse prone 8 (SAMP8). We found an improvement in glucose intolerance induced by HFD in mice treated with RL-118, a significant reduction in 11β-HSD1 and glucocorticoid receptor (GR) protein levels. Furthermore, specific modifications in the FGF21 activation after treatment with 11β-HSD1i, RL-118, which induced changes in SIRT1/PGC1α/AMPKα pathway, were found. Oxidative stress (OS) and reactive oxygen species (ROS), as well as inflammatory markers and microglial activation, were significantly diminished in HFD mice treated with 11β-HSD1i. Remarkably, treatment with 11β-HSD1i altered PERK pathway in both diet groups, increasing autophagy only in HFD mice group. After RL-118 treatment, a decrease in glycogen synthase kinase 3 (GSK3β) activation, Tau hyperphosphorylation, BACE1 protein levels and the product β-CTF were found. Increases in the non-amyloidogenic secretase ADAM10 protein levels and the product sAPPα were found in both treated mice, regardless of the diet. Consequently, beneficial effects on social behaviour and cognitive performance were found in treated mice. Thus, our results support the therapeutic strategy of selective 11β-HSD1i for the treatment of age-related cognitive decline and AD

L’Artritis reumatoide

Treballs d'Educació Farmacètica als ciutadans. Unitat Docent d'Estades en Pràctiques Tutelades. Facultat de Farmàcia, Universitat de Barcelona. Curs: 2014/2015, Tutors: David Berlana Martin, Ignasi Cardona Pascual i Marian March Pujol.L’artritis reumatoide és una malaltia autoimmunitària que afecta a tots els grups poblacionals, i que cursa amb inflamació de les articulacions. La seva etiologia és encara desconeguda, fet que provoca que sigui un camp d’interès actual d’investigació. El tractament de primera línia consisteix en l’administració d’antiinflamatoris, analgèsics i/o corticoides, per tal de calmar el dolor i controlar la inflamació. A més s’afegeix FAME’s per alentir la progressió de la malaltia. Si amb aquest tractament no és suficient per mantenir un control, es passa al de segona línia que consisteix en l’administració d’anticossos monoclonals (teràpia biològica). Amb l’elaboració d’aquest treball i la realització de les activitats proposades, hem aplicat el rol de farmacèutic en l’educació ciutadana, proporcionant informació als malalts d’artritis per tal de promoure la seva salut. Cal destacar la importància que no només el pacient, sinó també el seu entorn familiar coneguin les característiques i evolució de la malaltia, amb l’objectiu de millorar la qualitat de vida dels malalts

Understanding Epigenetics in the Neurodegeneration of Alzheimer's Disease: SAMP8 Mouse Model

Epigenetics is emerging as the missing link among genetic inheritance, environmental influences, and body and brain health status. In the brain, specific changes in nucleic acids or their associated proteins in neurons and glial cells might imprint differential patterns of gene activation that will favor either cognitive enhancement or cognitive loss for more than one generation. Furthermore, derangement of age-related epigenetic signaling is appearing as a significant risk factor for illnesses of aging, including neurodegeneration and Alzheimer's disease (AD). In addition, better knowledge of epigenetic mechanisms might provide hints and clues in the triggering and progression of AD. Intense research in experimental models suggests that molecular interventions for modulating epigenetic mechanisms might have therapeutic applications to promote cognitive maintenance through an advanced age. The SAMP8 mouse is a senescence model with AD traits in which the study of epigenetic alterations may unveil epigenetic therapies against the AD. Keywords: Aging, DNA methylation, epigenetics, histone modification, neurodegeneratio

Inhibition of 11β-HSD1 Ameliorates Cognition and Molecular Detrimental Changes after Chronic Mild Stress in SAMP8 Mice

Impaired glucocorticoid (GC) signaling is a significant factor in aging, stress, and neurodegenerative diseases such as Alzheimer’s disease. Therefore, the study of GC-mediated stress responses to chronic moderately stressful situations, which occur in daily life, is of huge interest for the design of pharmacological strategies toward the prevention of neurodegeneration. To address this issue, SAMP8 mice were exposed to the chronic mild stress (CMS) paradigm for 4 weeks and treated with RL-118, an 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor. The inhibition of this enzyme is linked with a reduction in GC levels and cognitive improvement, while CMS exposure has been associated with reduced cognitive performance. The aim of this project was to assess whether RL-118 treatment could reverse the deleterious effects of CMS on cognition and behavioral abilities and to evaluate the molecular mechanisms that compromise healthy aging in SAMP8 mice. First, we confirmed the target engagement between RL-118 and 11β-HSD1. Additionally, we showed that DNA methylation, hydroxymethylation, and histone phosphorylation were decreased by CMS induction, and increased by RL-118 treatment. In addition, CMS exposure caused the accumulation of reactive oxygen species (ROS)-induced damage and increased pro-oxidant enzymes—as well as pro-inflammatory mediators—through the NF-κB pathway and astrogliosis markers, such as GFAP. Of note, these modifications were reversed by 11β-HSD1 inhibition. Remarkably, although CMS altered mTORC1 signaling, autophagy was increased in the SAMP8 RL-118-treated mice. We also showed an increase in amyloidogenic processes and a decrease in synaptic plasticity and neuronal remodeling markers in mice under CMS, which were consequently modified by RL-118 treatment. In conclusion, 11β-HSD1 inhibition through RL-118 ameliorated the detrimental effects induced by CMS, including epigenetic and cognitive disturbances, indicating that GC-excess attenuation shows potential as a therapeutic strategy for age-related cognitive decline and AD

Behaviour and cognitive changes correlated with hippocampal neuroinflammaging and neuronal markers in female SAMP8, a model of accelerated senescence

Senescence accelerated mice P8 (SAMP8) is a phenotypic model of age, characterized by deficits in memory and altered behaviour. Here determined the effect of age in SAMP8, compared with the resistant strain, SAMR1, in behaviour and learning parameters linking these disturbances with oxidative stress environment. We found impairment in emotional behaviour with regard to fear and anxiety in young SAMP8 vs. age-mated SAMR1. Differences were attenuated with age. In contrast, learning capabilities are worse in SAMP8, both in young and aged animals, with regard to SAMR1. These waves in behaviour and cognition were correlated with an excess of Oxidative stress (OS) in SAMP8 at younger ages that diminished with age. In this manner, we found changes in the hippocampal expression of ALDH2, IL-6, HMOX1, COX2, CXCL10, iNOS, and MCP-1 with an altered amyloidogenic pathway by increasing the Amyloid beta precursor protein (APP) and BACE1, and reduced ADAM10 expression; in addition, astrogliosis and neuronal markers decreased. Moreover, Superoxide dismutase 1 (SOD1) and Nuclear factor-kappa beta (NF-kβ) expression and protein levels were higher in younger SAMP8 than in SAMR1. In conclusion, the accelerated senescence process present in SAMP8 can be linked with an initial deregulation in redox homeostasis, named neuroinflammaging, by inducing molecular changes that lead to neuroinflammation and the neurodegenerative process. These changes are reflected in the emotional and cognitive behaviour of SAMP8 that differs from that of SAMR1 and that highlighted the importance of earlier oxidative processes in the onset of neurodegeneration

Inhibition of 11β-HSD1 Ameliorates Cognition and Molecular Detrimental Changes after Chronic Mild Stress in SAMP8 Mice

Impaired glucocorticoid (GC) signaling is a significant factor in aging, stress, and neurodegenerative diseases such as Alzheimer's disease. Therefore, the study of GC-mediated stress responses to chronic moderately stressful situations, which occur in daily life, is of huge interest for the design of pharmacological strategies toward the prevention of neurodegeneration. To address this issue, SAMP8 mice were exposed to the chronic mild stress (CMS) paradigm for 4 weeks and treated with RL-118, an 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor. The inhibition of this enzyme is linked with a reduction in GC levels and cognitive improvement, while CMS exposure has been associated with reduced cognitive performance. The aim of this project was to assess whether RL-118 treatment could reverse the deleterious effects of CMS on cognition and behavioral abilities and to evaluate the molecular mechanisms that compromise healthy aging in SAMP8 mice. First, we confirmed the target engagement between RL-118 and 11β-HSD1. Additionally, we showed that DNA methylation, hydroxymethylation, and histone phosphorylation were decreased by CMS induction, and increased by RL-118 treatment. In addition, CMS exposure caused the accumulation of reactive oxygen species (ROS)-induced damage and increased pro-oxidant enzymes as well as pro-inflammatory mediators through the NF-κB pathway and astrogliosis markers, such as GFAP. Of note, these modifications were reversed by 11β-HSD1 inhibition. Remarkably, although CMS altered mTORC1 signaling, autophagy was increased in the SAMP8 RL-118-treated mice. We also showed an increase in amyloidogenic processes and a decrease in synaptic plasticity and neuronal remodeling markers in mice under CMS, which were consequently modified by RL-118 treatment. In conclusion, 11β-HSD1 inhibition through RL-118 ameliorated the detrimental effects induced by CMS, including epigenetic and cognitive disturbances, indicating that GC-excess attenuation shows potential as a therapeutic strategy for age-related cognitive decline and AD

Environmental Enrichment Modified Epigenetic Mechanisms in SAMP8 Mouse Hippocampus by Reducing Oxidative Stress and Inflammaging and Achieving Neuroprotection

With the increase in life expectancy, aging and age-related cognitive impairments arebecoming one of the most important issues for human health. At the same time, ithas been shown that epigenetic mechanisms are emerging as universally importantfactors in life expectancy. The Senescence Accelerated Mouse P8 (SAMP8) strainexhibits age-related deterioration evidenced in learning and memory abilities and is auseful model of neurodegenerative disease. In SAMP8, Environmental Enrichment (EE)increased DNA-methylation levels (5-mC) and reduced hydroxymethylation levels (5-hmC), as well as increased histone H3 and H4 acetylation levels. Likewise, we foundchanges in the hippocampal gene expression of some chromatin-modifying enzymegenes, such asDnmt3b,Hdac1,Hdac2,Sirt2, andSirt6.Subsequently, we assessedthe effects of EE on neuroprotection-related transcription factors, such as the Nuclearregulatory factor 2 (Nrf2)-Antioxidant Response Element pathway and Nuclear Factorkappa Beta (NF-κB), which play critical roles in inflammation. We found that EE producesan increased expression of antioxidant genes, such asHmox1,Aox1, andCox2, andreduced the expression of inflammatory genes such asIL-6andCxcl10, all of this withinthe epigenetic context modified by EE. In conclusion, EE prevents epigenetic changesthat promote or drive oxidative stress and inflammagin

Utilización de casos clínicos en farmacología para mejorar las habilidades y actitudes en el consejo farmacéutico del estudiante de Farmacia

El estudio de la Farmacología es esencial para formar a los futuros profesionales del medicamento en el grado de Farmacia. Sin embargo, la Farmacología es una materia muy extensa que exige un alto grado no solo de aprendizaje, sino de comprensión y capacidad de integración. Todos estos procesos de enseñanza-aprendizaje requieren, además de dedicación, un grado de motivación elevado por parte del estudiante. Por este motivo, en la asignatura Farmacología y Terapéutica II del grado de Farmacia de la Universidad de Barcelona, se utilizan estrategias de aprendizaje activo con la finalidad de aumentar la motivación del estudiante y, en consecuencia, su aprendizaje