Role of Smad2 in the processes of neuroplasticity related to hippocampal-dependent spatial learning and memory

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 30-03-2017Esta tesis tiene embargado el acceso al texto completo hasta el 30-09-201

Can Exercise Make You Smarter, Happier, and Have More Neurons? A Hormetic Perspective

Exercise can make you smarter, happier and have more neurons depending on the dose (intensity) of the training program. It is well recognized that exercise protocols induce both positive and negative effects depending on the intensity of the exercise, among other key factors, a process described as a hormetic-like biphasic dose-response. However, no evidences have been reported till very recently about the biphasic response of some of the potential mediators of the exercise-induced actions. This hypothesis and theory will focus on the adult hippocampal neurogenesis (AHN) as a putative physical substrate for hormesis responses to exercise in the context of exercise-induced actions on cognition and mood, and on the molecular pathways which might potentially be mediating these actions.The authors acknowledge the support of CSIC (Spanish Council for Scientific Investigation) and the Ministerio de Economía y Competitividad, Spain (research grant reference BFU2013-48907-R).Peer reviewedPeer Reviewe

Meta-Analysis Design and Results in Real Life: Problem Solvers or Detour to Maze. A Critical Review of Meta-Analysis of DAPT Randomized Controlled Trials.

Therapeutic strategies - such as duration of dual antiplatelet therapy after coronary artery stenting - usually generate a large quantity of meta-analyses. The meta-analyses that include the same randomized clinical trials should produce similar results. Our aim in the study is to analyze the quality and to compare the results of meta-analyses focused on a controversial topic such as dual antiplatelet therapy after percutaneous coronary intervention. We searched all published meta-analyses published up to November 2015 (near DAPT trial publication) selecting those that included the same randomized clinical trials comparing patterns of briefer versus longer-term double antiplatelet therapy. Seventeen meta-analyses achieved our selection criteria. Of the seventeen analyzed, we identified seven (41.1%) based on the same ten randomized clinical trials (RCTs), yet their results varied widely. Many of the meta-analyses differed in only some minor aspect of the design (i.e. eligible studies, length of comparators and statistical methods used). Some authors differed in the number of patients participating in RCTs and even, despite reviewing the same underlying trials, only 2 of the 7 meta-analyses included the same number of patients. Meta-analyses around cardiovascular, all-cause or non-cardiovascular death differ frequently. In the DAPT duration setting, several meta-analyses have been recently published based on the same data, presenting several issues making it difficult to determine clear recommendations on certain points.IN receives research funding from Astrazeneca; has received minor consulting fees from Boston, Medtronic, Astrazeneca; and speaking fees or support for attending scientificmeetings fromBoehringer, Daiichi-Sankyo, Lilly, AstraZeneca and Pfizer. AE is Astrazeneca employee. HB receives research funding from the Instituto de Salud Carlos III (PIE16/00021), AstraZeneca, BMS, Janssen and Novartis; has received consulting fees from Abbott, AstraZeneca, Bayer, BMS-Pfizer, Novartis; and speaking fees or support for attending scientificmeetings from AstraZeneca, Bayer, BMS-Pfizer, Ferrer, Novartis, Servier and MEDSCAPE-the heart.og. The other authors pose no relevant disclosures regarding this manuscript.S

Cost-effectiveness of sodium zirconium cyclosilicate for the treatment of hyperkalemia in patients with chronic kidney disease or heart failure in Spain

[Resumen] Antecedentes y objetivo. La hiperpotasemia (HK) es una alteración electrolítica en la concentración de iones potasio (K+), cuyo riesgo aumenta en pacientes con enfermedad renal crónica (ERC) o insuficiencia cardiaca (IC) y/o en pacientes en tratamiento con inhibidores del sistema renina-angiotensina-aldosterona (iSRAA). Los nuevos quelantes orales de K+ ofrecen un tratamiento seguro y eficaz para mantener la normopotasemia en estos pacientes. El objetivo del análisis es estimar el coste-efectividad del ciclosilicato de sodio y zirconio (CSZ) para el tratamiento de la HK crónica en pacientes con ERC o IC vs. tratamiento estándar (poliestireno sulfonato cálcico y modificaciones del estilo de vida) desde la perspectiva del Sistema Nacional de Salud (SNS) español. Materiales y métodos. Se utilizaron dos modelos de microsimulación que reflejan la historia natural de la ERC y de la IC. En ambos modelos se realizó una simulación de forma individual de los niveles de K+. Con base en la eficacia (reducción de los niveles de K+), la calidad de vida de los pacientes (utilidades según estado de salud, y disutilidades de los eventos derivados de cada patología y los eventos adversos [EA] del tratamiento) y a los costes contemplados (coste del tratamiento para la HK, del tratamiento con iSRAA y su modificación, de los estados de salud, del manejo de los eventos derivados de cada patología, de los episodios de HK, y de los EA del tratamiento) (€, 2022), se obtuvieron resultados de beneficio clínico (años de vida ajustados por calidad [AVAC]) y costes. Se empleó un horizonte temporal de toda la vida del paciente y se aplicó una tasa de descuento del 3% para costes y resultados. Resultados. El CSZ resulta una opción más efectiva en ambas patologías, con una diferencia de AVAC de 0,476 en ERC, y de 0,978 en IC vs. tratamiento estándar, y supone un coste incremental de 3.616 € y 14.749 €, respectivamente, obteniéndose un ratio coste-utilidad incremental (RCUI) de 7.605 €/AVAC en ERC y 15.078 €/AVAC en IC. Conclusiones. El CSZ es una alternativa con una buena relación coste-efectividad para el tratamiento de la HK en pacientes con ERC o IC, teniendo en cuenta los valores de eficiencia de referencia empleados habitualmente en España.[Abstract] Background and objective. Hyperkalemia (HK) is an electrolyte disturbance in the concentration of potassium ions (K+), whose risk increases in patients with chronic kidney disease (CKD) or heart failure (HF) and/or in patients being treated with renin-angiotensin-aldosterone system inhibitors (RAASi). The new oral K+ chelators offer a safe and effective treatment to maintain normokalemia in these patients. The objective of the analysis is to estimate the cost-effectiveness of sodium zirconium cyclosilicate (SZC) for the treatment of chronic HK in patients with CKD or HF versus standard treatment (calcium polystyrene sulfonate and lifestyle modifications) from the perspective of the Spanish National Health System. Materials and methods. Two microsimulation models reflecting the natural history of CKD and HF were used. In both models, K+ levels were simulated individually. Based on efficacy (reduction of K+ levels), quality of life of patients (utilities according to health states, and disutilities of events derived from each pathology and adverse events [AEs] of treatment) and costs considered (cost of treatment for HK, of RAASi treatment and its modification, health states, management of events derived from each pathology, HK episodes, and AEs treatment) (€, 2022), clinical benefit (quality-adjusted life years [QALYs]) and cost results were obtained. A time horizon of the patient's lifetime was used and a discount rate of 3% was applied for costs and outcomes. Results. SZC is a more effective option in both pathologies, with a difference in QALYs of 0.476 in CKD and 0.978 in HF compared to standard treatment, and it represents an incremental cost of € 3,616 and € 14,749, respectively, obtaining an incremental cost-utility ratio of € 7,605 /QALY in CKD and € 15,078 /QALY in HF. Conclusions. SZC is a cost-effective alternative for the treatment of HK in patients with CKD or HF, taking into account the reference efficiency values commonly used in Spain

The growth factors cascade and the dendrito-/synapto-genesis versus cell survival in adult hippocampal neurogenesis: The chicken or the egg

The decision between cellular survival and death is governed by a balance between proapoptotic versus antiapoptotic signaling cascades. Growth factors are key actors, playing two main roles both at developmental and adult stages: a supporting antiapoptotic role through diverse actions converging in the mitochondria, and a promoter role of cell maturation and plasticity through dendritogenesis and synaptogenesis, especially relevant for the adult hippocampal neurogenesis, a case of development during adulthood. Here, both parallel roles mutually feed forward each other (the success in avoiding apoptosis lets the cell to grow and differentiate, which in turn lets the cell to reach new targets and form new synapses accessing new sources of growth factors to support cell survival) in a circular cause and consequence, or a >the chicken or the egg> dilemma. While identifying the first case of this dilemma makes no sense, one possible outcome might have biological relevance: the decision between survival and death in the adult hippocampal neurogenesis is mainly concentrated at a specific time window, and recent data suggest some divergences between the survival and the maturational promoter effect of growth factors. This review summarizes these evidences suggesting how growth factors might contribute to the live-or-die decision of adult-born immature granule neurons through influencing the maturation of the young neuron by means of its connectivity into a mature functional circuit. © 2013 Elsevier B.V.Peer Reviewe

The Role of Smad2 in Adult Neuroplasticity as Seen through Hippocampal-Dependent Spatial Learning/Memory and Neurogenesis

© 2021 the authorsAdult neural plasticity is an important and intriguing phenomenon in the brain, and adult hippocampal neurogenesis is directly involved in modulating neural plasticity by mechanisms that are only partially understood. We have performed gain-of-function and loss-of-function experiments to study Smad2, a transcription factor selected from genes that are demethylated after exercise through the analysis of an array of physical activity-induced factors, and their corresponding gene expression, and an efficient inducer of plasticity. In these studies, changes in cell number and morphology were analyzed in the hippocampal dentate gyrus (cell proliferation and survival, including regional distribution, and structural maturation/differentiation, including arborization, dendritic spines, and neurotransmitter-specific vesicles) of sedentary male mice, after evaluation in a battery of behavioral tests. As a result, we reveal a role for Smad2 in the balance of proliferation versus maturation of differentiating immature cells (Smad2 silencing increases both the proliferation and survival of cycling cells in the dentate granule cell layer), and in the plasticity of both newborn and mature neurons in mice (by decreasing dendritic arborization and dendritic spine number). Moreover, Smad2 silencing specifically compromises spatial learning in mice (through impairments of spatial tasks acquisition both in long-term learning and working memory). These data suggest that Smad2 participates in adult neural plasticity by influencing the proliferation and maturation of dentate gyrus neurons.Peer reviewe

Noggin rescues age-related stem cell loss in the brain of senescent mice with neurodegenerative pathology

6 páginas, 7 figuras. Información suplementaria online en: www.pnas.org/lookup/suppl/doi:10.073/pnas.1813205115/-/DCSupplementalIncreasing age is the greatest known risk factor for the sporadic late-onset forms of neurodegenerative disorders such as Alzheimer's disease (AD). One of the brain regions most severely affected in AD is the hippocampus, a privileged structure that contains adult neural stem cells (NSCs) with neurogenic capacity. Hippocampal neurogenesis decreases during aging and the decrease is exacerbated in AD, but the mechanistic causes underlying this progressive decline remain largely unexplored. We here investigated the effect of age on NSCs and neurogenesis by analyzing the senescence accelerated mouse prone 8 (SAMP8) strain, a nontransgenic short-lived strain that spontaneously develops a pathological profile similar to that of AD and that has been employed as a model system to study the transition from healthy aging to neurodegeneration. We show that SAMP8 mice display an accelerated loss of the NSC pool that coincides with an aberrant rise in BMP6 protein, enhanced canonical BMP signaling, and increased astroglial differentiation. In vitro assays demonstrate that BMP6 severely impairs NSC expansion and promotes NSC differentiation into postmitotic astrocytes. Blocking the dysregulation of the BMP pathway and its progliogenic effect in vivo by intracranial delivery of the antagonist Noggin restores hippocampal NSC numbers, neurogenesis, and behavior in SAMP8 mice. Thus, manipulating the local microenvironment of the NSC pool counteracts hippocampal dysfunction in pathological aging. Our results shed light on interventions that may allow taking advantage of the brain's natural plastic capacity to enhance cognitive function in late adulthood and in chronic neurodegenerative diseases such as AD.This work was supported by a predoctoral fellowship from the Spanish Ministerio de Educación (to M.D.-M.), Spanish Ministerio de Economía y Competitividad Grant BFU2013-48907-R (to J.L.T.), and Grants PI12/101 and SAF2015-70433-R (to H.M.). We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).Peer reviewe