Oral administration of the KATP channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis

Background Multiple Sclerosis (MS) is an acquired inflammatory demyelinating disorder of the central nervous system (CNS) and is the leading cause of nontraumatic disability among young adults. Activated microglial cells are important effectors of demyelination and neurodegeneration, by secreting cytokines and others neurotoxic agents. Previous studies have demonstrated that microglia expresses ATP-sensitive potassium (KATP) channels and its pharmacological activation can provide neuroprotective and anti-inflammatory effects. In this study, we have examined the effect of oral administration of KATP channel opener diazoxide on induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Methods Anti-inflammatory effects of diazoxide were studied on lipopolysaccharide (LPS) and interferon gamma (IFNy)-activated microglial cells. EAE was induced in C57BL/6J mice by immunization with myelin oligodendrocyte glycoprotein peptide (MOG35-55). Mice were orally treated daily with diazoxide or vehicle for 15 days from the day of EAE symptom onset. Treatment starting at the same time as immunization was also assayed. Clinical signs of EAE were monitored and histological studies were performed to analyze tissue damage, demyelination, glial reactivity, axonal loss, neuronal preservation and lymphocyte infiltration. Results Diazoxide inhibited in vitro nitric oxide (NO), tumor necrosis factor alpha (TNF-¿) and interleukin-6 (IL-6) production and inducible nitric oxide synthase (iNOS) expression by activated microglia without affecting cyclooxygenase-2 (COX-2) expression and phagocytosis. Oral treatment of mice with diazoxide ameliorated EAE clinical signs but did not prevent disease. Histological analysis demonstrated that diazoxide elicited a significant reduction in myelin and axonal loss accompanied by a decrease in glial activation and neuronal damage. Diazoxide did not affect the number of infiltrating lymphocytes positive for CD3 and CD20 in the spinal cord. Conclusion Taken together, these results demonstrate novel actions of diazoxide as an anti-inflammatory agent, which might contribute to its beneficial effects on EAE through neuroprotection. Treatment with this widely used and well-tolerated drug may be a useful therapeutic intervention in ameliorating MS disease

Enseñar en Educación Secundaria, un compromiso con la construcción de aprendizajes relevantes y duraderos. Unidades didácticas, secuencias y proyectos, y sus propuestas de evaluación (2019). Parte 2. Propuestas para Matemática y Tecnologías

Fil: Ferreyra, Horacio Ademar. Universidad Católica de Córdoba. Facultad de Educación; ArgentinaFil: Vidales, Silvia Noemí. Universidad Católica de Córdoba. Facultad de Educación; Argentin

ICO-ICS Praxi per al tractament mèdic i amb irradiació de càncer gàstric i d'unió esofagogàstrica

Tractament mèdic; Tractament amb irradiació; Càncer de la unió esofagogàstricaTratamiento médico; Tratamiento con irradiación; Cáncer de la unión esofagogástricaMedical treatment; Irradiation treatment; Esophagogastric union cancerEl càncer gàstric (CG) és actualment el vuitè tipus de càncer més prevalent a la Unió Europea on, segons les estimacions, el 2018 es calculen 80.211 casos diagnosticats en ambdós sexes amb una taxa estimada d'incidència estandarditzada per edat de 6,4 casos per cada 100.000 habitants. En el cas d'Espanya, segons dades d'incidència i mortalitat del projecte GLOBOCAN i de l'Observatori Europeu del Càncer, se situa en novè lloc, després del càncer de bufeta i el càncer uterí, pel que fa a freqüència. Els objectius d'aquesta guia són: Desenvolupar, difondre, implementar i avaluar resultats de l'ICO-ICSPraxi de càncer gàstric i d'unió esofagogàstrica. Disminuir la variabilitat terapèutica entre els pacients tractats als diferents centres d'aquesta institució. Implementar els resultats de la terapèutica en els pacients amb càncer gàstric i d'unió esofagogàstrica tractats d'acord amb les recomanacions d'aquesta guia.El cáncer gástrico (CG) es actualmente el octavo tipo de cáncer más prevalente en la Unión Europea donde, según las estimaciones, el 2018 se calculan 80.211 casos diagnosticados en ambos sexos con una tasa estimada de incidencia estandarizada por edad de 6,4 casos por cada 100.000 habitantes. En el caso de España, según datos de incidencia y mortalidad del proyecto GLOBOCAN y del Observatorio Europeo del Cáncer, se sitúa en noveno lugar, después del cáncer de vejiga y el cáncer uterino, en cuanto a frecuencia. Los objetivos de esta guía son: Desarrollar, difundir, implementar y evaluar resultados del ICO-ICSPraxi de cáncer gástrico y de unión esofagogástrica. Disminuir la variabilidad terapéutica entre los pacientes tratados en los diferentes centros de esta institución. Implementar los resultados de la terapéutica en los pacientes con cáncer gástrico y de unión esofagogástrica tratados de acuerdo con las recomendaciones de esta guía.Gastric cancer (GC) is currently the eighth most prevalent type of cancer in the European Union where, according to estimates, 80,211 cases diagnosed in both sexes are estimated at an estimated rate of incidence standardized by age of 6.4 cases per 100,000 people. In the case of Spain, according to the incidence and mortality data of the GLOBOCAN project and the European Cancer Observatory, it is placed ninth, after bladder cancer and uterine cancer, as it happens frequently. The objectives of this guide are: Developing, disseminating, implementing and evaluating the results of the ICO-ICSPraxi of gastric cancer and esophagogastric binding. Decrease the therapeutic variability between patients treated at the different centers of this institution. Implement the results of therapeutic treatment in patients with gastric cancer and esphagogastric binding treated in accordance with the recommendations of this guide

Enseñar en educación secundaria, un compromiso con la construcción de aprendizajes relevantes y duraderos: secuencias didácticas implementadas en los distintos ciclos y años de la educación secundaria y modalidades : ciencias naturales, matemáticas y tecnologías

Fil: Ferreyra, Horacio Ademar. Universidad Católica de Córdoba. Facultad de Educación; Argentin

Correction: KATP Channel Opener Diazoxide Prevents Neurodegeneration: A New Mechanism of Action via Antioxidative Pathway Activation.

[This corrects the article DOI: 10.1371/journal.pone.0075189.]

K(ATP) channel opener diazoxide prevents neurodegeneration: a new mechanism of action via antioxidative pathway activation.

Pharmacological modulation of ATP-sensitive potassium channels has become a promising new therapeutic approach for the treatment of neurodegenerative diseases due to their role in mitochondrial and cellular protection. For instance, diazoxide, a well-known ATP-sensitive potassium channel activator with high affinity for mitochondrial component of the channel has been proved to be effective in animal models for different diseases such as Alzheimer's disease, stroke or multiple sclerosis. Here, we analyzed the ability of diazoxide for protecting neurons front different neurotoxic insults in vitro and ex vivo. Results showed that diazoxide effectively protects NSC-34 motoneurons from glutamatergic, oxidative and inflammatory damage. Moreover, diazoxide decreased neuronal death in organotypic hippocampal slice cultures after exicitotoxicity and preserved myelin sheath in organotypic cerebellar cultures exposed to pro-inflammatory demyelinating damage. In addition, we demonstrated that one of the mechanisms of actions implied in the neuroprotective role of diazoxide is mediated by the activation of Nrf2 expression and nuclear translocation. Nrf2 expression was increased in NSC-34 neurons in vitro as well as in the spinal cord of experimental autoimmune encephalomyelitis animals orally administered with diazoxide. Thus, diazoxide is a neuroprotective agent against oxidative stress-induced damage and cellular dysfunction that can be beneficial for diseases such as multiple sclerosis

Diazoxide effects in NMDA-induced neurodegeneration in hippocampal slice culture.

<p>At 7 DIV, treatment with 10 µM NMDA for 4 h induced a region-specific increase neuronal cell death of the CA1 layer compared to undamaged slices, as determined as PI uptake (PI, red) in colocalization with the neuronal nuclear marker NeuN (green) (A, B). Treatment 30 min before NMDA lesion with diazoxide prevented cell death, significantly at 100 µM but also at lowest dose 1 µM (C, D). Upon quantification, results showed a significant decrease at 100 µM (65±5% in PI uptake compared to control) and 1 µM (67±7% in PI uptake compared to control (E). When microglia was removed from the slices, cell protection remained at the lowest dose 1 µM (62±10% in PI uptake compared to control) (F-J). Data are a summary of four to seven individual experiments with 6 slices per conditions analyzed in each experiment. Results are shown as mean ± SEM. * p<0.05, ** p<0.01. Scale bar 300 µm</p

Diazoxide increases Nrf2 nuclear translocation in NSC-34 motoneurons and prevents endogenous oxidative damage.

<p>Western blot showed an increase of Nrf2 signaling in the nuclear extracts from NSC-34 neurons treated with different doses of diazoxide for 24 h. The higher increase of Nrf2 was found at lower doses (10 and 1 µM) (A). Cell viability of NSC-34 cells was measured after 24 h AAPH oxidative stress activation and results demonstrated that diazoxide treatment effectively ameliorates cell viability at low doses (B). Results expressed as mean ± SEM. n≥4 experiments. *: p < 0.05, ** p<0.01. Scale bar  =  30 µm</p