Person: Cuartero Desviat, María Isabel
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First Name
María Isabel
Last Name
Cuartero Desviat
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Medicina
Department
Farmacología y Toxicología
Area
Farmacología
Identifiers
22 results
Search Results
Now showing 1 - 10 of 22
Item TLR4-Binding DNA Aptamers Show a Protective Effect against Acute Stroke in Animal Models(Molecular Therapy, 2018) Fernández Gómez-Chacón, Gerónimo Félix; Moraga Yébenes, Ana; Cuartero Desviat, María Isabel; García Culebras, Alicia; Peña Martínez, Carolina Belén; Pradillo Justo, Jesús Miguel; Lizasoaín Hernández, IgnacioSince Toll-like receptor 4 (TLR4) mediates brain damage after stroke, development of TLR4 antagonists is a promising therapeutic strategy for this disease. Our aim was to generate TLR4-blocking DNA aptamers to be used for stroke treatment. From a random oligonucleotide pool, we identified two aptamers (ApTLR#1R, ApTLR#4F) with high affinity for human TLR4 by systematic evolution of ligands by exponential enrichment (SELEX). Optimized truncated forms (ApTLR#1RT, ApTLR#4FT) were obtained. Our data demonstrate specific binding of both aptamers to human TLR4 as well as a TLR4 antagonistic effect. ApTLR#4F and ApTLR#4FT showed a long-lasting protective effect against brain injury induced by middle cerebral artery occlusion (MCAO), an effect that was absent in TLR4-deficient mice. Similar effects were obtained in other MCAO models, including in rat. Additionally, efficacy of ApTLR#4FT in a model of brain ischemia-reperfusion in rat supports the use of this aptamer in patients undergoing artery recanalization induced by pharmacological or mechanical interventions. The absence of major toxicology aspects and the good safety profile of the aptamers further encourage their future clinical positioning for stroke therapy and possibly other diseases in which TLR4 plays a deleterious role.Item N2 Neutrophils, Novel Players in Brain Inflammation After Stroke(Stroke, 2013) Cuartero Desviat, María Isabel; Ballesteros Martín, Iván; Moraga Yébenes, Ana; Nombela, Florentino; Vivancos Mora, José; Hamilton, John A.; Corbí, Ángel L.; Lizasoaín Hernández, Ignacio; Moro Sánchez, María ÁngelesBackground and Purpose—Neutrophils have been traditionally recognized as major mediators of a deleterious inflammatory response in acute ischemic stroke, but their potential as a therapeutic target remains unexplored. Recent evidence indicates that neutrophils may acquire different phenotypes and contribute to resolution of inflammation through the release of anti-inflammatory mediators. Thus, similar to M2 macrophages, neutrophils have been proposed to shift toward an N2 phenotype, a polarization that is peroxisome proliferator-activated receptor-γ dependent in macrophages. We hypothesize that peroxisome proliferator-activated receptor-γ activation with rosiglitazone induces changes in neutrophilic mobilization and phenotype that might influence stroke outcome. MethoBrain sections and cell suspensions were prepared from mice exposed to permanent distal middle cerebral artery occlusion. Double immunostaining with stereological counting of brain sections and flow-cytometry analysis of brain cell suspensions were performed. Results—Rosiglitazone accelerated neutrophil infiltration to the ischemic core, concomitantly to neuroprotection. Some neutrophils (≈31%) expressed M2 markers, namely Ym1 and CD206 (mannose receptor). After treatment with the peroxisome proliferator-activated receptor-γ agonist rosiglitazone, most neutrophils (≈77%) acquired an N2 phenotype. Interestingly, rosiglitazone increased neutrophil engulfment by microglia/macrophages, a clearance that preferentially affected the N2 subset. Conclusions—We present the first evidence of neutrophil reprogramming toward an N2 phenotype in brain inflammation, which can be modulated by activation of the peroxisome proliferator-activated receptor-γ nuclear receptor. We also show that N2 polarization is associated with an increased neutrophil clearance, thus suggesting that this switch is a crucial event for resolution of inflammation that may participate in neuroprotection.Item Stereological and Flow Cytometry Characterization of Leukocyte Subpopulations in Models of Transient or Permanent Cerebral Ischemia(Journal of Visualized Experiments (JoVE), 2014) Ballesteros Martín, Iván; Cuartero Desviat, María Isabel; Moraga Yébenes, Ana; Parra, Juan de la; Lizasoaín Hernández, Ignacio; Moro Sánchez, María ÁngelesMicroglia activation, as well as extravasation of haematogenous macrophages and neutrophils, is believed to play a pivotal role in brain injury after stroke. These myeloid cell subpopulations can display different phenotypes and functions and need to be distinguished and characterized to study their regulation and contribution to tissue damage. This protocol provides two different methodologies for brain immune cell characterization: a precise stereological approach and a flow cytometric analysis. The stereological approach is based on the optical fractionator method, which calculates the total number of cells in an area of interest (infarcted brain) estimated by a systematic random sampling. The second characterization approach provides a simple way to isolate brain leukocyte suspensions and to characterize them by flow cytometry, allowing for the characterization of microglia, infiltrated monocytes and neutrophils of the ischemic tissue. In addition, it also details a cerebral ischemia model in mice that exclusively affects brain cortex, generating highly reproducible infarcts with a low rate of mortality, and the procedure for histological brain processing to characterize infarct volume by the Cavalieri method.Item Imaging the role of toll-like receptor 4 on cell proliferation and inflammation after cerebral ischemia by positron emission tomography(Journal of Cerebral Blood Flow and Metabolism (JCBFM), 2016) Moraga Yébenes, Ana; Gómez Vallejo, Vanessa; Cuartero Desviat, María Isabel; Szczupak, Boguslaw; San Sebastián, Eneko; Markuerkiaga, Irati; Pradillo Justo, Jesús Miguel; Higuchi, Makoto; Llop, Jordi; Moro Sánchez, María Ángeles; Martín, Abraham; Lizasoaín Hernández, IgnacioThe influence of toll-like receptor 4 on neurogenesis and inflammation has been scarcely explored so far by using neuroimaging techniques. For this purpose, we performed magnetic resonance imaging and positron emission tomography with 3'-deoxy-3'-[(18)F]fluorothymidine and [(11)C]PK11195 at 2, 7, and 14 days following cerebral ischemia in TLR4(+/+)and TLR4(-/-)mice. MRI showed similar infarction volumes in both groups. Despite this, positron emission tomography with 3'-deoxy-3'-[(18)F]fluorothymidine and [(11)C]PK11195 evidenced an increase of neurogenesis and a decrease of inflammation in TLR4(-/-)mice after ischemia. These results evidence the versatility of neuroimaging techniques to monitor the role of toll-like receptor 4 after cerebral ischemia.Item Implicación del receptor AhR en neuroprotección y neurorreparación en ictus isquémico experimental(2013) Cuartero Desviat, María Isabel; Moro Sánchez, María Ángeles; Lizasoain Hernández, Ignacio; Corbí López, ÁngelEl receptor de hidrocarburos de arilo (AhR) es un factor de transcripción que pertenece a la familia de proteínas altamente conservadas bHLH (dominio hélice-bucle-hélice)/PAS(Per-ARNT-Sim). Una de las principales funciones de AhR es mediar los efectos tóxicos y carcinogénicos de los xenobióticos. Sin embargo, cada vez son más las evidencias que indican un importante papel del receptor en funciones fisiológicas. Aunque AhR se expresa ampliamente en el SNC (Sistema Nervioso Central) sus funciones a nivel fisiológico y patológico en esta estructura son aún desconocidas. Con el fin de profundizar en la función fisiológica y patológica del receptor AhR en el cerebro, decidimos explorar la contribución de AhR al daño isquémico ocasionado por la oclusión permanente de la arteria cerebral media (pMCAO) y la privación de oxígeno y glucosa (OGD). Los resultados presentados en esta Tesis doctoral muestran por primera vez cómo tras modelos experimentales de isquemia cerebral, la expresión del receptor AhR se incrementa siguiendo un patrón temporal y espacial concreto. Este incremento en la expresión del receptor presenta una localización principalmente neuronal. La inhibición del receptor AhR mediante los antagonistas específicos 2',4',6-trimetoxiflavona (TMF) y CH-223191 (CH) (Murray et al., 2010a; Zhao et al., 2010) o a través del uso de ratones heterocigotos para AhR (Fernández-Salguero et al., 1995) resultó neuroprotectora en nuestros modelos de isquemia cerebral y excitotoxicidad in vitro e in vivo.. [ABSTRACT]AhR (Aryl hydrocarbon receptor) is a transcription factor that belongs to the bHLH (basic helix-loop-helix)/PAS(Per-Arnt-Sim homology domain) family of highly conserved proteins. One of the main known functions of AhR is to mediate the toxic and carcinogenic effects of xenobiotics. Furthermore, several evidences indicate a physiological role of this receptor in normal cell physiology and function. Although AhR is widely expressed in the CNS (Central Nervous System), its physiological and pathological roles are still unclear. To further define the roles of this receptor in normal and pathologic brain function, we decided to explore the contribution of AhR to cerebral ischemic damage caused by permanent middle cerebral artery occlusion (pMCAO) and oxygen-glucose deprivation (OGD). The results presented in this Thesis show for the first time that AhR is induced after different experimental models of cerebral ischemia with specific temporal and regional profiles. In this context, AhR is mainly located in neurons placed in peri-infarct areas surrounding core region. Pharmacological or genetic loss-offunction approaches using the AhR antagonists 2',4',6-trimethoxyflavone (TMF) and CH-223191 (CH) (Murray et al., 2010a; Zhao et al., 2010) or AhR heterozygous mice (Fernández-Salguero et al., 1995) resulted in neuroprotection in our in vitro and in vivo models of brain ischemia and excitotoxicity...Item Silent Information Regulator 1 Protects the Brain Against Cerebral Ischemic Damage(Stroke, 2013) Hernández Jiménez, Macarena; Hurtado Moreno, Olivia; Cuartero Desviat, María Isabel; Ballesteros Martín, Iván; Moraga Yébenes, Ana; Pradillo Justo, Jesús Miguel; McBurney, Michael W.; Lizasoaín Hernández, Ignacio; Moro Sánchez, María ÁngelesBackground and purpose: Sirtuin 1 (SIRT1) is a member of NAD+-dependent protein deacetylases implicated in a wide range of cellular functions and has beneficial properties in pathologies including ischemia/reperfusion processes and neurodegeneration. However, no direct evidence has been reported on the direct implication of SIRT1 in ischemic stroke. The aim of this study was to establish the role of SIRT1 in stroke using an experimental model in mice. Methods: Wild-type and Sirt1-/- mice were subjected to permanent focal ischemia by permanent ligature. In another set of experiments, wild-type mice were treated intraperitoneally with vehicle, activator 3 (SIRT1 activator, 10 mg/kg), or sirtinol (SIRT1 inhibitor, 10 mg/kg) for 10 minutes, 24 hours, and 40 hours after ischemia. Brains were removed 48 hours after ischemia for determining the infarct volume. Neurological outcome was evaluated using the modified neurological severity score. Results: Exposure to middle cerebral artery occlusion increased SIRT1 expression in neurons of the ipsilesional mouse brain cortex. Treatment of mice with activator 3 reduced infarct volume, whereas sirtinol increased ischemic injury. Sirt1-/- mice displayed larger infarct volumes after ischemia than their wild-type counterparts. In addition, SIRT1 inhibition/deletion was concomitant with increased acetylation of p53 and nuclear factor κB (p65). Conclusions: These results support the idea that SIRT1 plays an important role in neuroprotection against brain ischemia by deacetylation and subsequent inhibition of p53-induced and nuclear factor κB-induced inflammatory and apoptotic pathways.- Project number: 204
Item Perspectiva de género en la asignatura de farmacología() Acevedo Couto, Érika Del Carmen; Cuartero Desviat, María Isabel; García Culebras, Alicia; Hernández Jiménez, Macarena; Moraga Yébenes, Ana; Ortego Merino, Fernando; Pradillo Justo, Jesús Miguel; Sánchez Fernández, Marina; Hurtado Moreno, Olivia; Gallego Matud, Julieta; Sánchez Mayordomo, AndreaEn este proyecto de innovación docente hemos trabajo para comenzar a poner las bases de posibles diferencias que pueden existir en la farmacología de los medicamentos, atendiendo a si la persona que los toma es un hombre o una mujer. Con alumnos del grado de Nutrición Humana y Dietética y de Odontología hemos buscado bibliografía que nos demuestre si efectivamente se dan estas diferencias en la farmacocinética, en la farmacodinamia y en los efectos adversos. Los resultados encontrados nos han permitido presentar 2 comunicaciones en congresos y realizar un TFG - Project number: PIMCD271/23-24
Item Charlas de investigación como vehículo para la integración de conceptos y la mejora del aprendizaje en ciencias de la salud(2024) Del Campo Milán, Lara; Castañer de Diego, Margarita; Cuartero Desviat, María Isabel; García Culebras, Alicia; García del Villar, Silvia; Gómez Del Moral Martín-Consuegra, Manuel María; López Gómez, Ana; Lozano Pérez, María Encarnación; Moraga Yébenes, Ana; Peña Martínez, Carolina Belén; Rodrigues Díez, Raúl; Vázquez Reyes, Sandra; Sánchez Álvarez, Miguel; Del Campo Milán, Lara Item Specific Features of SVZ Neurogenesis After Cortical Ischemia: a Longitudinal Study(Scientific Reports, 2017) Palma Tortosa, S.; García Culebras, Alicia; Moraga Yébenes, Ana; Hurtado Moreno, Olivia; Pérez Ruiz, Alberto; Durán Laforet, Violeta; Parra Gonzalo, Juan De La; Cuartero Desviat, María Isabel; Pradillo, J. M.; Moro Sánchez, María Ángeles; Lizasoaín Hernández, IgnacioStroke is a devastating disease with an increasing prevalence. Part of the current development in stroke therapy is focused in the chronic phase, where neurorepair mechanisms such as neurogenesis, are involved. In the adult brain, one of the regions where neurogenesis takes place is the subventricular zone (SVZ) of the lateral ventricles. Given the possibility to develop pharmacological therapies to stimulate this process, we have performed a longitudinal analysis of neurogenesis in a model of cortical ischemia in mice. Our results show an initial decrease of SVZ proliferation at 24 h, followed by a recovery leading to an increase at 14d and a second decrease 28d after stroke. Coinciding with the 24 h proliferation decrease, an increase in the eutopic neuroblast migration towards the olfactory bulb was observed. The analysis of the neuroblast ectopic migration from the SVZ toward the lesion showed an increase in this process from day 14 after the insult. Finally, our data revealed an increased number of new cortical neurons in the peri-infarct cortex 65d after the insult. In summary, we report here critical check-points about post-stroke neurogenesis after cortical infarcts, important for the pharmacological modulation of this process in stroke patients.Item Daidzein has neuroprotective effects through ligand-binding-independent PPARγ activation(Neurochemistry International, 2012) Hurtado Moreno, Olivia; Ballesteros Martin, Ivan; Cuartero Desviat, María Isabel; Moraga Yébenes, Ana; Pradillo Justo, Jesús Miguel; Ramírez Franco, Jose Jorge; Bartolomé Martín, David; Torres Muñoz, Margarita; Sánchez Prieto, J.; Lizasoaín Hernández, Ignacio; Moro Sánchez, María ÁngelesPhytoestrogens are a group of plant-derived compounds that include mainly isoflavones like daidzein. Phytoestrogens prevent neuronal damage and improve outcome in experimental stroke; however, the mechanisms of this neuroprotective action have not been fully elucidated. In this context, it has been postulated that phytoestrogens might activate the peroxisome proliferator-activated receptor-γ (PPARγ), which exerts neuroprotective effects in several settings. The aim of this study was to determine whether the phytoestrogen daidzein elicits beneficial actions in neuronal cells by mechanisms involving activation of PPARγ. Our results show that daidzein (0.05-5 μM) decreases cell death induced by exposure to oxygen-glucose deprivation (OGD) from rat cortical neurons and that improves synaptic function, in terms of increased synaptic vesicle recycling at nerve terminals, being both effects inhibited by the PPARγ antagonist T0070907 (1 μM). In addition, this phytoestrogen activated PPARγ in neuronal cultures, as shown by an increase in PPARγ transcriptional activity. Interestingly, these effects were not due to binding to the receptor ligand site, as shown by a TR-FRET PPARγ competitive binding assay. Conversely, daidzein increased PPARγ nuclear protein levels and decreased cytosolic ones, suggesting nuclear translocation. We have used the receptor antagonist (RE) fulvestrant to study the neuroprotective participation of daidzein via estrogen receptor and at least in our model, we have discarded this pathway. These results demonstrate that the phytoestrogen daidzein has cytoprotective properties in neurons, which are due to an increase in PPARγ activity not mediated by direct binding to the receptor ligand-binding domain but likely due to post-translational modifications affecting its subcellular location and not depending to the RE and it is not additive with the agonist rosiglitazone.
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