Person:
Cuartero Desviat, María Isabel

First Name

María Isabel

Last Name

Cuartero Desviat

URI

https://hdl.handle.net/20.500.14352/86356

Affiliation

Universidad Complutense de Madrid

Faculty / Institute

Medicina

Department

Farmacología y Toxicología

Area

Farmacología

Identifiers

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Search Results

Now showing 1 - 10 of 21

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 Ángeles
Phytoestrogens 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.
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 Ángeles
Background 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.
Ipsilesional Hippocampal Gaba is elevated and correlates with cognitive impairment and maladaptive neurogenesis after cortical stroke in mice
(stroke, 2023) Cuartero Desviat, María Isabel; García Culebras, Alicia; Parra Gonzalo, Juan De La; Fernández Valle, María Encarnación; Benito, Marina; Vázquez Reyes, Sandra; Jareño Flores, Tania; Castro Millán, Francisco Javier de; Hurtado Moreno, Olivia; Buckwalter, Marion S.; García Segura, Juan Manuel; Lizasoaín Hernández, Ignacio; Moro Sánchez, María Ángeles
Cognitive dysfunction is a frequent stroke sequela but its pathogenesis and treatment remain unresolved. Involvement of aberrant hippocampal neurogenesis and maladaptive circuitry remodelling has been proposed but their mechanisms are unknown. Our aim was to evaluate potential underlying molecular/cellular events implicated. Stroke was induced by permanent occlusion of the middle cerebral artery (MCAO) in 2-month-old C57BL/6 male mice. Hippocampal metabolites/neurotransmitters were analysed longitudinally by magnetic resonance spectroscopy (MRS). Cognitive function was evaluated with the contextual fear conditioning test. Microglia, astrocytes, neuroblasts and interneurons were analysed by immunofluorescence. Approximately 50% of mice exhibited progressive post-MCAO cognitive impairment. Notably, immature hippocampal neurons in the impaired group displayed more severe aberrant phenotypes than those from the non-impaired group. Using MRS, significant bilateral changes in hippocampal metabolites such as or N-acetylaspartic acid (NAA) were found that correlated, respectively, with numbers of glia and immature neuroblasts in the ischemic group. Importantly, some metabolites were specifically altered in the ipsilateral hippocampus suggesting its involvement in aberrant neurogenesis and remodelling processes. Specifically, MCAO animals with higher hippocampal GABA levels displayed worse cognitive outcome. Implication of GABA in this setting was supported by the amelioration of ischemia-induced memory deficits and aberrant hippocampal neurogenesis after blocking pharmacologically GABAergic neurotransmission. These data suggest that GABA exerts its detrimental effect, at least partly, by affecting morphology and integration of newborn neurons into the hippocampal circuits. Hippocampal GABAergic neurotransmission could be considered a novel diagnostic and therapeutic target for post-stroke cognitive impairment.
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, Ignacio
Stroke 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.
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, Ángel
El 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...
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 Ángeles
Background 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.
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 Ángeles
Background 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.
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 Ángeles
Microglia 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.
The role of gut microbiota in cerebrovascular disease and related dementia
(British Journal of Pharmacology, 2023) Cuartero Desviat, María Isabel; García Culebras, Alicia; Nieto Vaquero, Carmen; Fraga, Enrique; Torres López, Cristina; Pradillo Justo, Jesús Miguel; Lizasoaín Hernández, Ignacio; Moro Sánchez, María Ángeles
In recent years, increasing evidence suggests that commensal microbiota may play an important role not only in health but also in disease including cerebrovascular disease. Gut microbes impact physiology, at least in part, by metabolizing dietary factors and host-derived substrates and then generating active compounds including toxins. The purpose of this current review is to highlight the complex interplay between microbiota, their metabolites. and essential functions for human health, ranging from regulation of the metabolism and the immune system to modulation of brain development and function. We discuss the role of gut dysbiosis in cerebrovascular disease, specifically in acute and chronic stroke phases, and the possible implication of intestinal microbiota in post-stroke cognitive impairment and dementia, and we identify potential therapeutic opportunities of targeting microbiota in this context.
Cannabinoid Type-2 Receptor Drives Neurogenesis and Improves Functional Outcome After Stroke
(Stroke, 2017) Bravo Ferrer, Isbel; Cuartero Desviat, María Isabel; Zarruk, Juan G.; Pradillo, Jesús M.; Hurtado Moreno, Olivia; Romera, Victor G.; Díaz Alonso, Javier; García Segura, Juan Manuel; Guzmán, Manuel; Lizasoaín, Ignacio; Galve Roperh, Ismael; Moro, María A.
Background and Purpose—Stroke is a leading cause of adult disability characterized by physical, cognitive, and emotional disturbances. Unfortunately, pharmacological options are scarce. The cannabinoid type-2 receptor (CB2R) is neuroprotective in acute experimental stroke by anti-inflammatory mechanisms. However, its role in chronic stroke is still unknown. Methods—Stroke was induced by permanent middle cerebral artery occlusion in mice; CB2R modulation was assessed by administering the CB2R agonist JWH133 ((6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6Hdibenzo[b,d]pyran) or the CB2R antagonist SR144528 (N-[(1S)-endo-1,3,3-trimethylbicyclo-[2.2.1]-heptan-2-yl]-5-(4- chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide) once daily from day 3 to the end of the experiment or by CB2R genetic deletion. Analysis of immunofluorescence-labeled brain sections, 5-bromo-2´-deoxyuridine (BrdU) staining, fluorescence-activated cell sorter analysis of brain cell suspensions, and behavioral tests were performed. Results—SR144528 decreased neuroblast migration toward the boundary of the infarct area when compared with vehicletreated mice 14 days after middle cerebral artery occlusion. Consistently, mice on this pharmacological treatment, like mice with CB2R genetic deletion, displayed a lower number of new neurons (NeuN+ /BrdU+ cells) in peri-infarct cortex 28 days after stroke when compared with vehicle-treated group, an effect accompanied by a worse sensorimotor performance in behavioral tests. The CB2R agonist did not affect neurogenesis or outcome in vivo, but increased the migration of neural progenitor cells in vitro; the CB2R antagonist alone did not affect in vitro migration. Conclusions—Our data support that CB2R is fundamental for driving neuroblast migration and suggest that an endocannabinoid tone is required for poststroke neurogenesis by promoting neuroblast migration toward the injured brain tissue, increasing the number of new cortical neurons and, conceivably, enhancing motor functional recovery after stroke.