Cuartero Desviat, María Isabel

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First Name
María Isabel
Last Name
Cuartero Desviat
Universidad Complutense de Madrid
Faculty / Institute
Farmacología y Toxicología
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Now showing 1 - 10 of 19
  • Publication
    Ipsilesional Hippocampal Gaba is elevated and correlates with cognitive impairment and maladaptive neurogenesis after cortical stroke in mice
    (Wolters Kluwer, 2023-09-11) Torres López, Cristina; 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.ConclusionsHippocampal GABAergic neurotransmission could be considered a novel diagnostic and therapeutic target for post-stroke cognitive impairment.
  • Publication
    Defective hippocampal neurogenesis underlies cognitive impairment by carotid stenosis-induced cerebral hypoperfusion in mice
    (2023-08-11) Fraga, Enrique; Medina, Violeta; Cuartero Desviat, María Isabel; García Culebras, Alicia; Bravo Ferrer, Isabel; Hernández Jiménez, Macarena; García Segura, Juan Manuel; Hurtado Moreno, Olivia; Pradillo Justo, Jesús Miguel; Lizasoaín Hernández, Ignacio; Moro Sánchez, María Ángeles
    Chronic cerebral hypoperfusion due to carotid artery stenosis is a major cause of vascular cognitive impairment and dementia (VCID). Bilateral carotid artery stenosis (BCAS) in rodents is a well-established model of VCID where most studies have focused on white matter pathology and subsequent cognitive deficit. Therefore, our aim was to study the implication of adult hippocampal neurogenesis in hypoperfusion-induced VCID in mice, and its relationship with cognitive hippocampal deficits. Mice were subjected to BCAS; 1 and 3 months later, hippocampal memory and neurogenesis/cell death were assessed, respectively, by the novel object location (NOL) and spontaneous alternation performance (SAP) tests and by immunohistology. Hypoperfusion was assessed by arterial spin labeling-magnetic resonance imaging (ASL-MRI). Hypoperfused mice displayed spatial memory deficits with decreased NOL recognition index. Along with the cognitive deficit, a reduced number of newborn neurons and their aberrant morphology indicated a remarkable impairment of the hippocampal neurogenesis. Both increased cell death in the subgranular zone (SGZ) and reduced neuroblast proliferation rate may account for newborn neurons number reduction. Our data demonstrate quantitative and qualitative impairment of adult hippocampal neurogenesis disturbances associated with cerebral hypoperfusion-cognitive deficits in mice. These findings pave the way for novel diagnostic and therapeutic targets for VCID.
  • Publication
    Cannabinoid Type-2 Receptor Drives Neurogenesis and Improves Functional Outcome After Stroke
    (American Heart Association, 2017-01) 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.
  • Publication
    Implicación del receptor AhR en neuroprotección y neurorreparación en ictus isquémico experimental
    (Universidad Complutense de Madrid, 2013-12-05) 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...
  • Publication
    Post-stroke Neurogenesis: Friend or Foe?
    (2021-03-23) Violeta Medina; Enrique Fraga; Sandra Vázquez-Reyes; Tania Jareño-Flores; Cuartero Desviat, María Isabel; García Culebras, Alicia; Torres López, Cristina; García Segura, Juan Manuel; Lizasoaín Hernández, Ignacio; Moro Sánchez, María Ángeles
    The substantial clinical burden and disability after stroke injury urges the need to explore therapeutic solutions. Recent compelling evidence supports that neurogenesis persists in the adult mammalian brain and is amenable to regulation in both physiological and pathological situations. Its ability to generate new neurons implies a potential to contribute to recovery after brain injury. However, post-stroke neurogenic response may have different functional consequences. On the one hand, the capacity of newborn neurons to replenish the damaged tissue may be limited. In addition, aberrant forms of neurogenesis have been identified in several insult settings. All these data suggest that adult neurogenesis is at a crossroads between the physiological and the pathological regulation of the neurological function in the injured central nervous system (CNS). Given the complexity of the CNS together with its interaction with the periphery, we ultimately lack in-depth understanding of the key cell types, cell–cell interactions, and molecular pathways involved in the neurogenic response after brain damage and their positive or otherwise deleterious impact. Here we will review the evidence on the stroke-induced neurogenic response and on its potential repercussions on functional outcome. First, we will briefly describe subventricular zone (SVZ) neurogenesis after stroke beside the main evidence supporting its positive role on functional restoration after stroke. Then, we will focus on hippocampal subgranular zone (SGZ) neurogenesis due to the relevance of hippocampus in cognitive functions; we will outline compelling evidence that supports that, after stroke, SGZ neurogenesis may adopt a maladaptive plasticity response further contributing to the development of post-stroke cognitive impairment and dementia. Finally, we will discuss the therapeutic potential of specific steps in the neurogenic cascade that might ameliorate brain malfunctioning and the development of post-stroke cognitive impairment in the chronic phase.
  • Publication
    Abolition of aberrant neurogenesis ameliorates cognitive impairment after stroke in mice
    (American Society for Clinical Investigation, 2019-02-25) Cuartero Desviat, María Isabel; Parra Gonzalo, Juan De La; Pérez Ruiz, Alberto; Bravo-Ferrer, Isabel; Durán Laforet, Violeta; García Culebras, Alicia; García Segura, Juan Manuel; Jagroop Dhaliwal; Paul W. Frankland; Lizasoaín Hernández, Ignacio; Moro Sánchez, María Ángeles
    Poststroke cognitive impairment is considered one of the main complications during the chronic phase of ischemic stroke. In the adult brain, the hippocampus regulates both encoding and retrieval of new information through adult neurogenesis. Nevertheless, the lack of predictive models and studies based on the forgetting processes hinders the understanding of memory alterations after stroke. Our aim was to explore whether poststroke neurogenesis participates in the development of long-term memory impairment. Here, we show a hippocampal neurogenesis burst that persisted 1 month after stroke and that correlated with an impaired contextual and spatial memory performance. Furthermore, we demonstrate that the enhancement of hippocampal neurogenesis after stroke by physical activity or memantine treatment weakened existing memories. More importantly, stroke-induced newborn neurons promoted an aberrant hippocampal circuitry remodeling with differential features at ipsi- and contralesional levels. Strikingly, inhibition of stroke-induced hippocampal neurogenesis by temozolomide treatment or using a genetic approach (Nestin-CreERT2/NSE-DTA mice) impeded the forgetting of old memories. These results suggest that hippocampal neurogenesis modulation could be considered as a potential approach for treatment of poststroke cognitive impairment.
  • Publication
    TLR4-Binding DNA Aptamers Show a Protective Effect against Acute Stroke in Animal Models
    (Cell Press, 2018-08) 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, Ignacio
    Since 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.
  • Publication
    Silent information regulator 1 protects the brain against cerebral ischemic damage
    (Lippincott, Williams & Wilkins, 2013-08) Hernández Jiménez, Macarena; Hurtado Moreno, Olivia; Cuartero Desviat, María Isabel; Ballesteros, Ivan; 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.
  • Publication
    Role of TLR4 (Toll-Like Receptor 4) in N1/N2 Neutrophil Programming After Stroke
    (Lippincott, Williams & Wilkins, 2019-10) García Culebras, Alicia; Durán Laforet, Violeta; Peña Martínez, Carolina Belén; Moraga Yébenes, Ana; Ballesteros Martín, Iván; Cuartero Desviat, María Isabel; Parra, Juan de la; Palma Tortosa, Sara; Hidalgo, Andrés; Corbí, Ángel L.; Moro Sánchez, María Ángeles; Lizasoaín Hernández, Ignacio
    Background and Purpose- After stroke, the population of infiltrated neutrophils in the brain is heterogeneous, including a population of alternative neutrophils (N2) that express M2 phenotype markers. We explored the role of TLR4 (toll-like receptor 4) on neutrophil infiltration and polarization in this setting. Methods- Focal cerebral ischemia was induced by occlusion of the middle cerebral artery occlusion in TLR4-KO and WT (wild type) mice. Infarct size was measured by Nissl staining and magnetic resonance imaging. Leukocyte infiltration was quantified 48 hours after middle cerebral artery occlusion by immunofluorescence and flow cytometry. To elucidate mechanisms underlying TLR4-mediated N2 phenotype, a cDNA microarray analysis was performed in neutrophils isolated from blood 48 hours after stroke in WT and TLR4-KO mice. Results- As demonstrated previously, TLR4-deficient mice presented lesser infarct volumes than WT mice. TLR4-deficient mice showed higher density of infiltrated neutrophils 48 hours after stroke compared with WT mice, concomitantly to neuroprotection. Furthermore, cytometric and stereological analyses revealed an increased number of N2 neutrophils (YM1+ cells) into the ischemic core in TLR4-deficient mice, suggesting a protective effect of this neutrophil subset that was corroborated by depleting peripheral neutrophils or using mice with TLR4 genetically ablated in the myeloid lineage. Finally, cDNA microarray analysis in neutrophils, confirmed by quantitative polymerase chain reaction, showed that TLR4 modulates several pathways associated with ischemia-induced inflammation, migration of neutrophils into the parenchyma, and their functional priming, which might explain the opposite effect on outcome of the different neutrophil subsets. Conclusions- TLR4 deficiency increased the levels of alternative neutrophils (N2)-an effect associated with neuroprotection after stroke-supporting that modulation of neutrophil polarization is a major target of TLR4 and highlighting the crucial role of TLR4 at the peripheral level after stroke. Visual Overview- An online visual overview is available for this article.
  • Publication
    Citicoline (CDP-choline) increases Sirtuin1 expression concomitant to neuroprotection in experimental stroke
    (Wiley, 2013-05-13) Hurtado Moreno, Olivia; Hernández Jiménez, Macarena; Zarruk, Juan G.; Cuartero Desviat, María Isabel; Ballesteros, Iván; Camarero, Guadalupe; Moraga Yébenes, Ana; Pradillo Justo, Jesús Miguel; Moro Sánchez, María Ángeles; Lizasoaín Hernández, Ignacio
    CDP-choline has shown neuroprotective effects in cerebral ischemia. In humans, although a recent trial International Citicoline Trial on Acute Stroke (ICTUS) has shown that global recovery is similar in CDP-choline and placebo groups, CDP-choline was shown to be more beneficial in some patients, such as those with moderate stroke severity and not treated with t-PA. Several mechanisms have been proposed to explain the beneficial actions of CDP-choline. We have now studied the participation of Sirtuin1 (SIRT1) in the neuroprotective actions of CDP-choline. Fischer rats and Sirt1⁻/⁻ mice were subjected to permanent focal ischemia. CDP-choline (0.2 or 2 g/kg), sirtinol (a SIRT1 inhibitor; 10 mg/kg), and resveratrol (a SIRT1 activator; 2.5 mg/kg) were administered intraperitoneally. Brains were removed 24 and 48 h after ischemia for western blot analysis and infarct volume determination. Treatment with CDP-choline increased SIRT1 protein levels in brain concomitantly to neuroprotection. Treatment with sirtinol blocked the reduction in infarct volume caused by CDP-choline, whereas resveratrol elicited a strong synergistic neuroprotective effect with CDP-choline. CDP-choline failed to reduce infarct volume in Sirt1⁻/⁻ mice. Our present results demonstrate a robust effect of CDP-choline like SIRT1 activator by up-regulating its expression. Our findings suggest that therapeutic strategies to activate SIRT1 may be useful in the treatment of stroke. Sirtuin 1 (SIRT1) is implicated in a wide range of cellular functions. Regarding stroke, there is no direct evidence. We have demonstrated that citicoline increases SIRT1 protein levels in brain concomitantly to neuroprotection. Citicoline fails to reduce infarct volume in Sirt1⁻/⁻ mice. Our findings suggest that therapeutic strategies acting on SIRT1 may be useful in the treatment of stroke.