Person: Aguado Sánchez, Tania
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First Name
Tania
Last Name
Aguado Sánchez
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Ciencias Biológicas
Department
Bioquímica y Biología Molecular
Area
Bioquímica y Biología Molecular
Identifiers
19 results
Search Results
Now showing 1 - 10 of 19
Item Targeting Cannabinoid Receptors in Brain Tumors(Cannabinoids and the brain, 2008) Velasco Díez, Guillermo; Carracedo, Arkaitz; Blázquez Ortiz, Cristina; Lorente Pérez, María Del Mar; Aguado Sánchez, Tania; Sánchez García, María Cristina; Galve Roperh, Ismael; Guzmán Pastor, Manuel; Köfalvi, AttilaCannabinoids, the active components of Cannabis sativa L., act in the body by mimicking endogenous substances — the endocannabinoids — that activate specific cell surface receptors. Cannabinoids exert various palliative effects in cancer patients. In addition, cannabinoids inhibit the growth of different types of tumor cells, including glioma cells, in laboratory animals. They do so by modulating key cell signaling pathways, mostly the endoplasmic reticulum stress response, thereby inducing antitumoral actions such as the apoptotic death of tumor cells and the inhibition of tumor angiogenesis. Of interest, cannabinoids seem to be selective antitumoral compounds as they kill glioma cells but not their nontransformed astroglial counterparts. On the basis of these preclinical findings, a pilot clinical study of Δ9-tetrahydrocannabinol (Δ9-THC) in patients with recurrent glioblastoma multiforme has been recently run. The fair safety profile of Δ9-THC, together with its possible growth-inhibiting action on tumor cells, may set the basis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids.Item Use of CB2 receptor agonists for promoting neurogenesis(2007) Galve Roperh, Ismael; Guzmán Pastor, Manuel; Raphael Mechoulam; Palazuelos Diego, Javier; Aguado Sánchez, Tania; Pharmos Ltd.The present invention relates to ligands of the peripheral cannabinoid receptor CB2, especially (+)-α-pinene derivatives, and to pharmaceutical compositions thereof, which are useful for promoting, inducing and enhancing neurogenesis including neural cell regeneration. In particular, pharmaceutical compositions of the invention will be useful for preventing, alleviating or treating neurological injuries or damages to the CNS or the PNS associated with physical injury, ischemia, neurodegenerative disorders, certain medical procedures or medications, tumors, infections, metabolic or nutritional disorders, cognition or mood disorders, and various medical conditions associated with neural damage or destruction.Item Microglial CB2 cannabinoid receptors are neuroprotective in Huntington's disease excitotoxicity(Brain, 2009) Palazuelos Diego, Javier; Aguado Sánchez, Tania; Pazos, M. Ruth; Julien, Boris; Carrasco, Carolina; Resel, Eva; Sagredo, Onintza; Benito, Cristina; Romero, Julián; Azcoitia Elías, Íñigo; Fernández Ruiz, José Javier; Guzmán Pastor, Manuel; Galve Roperh, IsmaelCannabinoid-derived drugs are promising agents for the development of novel neuroprotective strategies. Activation of neuronal CB1 cannabinoid receptors attenuates excitotoxic glutamatergic neurotransmission, triggers prosurvival signalling pathways and palliates motor symptoms in animal models of neurodegenerative disorders. However, in Huntington's disease there is a very early downregulation of CB1 receptors in striatal neurons that, together with the undesirable psychoactive effects triggered by CB1 receptor activation, foster the search for alternative pharmacological treatments. Here, we show that CB2 cannabinoid receptor expression increases in striatal microglia of Huntington's disease transgenic mouse models and patients. Genetic ablation of CB2 receptors in R6/2 mice, that express human mutant huntingtin exon 1, enhanced microglial activation, aggravated disease symptomatology and reduced mice lifespan. Likewise, induction of striatal excitotoxicity in CB2 receptor-deficient mice by quinolinic acid administration exacerbated brain oedema, microglial activation, proinflammatory-mediator state and medium-sized spiny neuron degeneration. Moreover, administration of CB2 receptor-selective agonists to wild-type mice subjected to excitotoxicity reduced neuroinflammation, brain oedema, striatal neuronal loss and motor symptoms. Studies on ganciclovir-induced depletion of astroglial proliferation in transgenic mice expressing thymidine kinase under the control of the glial fibrillary acidic protein promoter excluded the participation of proliferating astroglia in CB2 receptor-mediated actions. These findings support a pivotal role for CB2 receptors in attenuating microglial activation and preventing neurodegeneration that may pave the way to new therapeutic strategies for neuroprotection in Huntington's disease as well as in other neurodegenerative disorders with a significant excitotoxic component.Item Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington’s disease(Brain, 2010) Blázquez Ortiz, Cristina; Chiarlone, Anna; Sagredo Ezquioga, Onintza; Aguado Sánchez, Tania; Pazos, M. Ruth; Resel, Eva; Palazuelos Diego, Javier; Julien, Boris; Salazar, María; Börner, Christine; Benito, Cristina; Carrasco, Carolina; Diez Zaera, María; Paoletti, Paola; Díaz Hernández, Miguel; Ruiz, Carolina; Sendtner, Michael; Lucas, José J.; García de Yébenes, Justo; Marsicano, Giovanni; Monory, Krisztina; Lutz, Beat; Romero, Julián; Alberch, Jordi; Ginés, Silvia; Kraus, Jürgen; Fernández Ruiz, José Javier; Galve Roperh, Ismael; Guzmán Pastor, ManuelEndocannabinoids act as neuromodulatory and neuroprotective cues by engaging type 1 cannabinoid receptors. These receptors are highly abundant in the basal ganglia and play a pivotal role in the control of motor behaviour. An early downregulation of type 1 cannabinoid receptors has been documented in the basal ganglia of patients with Huntington’s disease and animal models. However, the pathophysiological impact of this loss of receptors in Huntington’s disease is as yet unknown. Here, we generated a double-mutant mouse model that expresses human mutant huntingtin exon 1 in a type 1 cannabinoid receptor-null background, and found that receptor deletion aggravates the symptoms, neuropathology and molecular pathology of the disease. Moreover, pharmacological administration of the cannabinoid Δ9-tetrahydrocannabinol to mice expressing human mutant huntingtin exon 1 exerted a therapeutic effect and ameliorated those parameters. Experiments conducted in striatal cells show that the mutant huntingtin-dependent downregulation of the receptors involves the control of the type 1 cannabinoid receptor gene promoter by repressor element 1 silencing transcription factor and sensitizes cells to excitotoxic damage. We also provide in vitro and in vivo evidence that supports type 1 cannabinoid receptor control of striatal brain-derived neurotrophic factor expression and the decrease in brain-derived neurotrophic factor levels concomitant with type 1 cannabinoid receptor loss, which may contribute significantly to striatal damage in Huntington’s disease. Altogether, these results support the notion that downregulation of type 1 cannabinoid receptors is a key pathogenic event in Huntington’s disease, and suggest that activation of these receptors in patients with Huntington’s disease may attenuate disease progression.Item The endocannabinoid system and the regulation of neural development: potential implications in psychiatric disorders(European Archives of Psychiatry and Clinical Neuroscience, 2009) Galve Roperh, Ismael; Palazuelos Diego, Javier; Aguado Sánchez, Tania; Guzmán Pastor, ManuelDuring brain development, functional neurogenesis is achieved by the concerted action of various steps that include the expansion of progenitor cells, neuronal specification, and establishment of appropriate synapses. Brain patterning and regionalization is regulated by a variety of extracellular signals and morphogens that, together with neuronal activity, orchestrate and regulate progenitor proliferation, differentiation, and neuronal maturation. In the adult brain, CB1 cannabinoid receptors are expressed at very high levels in selective areas and are engaged by endocannabinoids, which act as retrograde messengers controlling neuronal function and preventing excessive synaptic activity. In addition, the endocannabinoid system is present at early developmental stages of nervous system formation. Recent studies have provided novel information on the role of this endogenous neuromodulatory system in the control of neuronal specification and maturation. Thus, cannabinoid receptors and locally produced endocannabinoids regulate neural progenitor proliferation and pyramidal specification of projecting neurons. CB1 receptors also control axonal navigation, migration, and positioning of interneurons and excitatory neurons. Loss of function studies by genetic ablation or pharmacological blockade of CB1 receptors interferes with long-range subcortical projections and, likewise, prenatal cannabinoid exposure induces different functional alterations in the adult brain. Potential implications of these new findings, such as the participation of the endocannabinoid system in the pathogenesis of neurodevelopmental disorders (e.g., schizophrenia) and the regulation of neurogenesis in brain depression, are discussed herein.Item Endocannabinoid signaling controls pyramidal cell specification and long-range axon patterning(Proceedings of the National Academy of Sciences (PNAS), 2008) Mulder, Jan; Aguado Sánchez, Tania; Keimpema, Erik; Barabás, Klaudia; Ballester Rosado, Carlos J.; Nguyen, Laurent; Monory, Krisztina; Marsicano, Giovanni; Di Marzo, Vincenzo; Hurd, Yasmin L.; Guillemot, Francois; Mackie, Ken; Lutz, Beat; Guzmán Pastor, Manuel; Lu, Hui Chen; Galve Roperh, Ismael; Harkany, TiborEndocannabinoids (eCBs) have recently been identified as axon guidance cues shaping the connectivity of local GABAergic interneurons in the developing cerebrum. However, eCB functions during pyramidal cell specification and establishment of long-range axonal connections are unknown. Here, we show that eCB signaling is operational in subcortical proliferative zones from embryonic day 12 in the mouse telencephalon and controls the proliferation of pyramidal cell progenitors and radial migration of immature pyramidal cells. When layer patterning is accomplished, developing pyramidal cells rely on eCB signaling to initiate the elongation and fasciculation of their long-range axons. Accordingly, CB1 cannabinoid receptor (CB1R) null and pyramidal cell-specific conditional mutant (CB1Rf/f,NEX-Cre) mice develop deficits in neuronal progenitor proliferation and axon fasciculation. Likewise, axonal pathfinding becomes impaired after in utero pharmacological blockade of CB1Rs. Overall, eCBs are fundamental developmental cues controlling pyramidal cell development during corticogenesis.Item Mechanisms of Control of Neuron Survival by the Endocannabinoid System(Current Pharmaceutical Design, 2008) Galve Roperh, Ismael; Aguado Sánchez, Tania; Palazuelos Diego, Javier; Guzmán Pastor, ManuelEndocannabinoids act as retrograde messengers that, by inhibiting neurotransmitter release via presynaptic CB1 cannabinoid receptors, regulate the functionality of many synapses. In addition, the endocannabinoid system participates in the control of neuron survival. Thus, CB1 receptor activation has been shown to protect neurons from acute brain injury as well as in neuroinflammatory conditions and neurodegenerative diseases. Nonetheless, some studies have reported that cannabinoids can also exert neurotoxic actions. Cannabinoid neuroprotective activity relies on the inhibition of glutamatergic neurotransmission and on other various mechanisms, and is supported by the observation that the brain overproduces endocannabinoids upon damage. Coupling of neuronal CB1 receptors to cell survival routes such as the phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase pathways may contribute to cannabinoid neuroprotective action. These pro-survival signals occur, at least in part, by the cross-talk between CB1 receptors and growth factor tyrosine kinase receptors. Besides promoting neuroprotection, a role for the endocannabinoid system in the control of neurogenesis from neural progenitors has been put forward. In addition, activation of CB2 cannabinoid receptors on glial cells may also participate in neuroprotection by limiting the extent of neuroinflammation. Altogether, these findings support that endocannabinoids constitute a new family of lipid mediators that act as instructive signals in the control of neuron survival.Item Endocannabinoids: a new family of lipid mediators involved in the regulation of neural cell development(Current Pharmaceutical Design, 2006) Galve Roperh, Ismael; Aguado Sánchez, Tania; Rueda, Daniel; Velasco Díez, Guillermo; Guzmán Pastor, ManuelThe endocannabinoids (eCBs) anandamide and 2-arachidonoylglycerol are important retrograde messengers that inhibit neurotransmitter release via presynaptic CB1 receptors. In addition, cannabinoids are known to modulate the cell death/survival decision of different neural cell types, leading to different outcomes that depend on the nature of the target cell and its proliferative/differentiation status. Thus, cannabinoids protect primary neurons, astrocytes and oligodendrocytes from apoptosis, whereas transformed glial cells are prone to apoptosis by cannabinoid challenge. Moreover, a potential role of the eCB system in neurogenesis and neural differentiation has been proposed. Recent research shows that eCBs stimulate neural progenitor proliferation and inhibit hippocampal neurogenesis in normal adult brain. Cannabinoids inhibit cortical neuron differentiation and promote glial differentiation. On the other hand, experiments with differentiated neurons have shown that cannabinoids also regulate neuritogenesis, axonal growth and synaptogenesis. These new observations support that eCBs constitute a new family of lipid signaling cues responsible for the regulation of neural progenitor proliferation and differentiation, acting as instructive proliferative signals through the CB1 receptor.Item The CB1 Cannabinoid Receptor Drives Corticospinal Motor Neuron Differentiation through the Ctip2/Satb2 Transcriptional Regulation Axis(The Journal of Neuroscience, 2012) Díaz Alonso, Javier; Aguado Sánchez, Tania; Wu, Chia Shan; Palazuelos Diego, Javier; Hofmann, Clementine; Garcez, Patricia; Guillemot, François; Lu, Hui Chen; Lutz, Beat; Guzmán Pastor, Manuel; Galve Roperh, IsmaelThe generation and specification of pyramidal neuron subpopulations during development relies on a complex network of transcription factors. The CB1 cannabinoid receptor is the major molecular target of endocannabinoids and marijuana active compounds. This receptor has been shown to influence neural progenitor proliferation and axonal growth, but its involvement in neuronal differentiation and the functional impact in the adulthood caused by altering its signaling during brain development are not known. Here we show that the CB1 receptor, by preventing Satb2 (special AT-rich binding protein 2)-mediated repression, increased Ctip2 (COUP-TF interacting protein 2) promoter activity, and Ctip2-positive neuron generation. Unbalanced neurogenic fate determination found in complete CB1−/− mice and in glutamatergic neuron-specific Nex–CB1−/− mice induced overt alterations in corticospinal motor neuron generation and subcerebral connectivity, thereby resulting in an impairment of skilled motor function in adult mice. Likewise, genetic deletion of CB1 receptors in Thy1–YFP–H mice elicited alterations in corticospinal tract development. Altogether, these data demonstrate that the CB1 receptor contributes to the generation of deep-layer cortical neurons by coupling endocannabinoid signals from the neurogenic niche to the intrinsic proneurogenic Ctip2/Satb2 axis, thus influencing appropriate subcerebral projection neuron specification and corticospinal motor function in the adulthood.Item Corticospinal upper motor neurons, methods and compositions for differentiating neural stem cells by modulating CB1 cannabinoid receptor signaling and use thereof(2012) Galve Roperh, Ismael; Guzmán Pastor, Manuel; Díaz Alonso, Javier; Aguado Sánchez, Tania; UCM/CIBER Enfermedades Nurodegenerativas (CIBERNED)The present invention relates to compositions and methods for obtaining a corticospinal upper motor neuron from a neural stem cell comprising the use of a CB1 cannabinoid receptor agonist, or the use of an inhibitor of an endocannabinoid-degrading enzyme, or the modification of a neural stem cell to decrease the expression of an endocannabinoid-degrading enzyme under basal levels or to increase the expression of the CB1 cannabinoid receptor above basal levels. The invention also relates to the corticospinal upper motor neurons obtained and uses thereof.