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
7 results
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Now showing 1 - 7 of 7
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; Universidad Complutense de Madrid; Centro de Investigación Biomédica en Red Enfermedades NeurodegenerativasThe 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.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 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 Microglial CB2 cannabinoid receptors are neuroprotective in Huntington's disease excitotoxicity(Brain, 2009) Palazuelos Diego, Javier; Aguado Sánchez, Tania; Pazos, Ruth; Julien, Boris; Carrasco, Carolina; Resel, Eva; Sagredo Ezquioga, 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 Use of CB2 receptor agonists for promoting neurogenesis(2007) Galve Roperh, Ismael; Guzmán Pastor, Manuel; Mechoulam, Raphael ; 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 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 ; Nguyen, Laurent; Monory, Krisztina; Marsicano, Giovanni; Di Marzo, Vincenzo; Hurd, Yasmin ; 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 The CB1 Cannabinoid Receptor Mediates Excitotoxicity-induced Neural Progenitor Proliferation and Neurogenesis(Journal of Biological Chemistry, 2007) Aguado Sánchez, Tania; Romero, Eva; Monory, Krisztina; Palazuelos Diego, Javier; Sendtner, Michael; Marsicano, Giovanni; Lutz, Beat; Guzmán Pastor, Manuel; Galve Roperh, IsmaelEndocannabinoids are lipid signaling mediators that exert an important neuromodulatory role and confer neuroprotection in several types of brain injury. Excitotoxicity and stroke can induce neural progenitor (NP) proliferation and differentiation as an attempt of neuroregeneration after damage. Here we investigated the mechanism of hippocampal progenitor cell engagement upon excitotoxicity induced by kainic acid administration and the putative involvement of the CB1 cannabinoid receptor in this process. Adult NPs express kainate receptors that mediate proliferation and neurosphere generation in vitro via CB1 cannabinoid receptors. Similarly, in vivo studies showed that excitotoxicity-induced hippocampal NPs proliferation and neurogenesis are abrogated in CB1-deficient mice and in wild-type mice administered with the selective CB1 antagonist rimonabant (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazolecarboxamide; SR141716). Kainate stimulation increased basic fibroblast growth factor (bFGF) expression in cultured NPs in a CB1-dependent manner as this response was prevented by rimonabant and mimicked by endocannabinoids. Likewise, in vivo analyses showed that increased hippocampal expression of bFGF, as well as of brain-derived neurotrophic factor and epidermal growth factor, occurs upon excitotoxicity and that CB1 receptor ablation prevents this induction. Moreover, excitotoxicity increased the number of CB +1bFGF+ cells, and this up-regulation preceded NP proliferation. In summary, our results show the involvement of the CB1 cannabinoid receptor in NP proliferation and neurogenesis induced by excitotoxic injury and support a role for bFGF signaling in this process.