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
6 results
Search Results
Now showing 1 - 6 of 6
Item Cannabinoid CB1 receptor gene inactivation in oligodendrocyte precursors disrupts oligodendrogenesis and myelination in mice(Cell Death and Disease, 2022) Sánchez De La Torre, Aníbal; Aguado Sánchez, Tania; Huerga-Gómez, Alba; Santamaría, Silvia; Gentile, Antonietta; Chara, Juan Carlos; Matute, Carlos; Monory, Krisztina; Mato, Susana; Guzmán Pastor, Manuel; Lutz, Beat; Galve Roperh, Ismael; Palazuelos Diego, JavierCannabinoids are known to modulate oligodendrogenesis and developmental CNS myelination. However, the cell-autonomous action of these compounds on oligodendroglial cells in vivo, and the molecular mechanisms underlying these effects have not yet been studied. Here, by using oligodendroglial precursor cell (OPC)-targeted genetic mouse models, we show that cannabinoid CB1 receptors exert an essential role in modulating OPC differentiation at the critical periods of postnatal myelination. We found that selective genetic inactivation of CB1 receptors in OPCs in vivo perturbs oligodendrogenesis and postnatal myelination by altering the RhoA/ROCK signaling pathway, leading to hypomyelination, and motor and cognitive alterations in young adult mice. Conversely, pharmacological CB1 receptor activation, by inducing E3 ubiquitin ligase-dependent RhoA proteasomal degradation, promotes oligodendrocyte development and CNS myelination in OPCs, an effect that was not evident in OPC-specific CB1 receptordeficient mice. Moreover, pharmacological inactivation of ROCK in vivo overcomes the defects in oligodendrogenesis and CNS myelination, and behavioral alterations found in OPC-specific CB1 receptor-deficient mice. Overall, this study supports a cellautonomous role for CB1 receptors in modulating oligodendrogenesis in vivo, which may have a profound impact on the scientific knowledge and therapeutic manipulation of CNS myelination by cannabinoids.Item The CB2 cannabinoid receptor controls myeloid progenitor trafficking: involvement in the pathogenesis of animal model of multiple sclerosis(Journal of biological chemistry, 2008) Palazuelos Diego, Javier; Davoust, Natalie; Julien, Boris; Hatterer, Eric; Aguado Sánchez, Tania; Benito Villalvilla, Cristina; Mechoulam, Raphael; Romero, Julián; Silva, Augusto; Guzmán Pastor, Manuel; Nataf, Serge; Galve Roperh, IsmaelCannabinoids are potential agents for the development of therapeutic strategies against multiple sclerosis. Here we analyzed the role of the peripheral CB2 cannabinoid receptor in the control of myeloid progenitor cell trafficking toward the inflamed spinal cord and their contribution to microglial activation in an animal model of multiple sclerosis (experimental autoimmune encephalomyelitis, EAE). CB2 receptor knock-out mice showed an exacerbated clinical score of the disease when compared with their wild-type littermates, and this occurred in concert with extended axonal loss, T-lymphocyte (CD4+) infiltration, and microglial (CD11b+) activation. Immature bone marrow-derived CD34+ myeloid progenitor cells, which play a role in neuroinflammatory pathologies, were shown to express CB2 receptors and to be abundantly recruited toward the spinal cords of CB2 knock-out EAE mice. Bone marrow-derived cell transfer experiments further evidenced the increased contribution of these cells to microglial replenishment in the spinal cords of CB2-deficient animals. In line with these observations, selective pharmacological CB2 activation markedly reduced EAE symptoms, axonal loss, and microglial activation. CB2 receptor manipulation altered the expression pattern of different chemokines (CCL2, CCL3, CCL5) and their receptors (CCR1, CCR2), thus providing a mechanistic explanation for its role in myeloid progenitor recruitment during neuroinflammation. These findings demonstrate the protective role of CB2 receptors in EAE pathology; provide evidence for a new site of CB2 receptor action, namely the targeting of myeloid progenitor trafficking and its contribution to microglial activation; and support the potential use of non-psychoactive CB2 agonists in therapeutic strategies for multiple sclerosis and other neuroinflammatory disorders.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 Non‐psychoactive CB2cannabinoid agonists stimulate neural progenitor proliferation(The FASEB Journal, 2006) Palazuelos Diego, Javier; Aguado Sánchez, Tania; Egia, Ainara; Mechoulam, Raphael; Guzmán Pastor, Manuel; Galve Roperh, IsmaelCannabinoids, the active components ofmarijuana and their endogenous counterparts, act onthe brain and many other organs through the widelyexpressed CB1cannabinoid receptor. In contrast, theCB2cannabinoid receptor is abundant in the immunesystem and shows a restricted expression pattern inbrain cells. CB2-selective agonists are, therefore, veryattractive therapeutic agents as they do not causeCB1-mediated psychoactive effects. CB2receptor ex-pression in brain has been partially examined in differ-entiated cells, while its presence and function in neuralprogenitor cells remain unknown. Here we show thatthe CB2receptor is expressed, bothin vitroandin vivo,in neural progenitors from late embryonic stages toadult brain. Selective pharmacological activation of theCB2receptorin vitropromotes neural progenitor cellproliferation and neurosphere generation, an actionthat is impaired in CB2-deficient cells. Accordingly,invivoexperiments evidence that hippocampal progeni-tor proliferation is increased by administration of theCB2-selective agonist HU-308. Moreover, impaired pro-genitor proliferation was observed in CB2-deficientmice both in normal conditions and on kainate-inducedexcitotoxicity. These findings provide a novel physio-logical role for the CB2cannabinoid receptor and opena novel therapeutic avenue for manipulating neuralprogenitor cell fate.—Palazuelos, J., Aguado, T., Egia, A.,Mechoulam, R., Guzma ́n, M., Galve-Roperh, I. Non-psychoactive CB2cannabinoid agonists stimulate neuralprogenitor proliferation.FASEB J.20, E1773–E1779(2006).Item The Endocannabinoid System and Neurogenesis in Health and Disease(The neuroscientist, 2007) Galve Roperh, Ismael; Aguado Sánchez, Tania; Palazuelos Diego, Javier; Guzmán Pastor, ManuelThe endocannabinoid system exerts an important neuromodulatory function in different brain areas and is also known to be involved in the regulation of neural cell fate. Thus, CB1 cannabinoid receptors are neuroprotective in different models of brain injury, and their expression is altered in various neurodegenerative diseases. Recent findings have demonstrated the presence of a functional endocannabinoid system in neural progenitor cells that participates in the regulation of cell proliferation and differentiation. In this Research Update, the authors address the experimental evidence regarding the regulatory role of cannabinoids in neurogenesis and analyze them in the context of those pathological disorders in which cannabinoid function and altered neuronal or glial generation is most relevant, for example, stroke and multiple sclerosis.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.