Person:
Guzmán Pastor, Manuel

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First Name
Manuel
Last Name
Guzmán Pastor
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Ciencias Químicas
Department
Bioquímica y Biología Molecular
Area
Bioquímica y Biología Molecular
Identifiers
UCM identifierORCIDScopus Author IDDialnet ID

Search Results

Now showing 1 - 10 of 54
  • Publication
    BiP Heterozigosity Aggravates Pathological Deterioration in Experimental Amyotrophic Lateral Sclerosis
    (MDPI, 2021-11-20) Gómez Almería, Marta; Burgaz García-Oteyza, Sonia; Costas Insua, Carlos; Rodríguez Cueto, Carmen; Santos García, Irene; Rodríguez Crespo, Ignacio; García García, Concepción; Guzmán Pastor, Manuel; Fernández Ruiz, Javier
    In the present study, we investigated the involvement of the chaperone protein BiP (also known as GRP78 or Hspa5), a master regulator of intracellular proteostasis, in two mouse models of neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). To this end, we used mice bearing partial genetic deletion of the BiP gene (BiP+/− mice), which, for the ALS model, were crossed with mutant SOD1 (mSOD1) transgenic mice to generate mSOD1/BiP+/− double mutant mice. Our data revealed a more intense neurological decline in the double mutants, reflected in a greater deterioration of the neurological score and rotarod performance, with also a reduced animal survival, compared to mSOD1 transgenic mice. Such worsening was associated with higher microglial (labelled with Iba-1 immunostaining) and, to a lesser extent, astroglial (labelled with GFAP immunostaining) immunoreactivities found in the double mutants, but not with a higher loss of spinal motor neurons (labelled with Nissl staining) in the spinal cord. The morphological analysis of Iba-1 and GFAP-positive cells revealed a higher presence of activated cells, characterized by elevated cell body size and shorter processes, in double mutants compared to mSOD1 mice with normal BiP expression. In the case of the PD model, BiP+/− mice were unilaterally lesioned with the parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). In this case, however, we did not detect a greater susceptibility to damage in mutant mice, as the motor defects caused by 6-OHDA in the pole test and the cylinder rearing test, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity (labelled with CD68 and GFAP immunostaining) detected in the substantia nigra were of similar magnitude in BiP+/− mice compared with wildtype animals. Therefore, our findings support the view that a dysregulation of the protein BiP may contribute to ALS pathogenesis. As BiP has been recently related to cannabinoid type-1 (CB1) receptor function, our work also opens the door to future studies on a possible link between BiP and the neuroprotective effects of cannabinoids that have been widely reported in this neuropathological context. In support of this possibility, preliminary data indicate that CB1 receptor levels are significantly reduced in mSOD1 mice having partial deletion of BiP gene.
  • Publication
    Inhibition of striatonigral autophagy as a link between cannabinoid intoxication and impairment of motor coordination
    (eLife Sciences Publications, 2020-08-10) Blázquez Ortiz, Cristina; Ruiz-Calvo, Andrea; Bajo-Grañeras, Raquel; Baufreton, Jérôme M.; Resel, Eva; Varilh, Marjorie; Pagano Zottola, Antonio C.; Mariani, Yamuna; Cannich, Astrid; Rodríguez-Navarro, José A.; Marsicano, Giovanni; Galve Roperh, Ismael; Bellocchio, Luigi; Guzmán Pastor, Manuel
    The use of cannabis is rapidly expanding worldwide. Thus, innovative studies aimed to identify, understand and potentially reduce cannabis-evoked harms are warranted. Here, we found that D 9 -tetrahydrocannabinol, the psychoactive ingredient of cannabis, disrupts autophagy selectively in the striatum, a brain area that controls motor behavior, both in vitro and in vivo. Boosting autophagy, either pharmacologically (with temsirolimus) or by dietary intervention (with trehalose), rescued the D 9 -tetrahydrocannabinol-induced impairment of motor coordination in mice. The combination of conditional knockout mouse models and viral vector-mediated autophagymodulating strategies in vivo showed that cannabinoid CB1 receptors located on neurons belonging to the direct (striatonigral) pathway are required for the motor-impairing activity of D 9 - tetrahydrocannabinol by inhibiting local autophagy. Taken together, these findings identify inhibition of autophagy as an unprecedented mechanistic link between cannabinoids and motor performance, and suggest that activators of autophagy might be considered as potential therapeutic tools to treat specific cannabinoid-evoked behavioral alterations.
  • Publication
    BiP Heterozigosity Aggravates Pathological Deterioration in Experimental Amyotrophic Lateral Sclerosis
    (MPDI, 2021-11-20) Gómez Almería, Marta; Burgaz García-Oteyza, Sonia; Costas Insua, Carlos; Rodríguez Cueto, Carmen; Santos García, Irene; Rodríguez Crespo, Ignacio; García García, Concepción; Guzmán Pastor, Manuel; Lago Femia, Eva de; Fernández Ruiz, Javier
    In the present study, we investigated the involvement of the chaperone protein BiP (also known as GRP78 or Hspa5), a master regulator of intracellular proteostasis, in two mouse models of neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). To this end, we used mice bearing partial genetic deletion of the BiP gene (BiP+/− mice), which, for the ALS model, were crossed with mutant SOD1 (mSOD1) transgenic mice to generate mSOD1/BiP+/− double mutant mice. Our data revealed a more intense neurological decline in the double mutants, reflected in a greater deterioration of the neurological score and rotarod performance, with also a reduced animal survival, compared to mSOD1 transgenic mice. Such worsening was associated with higher microglial (labelled with Iba-1 immunostaining) and, to a lesser extent, astroglial (labelled with GFAP immunostaining) immunoreactivities found in the double mutants, but not with a higher loss of spinal motor neurons (labelled with Nissl staining) in the spinal cord. The morphological analysis of Iba-1 and GFAP-positive cells revealed a higher presence of activated cells, characterized by elevated cell body size and shorter processes, in double mutants compared to mSOD1 mice with normal BiP expression. In the case of the PD model, BiP+/− mice were unilaterally lesioned with the parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). In this case, however, we did not detect a greater susceptibility to damage in mutant mice, as the motor defects caused by 6-OHDA in the pole test and the cylinder rearing test, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity (labelled with CD68 and GFAP immunostaining) detected in the substantia nigra were of similar magnitude in BiP+/− mice compared with wildtype animals. Therefore, our findings support the view that a dysregulation of the protein BiP may contribute to ALS pathogenesis. As BiP has been recently related to cannabinoid type-1 (CB1) receptor function, our work also opens the door to future studies on a possible link between BiP and the neuroprotective effects of cannabinoids that have been widely reported in this neuropathological context. In support of this possibility, preliminary data indicate that CB1 receptor levels are significantly reduced in mSOD1 mice having partial deletion of BiP gene.
  • Publication
    Actas: Reunión Iberoamericana sobre cannabis medicinal
    (Carlos Brito Siso, 2020-11) Ramos Atance, José Antonio; Guzmán Pastor, Manuel; Manjón-Cabeza Olmeda, Araceli; Brito Siso, Carlos; Vitale Marino, Augusto; Reyes Alvarado, Yesid; Snapp, Zara; Pérez Martínez, Jordi; Pineda-Villegas, Paola; Peyraube, Raquel
    El día 5 de marzo de 2020 –a una semana de entrar en estado de alarma, con confinamientos, restricciones y vuelta al estado de alarma- pudimos celebrar en la Facultad de Ciencias de la Información de la Universidad Complutense de Madrid una reunión sobre cannabis medicinal. La organización se enmarca en una línea estrecha línea de colaboración mantenida durante los últimos años entre el Instituto Universitario de Investigación en Neuroquímica y el Proyecto de Investigación “Fiscalización internacional de drogas: problemas y soluciones”. Una vez más, quienes desde la UCM estudiamos distintos aspectos del cannabis medicinal, quisimos poner de manifiesto tres cuestiones. La primera, que a día de hoy existen evidencias suficientes sobre la utilidad medicinal del cannabis. La segunda, que resulta sin duda deseable obtener más evidencias, lo que requiere más investigación. Y, la tercera, que es necesario un marco legal que permita esa investigación y la dispensación del cannabis medicinal, como ocurre ya en muchos países de todo el planeta. En la reunión contamos con expertos de distintas áreas y del máximo nivel en sus respectivos ámbitos de salud o políticas legislativas. Sus valiosas aportaciones se recogen ahora y se hacen públicas como documentos muy relevantes en una discusión que continúa viva y que debemos seguir alimentando para que el conocimiento científico y la necesidad de los pacientes dejen de enfrentarse a unas políticas legislativas, nacionales e internacionales, irracionales y que desprecian dos enfoques básicos: el enfoque científico y el enfoque de derechos humanos. Especialmente relevante es la reciente posición de la OMS sobre el cannabis medicinal. En 2017 este organismo decidió realizar una revisión crítica sobre el valor medicinal de la planta, sus principios activos y algunos imitadores de síntesis. Las razones que llevaron a esta revisión fueron explicitadas así por la OMS: 1ª) No hay evidencias de muertes por sobredosis. 2ª) Es una sustancia relativamente segura. 3ª) Existe abundante literatura preclínica que avala su efectividad en cáncer, dolor crónico, dolor neuropático, epilepsias pediátricas, estimulación de apetito, estrés postraumático, trastornos del sueño y dependencia a opiáceos. 4ª) Los efectos adversos son posibles, pero leves. 5ª) La clasificación actual del cannabis como droga muy peligrosa, muy adictiva y sin ninguna indicación terapéutica no se justifica. Tras analizar evidencias y bibliografía, la OMS propuso a la Comisión de Estupefacientes una reclasificación del cannabis que permitiese su uso medicinal y facilitase la investigación sobre el potencial médico; además se indicaba que los extractos y las tinturas y el principio activo CBD no deberían ser objeto de clasificación en las Convenciones de drogas. La Comisión de Estupefacientes, sin razón que lo justifique, ha pospuesto por dos veces, en 2019 y en 2020, pronunciarse sobre las recomendaciones de la OMS. Se espera para diciembre de 2020 otra reunión de la Comisión de Estupefacientes en la que debería pronunciarse aceptando las recomendaciones, evitando así que dentro de Naciones Unidas existan dos voces opuestas sobre una misma cuestión. Con todo, son muchos los países y territorios que, sin esperar a la reclasificación en Naciones Unidas, han reglamentado programas de dispensación de cannabis medicinal. Se trata en concreto de Italia, Reino Unido, Portugal, Holanda, Alemania, República Checa, Dinamarca, Luxemburgo, Finlandia, Polonia, Israel, Canadá, Uruguay, Colombia, Perú, Chile, Argentina, Costa Rica, Ecuador, Jamaica, Sudáfrica, Malaui, Zimbabue, Tailandia, Australia, Nueva Zelanda y 33 estados de EE. UU. España posee condiciones y modelos suficientes para acometer prontamente la regulación del cannabis medicinal; solo falta la voluntad política de hacerlo.
  • Publication
    Cannabinoid-induced motor dysfunction via autophagy inhibition
    (Taylor & Francis, 2020-10-20) Blázquez Ortiz, Cristina; Ruiz Calvo, Andrea; Bajo Grañeras, Raquel; Baufreton, Jérôme M.; Resel, Eva; Varilh, Marjorie; Pagano Zottola, Antonio C.; Mariani, Yamuna; Cannich, Astrid; Rodríguez Navarro, José A.; Marsicano, Giovanni; Galve Roperh, Ismael; Bellocchio, Luigi; Guzmán Pastor, Manuel
    The recreational and medical use of cannabis is largely increasing worldwide. Cannabis use, however, can cause adverse side effects, so conducting innovative studies aimed to understand and potentially reduce cannabis-evoked harms is important. Previous research conducted on cultured neural cells had supported that CNR1/CB1R (cannabinoid receptor 1), the main molecular target of cannabis, affects macroautophagy/autophagy. However, it was not known whether CNR1 controls autophagy in the brain in vivo, and, eventually, what the functional consequences of a potential CNR1-autophagy connection could be. We have now found that Δ9-tetrahydrocannabinol (THC), the major intoxicating constituent of cannabis, impairs autophagy in the mouse striatum. Administration of autophagy activators (specifically, the rapalog temsirolimus and the disaccharide trehalose) rescues THC-induced autophagy inhibition and motor dyscoordination. The combination of various genetic strategies in vivo supports the idea that CNR1 molecules located on neurons belonging to the direct (striatonigral) pathway are required for the autophagy- and motor-impairing activity of THC. By identifying autophagy as a mechanistic link between THC and motor performance, our findings may open a new conceptual view on how cannabis acts in the brain.
  • Publication
    Hacia una Universidad Complutense más diversa: actividades de visibilización del colectivo LGTBI en las Facultades de Químicas y Biológicas
    (2022) Rodríguez Crespo, José Ignacio; García Ortega, Lucía; Guzmán Pastor, Manuel; Narbona Corral, Javier; Gutiérrez Carmona, Adrián; Arauco Arteche, Iñigo; Ballesteros Sanabria, Laura; Castromil Benito, Estela Soraya; Amigot Sánchez, Rafael; Cueto Remacha, Mateo; Martín Migallón, Guillermo
  • Publication
    Δ 9 ‐Tetrahydrocannabinol promotes functional remyelination in the mouse brain
    (Wiley, 2021-07-03) Aguado, Tania; Huerga Gómez, Alba; Sánchez de la Torre, Aníbal; Resel, Eva; Chara, Juan Carlos; Matute, Carlos; Mato, Susana; Galve Roperh, Ismael; Guzmán Pastor, Manuel; Palazuelos Diego, Javier
    Background and purpose: Research on demyelinating disorders aims to find novel molecules that are able to induce oligodendrocyte precursor cell differentiation to promote central nervous system remyelination and functional recovery. Δ9 -Tetrahydrocannabinol (THC), the most prominent active constituent of the hemp plant Cannabis sativa, confers neuroprotection in animal models of demyelination. However, the possible effect of THC on myelin repair has never been studied. Experimental approach: By using oligodendroglia-specific reporter mouse lines in combination with two models of toxin-induced demyelination, we analysed the effect of THC on the processes of oligodendrocyte regeneration and functional remyelination. Key results: We show that THC administration enhanced oligodendrocyte regeneration, white matter remyelination and motor function recovery. THC also promoted axonal remyelination in organotypic cerebellar cultures. THC remyelinating action relied on the induction of oligodendrocyte precursor differentiation upon cell cycle exit and via CB1 cannabinoid receptor activation. Conclusions and implications: Overall, our study identifies THC administration as a promising pharmacological strategy aimed to promote functional CNS remyelination in demyelinating disorders.
  • Publication
    CB2 Cannabinoid Receptors Promote Neural Progenitor Cell Proliferation via mTORC1 Signaling
    (Elsevier, 2012-01-06) Palazuelos Diego, Javier; Ortega, Zaira; Díaz-Alonso, Javier; Guzmán Pastor, Manuel; Galve Roperh, Ismael
    The endocannabinoid system is knownto regulate neural progenitor (NP) cell proliferation and neurogenesis. In particular, CB2 cannabinoid receptors have been shown to promote NP proliferation. As CB2 receptors are not expressed in differentiated neurons, CB2-selective agonists are promising candidates to manipulate NP proliferation and indirectly neurogenesis by overcoming the undesired psychoactive effects of neuronal CB1 cannabinoid receptor activation. Here, by using NP cells, brain organotypic cultures, and in vivo animal models, we investigated the signal transduction mechanism involved in CB2 receptorinduced NP cell proliferation and neurogenesis. Exposure of hippocampal HiB5 NP cells to the CB2 receptor-selective agonist HU-308 led to the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway, which, by inhibiting its downstream target p27Kip1, induced NP proliferation. Experiments conducted with the CB2 receptor-selective antagonist SR144528, inhibitors of the PI3K/Akt/mTORC1 axis, and CB2 receptor transienttransfection vector further supported that CB2 receptors control NP cell proliferation via activation of mTORC1 signaling. Likewise, CB2 receptor engagement induced cell proliferation in an mTORC1-dependent manner both in embryonic cortical slices and in adult hippocampal NPs. Thus, HU-308 increased ribosomal protein S6 phosphorylation and 5-bromo-2*-deoxyuridine incorporation in wild-type but not CB2 receptor-deficient NPs of the mouse subgranular zone. Moreover, adult hippocampal NP proliferation induced by HU-308 and excitotoxicity was blocked by the mTORC1 inhibitor rapamycin. Altogether, these findings provide a mechanism of action and a rationale for the use of nonpsychotomimetic CB2 receptor-selective ligands as a novel strategy for the control of NP cell proliferation and neurogenesis.
  • Publication
    Cannabinoids Induce Glioma Stem-like Cell Differentiation and Inhibit Gliomagenesis
    (Elsevier, 2007-01-02) Aguado Sánchez, Tania; Arkaitz Carracedo; Boris Julien; Velasco Díez, Guillermo; Garry Milman; Raphael Mechoulam; Luis Alvarez; Guzmán Pastor, Manuel; Galve Roperh, Ismael
    Glioma stem-like cells constitute one of the potential origins of gliomas, and therefore, their elimination is an essential factor for the development of efficient therapeutic strategies. Cannabinoids are known to exert an antitumoral action on gliomas that relies on at least two mechanisms: induction of apoptosis of transformed cells and inhibition of tumor angiogenesis. However, whether cannabinoids target human glioma stem cells and their potential impact in gliomagenesis are unknown. Here, we show that glioma stem-like cells derived from glioblastoma multiforme biopsies and the glioma cell lines U87MG and U373MG express cannabinoid type 1 (CB1) and type 2 (CB2) receptors and other elements of the endocannabinoid system. In gene array experiments, CB receptor activation altered the expression of genes involved in the regulation of stem cell proliferation and differentiation. The cannabinoid agonists HU-210 and JWH-133 promoted glial differentiation in a CB receptor-dependent manner as shown by the increased number of S-100β- and glial fibrillary acidic protein-expressing cells. In parallel, cannabinoids decreased the cell population expressing the neuroepithelial progenitor marker nestin. Moreover, cannabinoid challenge decreased the efficiency of glioma stem-like cells to initiate glioma formation in vivo, a finding that correlated with decreased neurosphere formation and cell proliferation in secondary xenografts. Gliomas derived from cannabinoid-treated cancer stem-like cells were characterized with a panel of neural markers and evidenced a more differentiated phenotype and a concomitant decrease in nestin expression. Overall, our results demonstrate that cannabinoids target glioma stem-like cells, promote their differentiation, and inhibit gliomagenesis, thus giving further support to their potential use in the management of malignant gliomas.
  • Publication
    Cannabinoid CB1 receptor gene inactivation in oligodendrocyte precursors disrupts oligodendrogenesis and myelination in mice
    (Springer Nature, 2022-07-07) 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, Javier
    Cannabinoids 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.