37 results on '"Ros-Bernal F"'
Search Results
2. Sistemas de clasificación y predicción de riesgo de malignidad de las lesiones anexiales
- Author
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Hidalgo Mora, J.J., Rams Llop, N., Ros Bernal, F., and Alcázar Zambrano, J.L.
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- 2018
- Full Text
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3. Glutamatergic Receptors in Parkinson’s Disease
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Sampedro, A., Tarragón, E., Yuste, J. E., Ros-Bernal, F., Ortiz, V., Campuzano, C. M., Gómez, A., Ros, C. M., Fernández-Villalba, E., Herrero, M. T., and Kostrzewa, Richard M., editor
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- 2014
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4. Neuroinflammation and Parkinson’s Disease
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Ros-Bernal, F., Yuste, J. E., Tarragón, E., Ortiz, V., Gómez, A., Ros, C. M., Fernández-Villalba, E., Herrero, M. T., and Kostrzewa, Richard M., editor
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- 2014
- Full Text
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5. Involvement of the Nucleus Incertus and Relaxin-3/RXFP3 Signaling System in Explicit and Implicit Memory
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Gil-Miravet I, Manas-Ojeda A, Ros-Bernal F, Castillo-Gomez E, Albert-Gasco H, Gundlach A, and Olucha-Bordonau F
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RXFP3 ,GABA ,nervous system ,hippocampus ,amygdala ,neuropeptide ,brainstem - Abstract
Telencephalic cognitive and emotional circuits/functions are strongly modulated by subcortical inputs. The main focus of past research on the nature of this modulation has been on the widespread monoamine projections to the telencephalon. However, the nucleus incertus (NI) of the pontine tegmentum provides a strong GABAergic and peptidergic innervation of the hippocampus, basal forebrain, amygdala, prefrontal cortex, and related regions; and represents a parallel source of ascending modulation of cognitive and emotional domains. NI GABAergic neurons express multiple peptides, including neuromedin-B, cholecystokinin, and relaxin-3, and receptors for stress and arousal transmitters, including corticotrophin-releasing factor and orexins/hypocretins. A functional relationship exists between NI neurons and their associated peptides, relaxin-3 and neuromedin-B, and hippocampal theta rhythm, which in turn, has a key role in the acquisition and extinction of declarative and emotional memories. Furthermore, RXFP3, the cognate receptor for relaxin-3, is a G(i/o) protein-coupled receptor, and its activation inhibits the cellular accumulation of cAMP and induces phosphorylation of ERK, processes associated with memory formation in the hippocampus and amygdala. Therefore, this review summarizes the role of NI transmitter systems in relaying stress- and arousal-related signals to the higher neural circuits and processes associated with memory formation and retrieval.
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- 2021
6. Relaxin-3 Innervation From the Nucleus Incertus to the Parahippocampal Cortex of the Rat
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Garcia-Diaz C, Gil-Miravet I, Albert-Gasco H, Manas-Ojeda A, Ros-Bernal F, Castillo-Gomez E, Gundlach A, and Olucha-Bordonau F
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calcium-binding proteins ,hippocampus ,amygdala ,synaptophysin (Syn) ,neuropeptide - Abstract
Spatial learning and memory processes depend on anatomical and functional interactions between the hippocampus and the entorhinal cortex. A key neurophysiological component of these processes is hippocampal theta rhythm, which can be driven from subcortical areas including the pontine nucleus incertus (NI). The NI contains the largest population of neurons that produce and presumably release the neuropeptide, relaxin-3, which acts via the G(i/o)-protein-coupled receptor, relaxin-family peptide 3 receptor (RXFP3). NI activation induces general arousal including hippocampal theta, and inactivation induces impairment of spatial memory acquisition or retrieval. The primary aim of this study was to map the NI/relaxin-3 innervation of the parahippocampal cortex (PHC), including the medial and lateral entorhinal cortex, endopiriform cortex, perirhinal, postrhinal, and ectorhinal cortex, the amygdalohippocampal transition area and posteromedial cortical amygdala. Retrograde tracer injections were placed in different parts of the medial and lateral entorhinal cortex, which produced prominent retrograde labeling in the ipsilateral NI and some labeling in the contralateral NI. Anterograde tracer injections into the NI and immunostaining for relaxin-3 produced fiber labeling in deep layers of all parahippocampal areas and some dispersed fibers in superficial layers. Double-labeling studies revealed that both hippocampal projecting and calcium-binding protein-positive (presumed GABAergic) neurons received a relaxin-3 NI innervation. Some of these fibers also displayed synaptophysin (Syn) immunoreactivity, consistent with the presence of the peptide at synapses; and relaxin-3-positive fibers containing Syn bouton-like staining were frequently observed in contact with hippocampal-projecting or calcium-binding protein-positive neuronal somata and more distal elements. Finally, in situ hybridization studies revealed that entorhinal neurons in the superficial layers, and to a lesser extent in deep layers, contain RXFP3 mRNA. Together, our data support functional actions of the NI/relaxin-3-parahippocampal innervation on processes related to memory, spatial navigation and contextual analysis.
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- 2021
7. MAP/ERK Signaling in Developing Cognitive and Emotional Function and Its Effect on Pathological and Neurodegenerative Processes
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Albert-Gasco H, Ros-Bernal F, Castillo-Gomez E, and Olucha-Bordonau F
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hippocampus, learning, long term depression, long term potentiation, memory, receptor, septum, synapse - Abstract
The signaling pathway of the microtubule-associated protein kinase or extracellular regulated kinase (MAPK/ERK) is a common mechanism of extracellular information transduction from extracellular stimuli to the intracellular space. The transduction of information leads to changes in the ongoing metabolic pathways and the modification of gene expression patterns. In the central nervous system, ERK is expressed ubiquitously, both temporally and spatially. As for the temporal ubiquity, this signaling system participates in three key moments: (i) Embryonic development; (ii) the early postnatal period; and iii) adulthood. During embryonic development, the system is partly responsible for the patterning of segmentation in the encephalic vesicle through the FGF8-ERK pathway. In addition, during this period, ERK directs neurogenesis migration and the final fate of neural progenitors. During the early postnatal period, ERK participates in the maturation process of dendritic trees and synaptogenesis. During adulthood, ERK participates in social and emotional behavior and memory processes, including long-term potentiation. Alterations in mechanisms related to ERK are associated with different pathological outcomes. Genetic alterations in any component of the ERK pathway result in pathologies associated with neural crest derivatives and mental dysfunctions associated with autism spectrum disorders. The MAP-ERK pathway is a key element of the neuroinflammatory pathway triggered by glial cells during the development of neurodegenerative diseases, such as Parkinson's and Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, as well as prionic diseases. The process triggered by MAPK/ERK activation depends on the stage of development (mature or senescence), the type of cellular element in which the pathway is activated, and the anatomic neural structure. However, extensive gaps exist with regards to the targets of the phosphorylated ERK in many of these processes.
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- 2020
8. Fernando de Castro: Cajal's Man on the Peripheral Nervous System
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Ros-Bernal, F, Castro, Fernando de, Ministerio de Economía y Competitividad (España), European Commission, and Fundación Inocente Inocente
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Corneille Heymans ,Arterial chemoreceptors ,sympathetic ,Spanish Neurological School ,Heinrich Hering - Abstract
Santiago Ramón y Cajal developed his initial scientific career working alone. After the publication of his opus magna (“Textura del sistema nervioso del hombre y los vertebrados”) and the general recognition of the scientific environments that crystallized with the concession of the International Moscow Prize (1900), the Spanish Government decided to officially support Cajal with a laboratory and the first salaries to pay collaborators. Is then when the Spanish Neurological School births: in 1902, Francisco Tello is the first one to be incorporated. With new additions, Cajal's work is complimented in new aspects, including Neuropathologies. Fernando de Castro is one of his youngest direct disciples, one of the closest and more beloved. Fernando de Castro worked from 1916 in Cajal's lab, until the death of El Maestro. He was specially committed by Cajal to unravel different aspects of the structure of the peripheral ganglia: sensitive and vegetative. Afterward, Fernando de Castro described by first time the nature of arterial chemoreceptors in the carotid body. While trying to confirm his anatomical description with physiological demonstrations, and accumulating delays because of scientific decision and the sociopolitical circumstances in Spain, Corneille Heymans was awarded with the Nobel Prize in Physiology or Medicine 1938 for his contributions to the knowledge of cardiorespiratory reflexes. The Karolinska Institutet forgot Heinrich Hering and Fernando de Castro in their decision. Undoubtedly, Fernando de Castro was the most important disciple of Cajal working in the different structures of the peripheral nervous system, and this work is now reviewed here. Anat Rec, 303:1206–1214, 2020. © 2019 American Association for Anatomy FdC research group is currently financed by the Spanish Ministry of Science (former Ministry of Economy; Grants SAF2016-77575-R and RD16/0015/0019 partially cofinanced by FEDER “Una manera de hacer Europa”) and Fundación Inocente Inocente (Spain).
- Published
- 2020
9. Evaluación prospectiva y validación externa del modelo ecográfico en tres pasos de IOTA para la valoración y cribado de la patología ovárica
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Hidalgo-Mora, J. J. (Juan José), Alcazar, J.L. (Juan Luis), and Ros-Bernal, F. (Francisco)
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Diagnóstico por imagen ,Ciencias de la Salud::Obstetricia y ginecología [Materias Investigacion] ,Ultrasonidos ,Ciencias de la Salud::Oncología [Materias Investigacion] - Abstract
Introducción. El cáncer de ovario presenta menos del 40% de supervivencia a los 5 años. El principal motivo es que el 75% de casos es diagnosticado en estadios avanzados. El objetivo diagnóstico en las masas anexiales debe ser clasificar su benignidad o malignidad precozmente. La ecografía es el método más preciso para el diagnóstico de las masas anexiales. La valoración ecográfica subjetiva por expertos es el mejor sistema para caracterizarlas, con sensibilidad de 88-98% y especificidad de 89-96%. Para que ecografistas no experimentados se aproximen a estos resultados se han propuesto modelos predictivos objetivos, aunque ninguno se ha generalizado en la práctica clínica. En 2012 el grupo IOTA propuso la estrategia en 3 pasos para la valoración de la patología anexial como un sistema de clasificación de benignidad y malignidad, consistente en aplicar 3 pasos diagnósticos: un primer paso evaluando 6 variables o descriptores simples (4 de benignidad y 2 de malignidad); un segundo paso, si el primero no es diagnóstico, aplicando las Simple Rules; y un tercer paso, si ninguno de los previos es aplicable, consistente en la valoración subjetiva por un experto. En estudios de validación se ha mostrado superior a modelos previos, con sensibilidad de 87-95% y especificidad de 87-100%. Objetivos: - Validación externa del modelo ecográfico en 3 pasos de IOTA empleado por ecografistas con nivel medio de experiencia en centros con diferente prevalencia de cáncer de ovario. - Comparación del rendimiento diagnóstico del modelo en 3 pasos con el del modelo de regresión logística LR2 de IOTA. - Propuesta y valoración de nuevo modelo diagnóstico en 2 pasos empleando Simple Rules Risk como segundo paso y prescindiendo de la valoración por un experto. Metodología. Estudio observacional prospectivo, con grupo único, durante 2 años, en un centro hospitalario de primer nivel y otro de tercer nivel, incluyendo pacientes con una lesión anexial intervenida quirúrgicamente o con seguimiento de al menos 1 año. Las masas anexiales fueron valoradas mediante el modelo en 3 pasos tomando como referencia el resultado histológico en caso de intervención o los cambios ecográficos sugestivos de malignidad durante el seguimiento. En un subgrupo de pacientes fue también calculado su riesgo de malignidad con el modelo LR2. Retrospectivamente se valoró la precisión diagnóstica del nuevo modelo propuesto en 2 pasos con Simple Rules Risk como segundo y último paso, asumiendo intervención quirúrgica en caso de riesgo alto o intermedio. Se calculó sensibilidad, especificidad, valor predictivo positivo y negativo y likelihood ratio positiva y negativa. El test de McNemar se empleó para comparar sensibilidad y especificidad entre los pasos de la estrategia, los centros participantes y los modelos comparados. Resultados. Fueron incluidas 302 pacientes. El 76,3% fueron intervenidas quirúrgicamente y el 23,7% realizaron seguimiento clínico y ecográfico. Con los 2 primeros pasos del modelo fueron diagnosticadas el 84% de lesiones y el 100% con todo el sistema. La sensibilidad y especificidad de la estrategia fue de 95,2% y 97,7% respectivamente. No hubo diferencias estadísticamente significativas entre los centros. Se observó diferencia estadísticamente significativa en especificidad a favor del modelo en 3 pasos respecto a LR2 y a la estrategia en 2 pasos. Conclusiones. El modelo ecográfico en 3 pasos de IOTA permite diagnosticar la mayoría de las masas anexiales por ecografistas no expertos con alta precisión diagnóstica en condiciones similares a la práctica clínica en centros con diferente prevalencia de cáncer de ovario. El rendimiento diagnóstico de la estrategia en 3 pasos es superior al de otros sistemas predictivos como el modelo de regresión logística LR2. Un modelo alternativo en 2 pasos con Simple Rules Risk como segundo paso puede permitir clasificar todas las lesiones por ecografistas no expertos con una elevada precisión diagnóstica.
- Published
- 2019
10. Evidence of oligodendrogliosis in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism
- Author
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Annese, V., Barcia, C., Ros-Bernal, F., Gómez, A., Ros, C. M., De Pablos, V., Fernández-Villalba, E., De Stefano, M. E., and Herrero, M.-T.
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- 2013
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11. 7-Nitroindazole down-regulates dopamine/DARPP-32 signaling in neostriatal neurons in a rat model of Parkinsonʼs disease
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Yuste, J. E., Echeverry, M. B., Ros-Bernal, F., Gomez, A., Ros, C. M., Campuzano, C. M., Fernandez-Villalba, E., and Herrero, M. T.
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- 2012
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12. Evidence of oligodendrogliosis in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism
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Annese, Valentina, Barcia, C., Ros Bernal, F., Gomez, A., Ros, C. m., De Pablos, V., Fernánzez Villalba, E., DE STEFANO, Maria Egle, and Herrero, M. t.
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Male ,glial response ,parkinson’s disease ,Dopaminergic Neurons ,neurodegeneration ,oligodendrocytes ,mptp ,Mice, Inbred C57BL ,Neostriatum ,Substantia Nigra ,Disease Models, Animal ,Mice ,Oligodendroglia ,Parkinsonian Disorders ,nervous system ,1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ,parkinson's disease ,Parkinson’s disease ,Animals ,Macaca ,MPTP - Abstract
Aims: Mice and nonhuman primates administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) represent elective experimental models of Parkinsonism, in which degeneration of the nigrostriatal dopaminergic pathway is associated with prominent neuroinflammation, characterized by activated microglia and astrocytes in both substantia nigra (SN) and striatum. To date, it is unknown whether oligodendrocytes play a role in these events. Methods: We performed a detailed qualitative and quantitative analysis of oligodendrocyte-associated changes induced by acute and chronic MPTP treatment, in the SN and striatum of mice and macaques respectively. Oligodendrocytes were immunolabelled by cell-specific markers and analysed by confocal microscopy. Results: In both experimental models, MPTP treatment induces an increase in oligodendrocyte cell number and average size, as well as in the total area occupied by this cell type per tissue section, accompanied by evident morphological changes. This multifaceted array of changes, herein referred to as oligodendrogliosis, significantly correlates with the reduction in the level of dopaminergic innervation to the striatum. Conclusions: This event, associated with early damage of the dopaminergic neurone axons and of the complex striatal circuits of which they are part, may result in an important, although neglected, aspect in the onset and progression of Parkinsonism.
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- 2013
13. Evidence of oligodendrogliosis in MPTP-induced Parkinsonism
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Annese, V., Barcia, C., Ros-Bernal, F., Gómez, A., Ros, C. M., De Pablos, V., Fernández-Villalba, E., De Stefano, M. E., Herrero, M. T., Centro de Investigaciòn Biomedica en Red de Enfermedades Neurodegenerativas, Universidad de Murcia, Department of Biology and Biotechnology 'Charles Darwin', Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Clinical and Experimental Neurosciences, Center for Research in Neurobiology 'Daniel Bovet', Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], and This work was supported by grants from: the Spanish Ministry of Science (SAF07-062262, FIS PI10-02827), Fundación Séneca (FS/15329/PI/10) and CIBERNED (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas) to M. T. H., and by ASI (Agenzia Spaziale Italiana) and MIUR (Ministero dell’Università e della Ricerca Scientifica) (AST 2008, 2009) to M.E.D.S. For this work, V.A. was recipient of an Erasmus PhD Scholarship and a Disease Models & Mechanisms Travelling Fellowship Award 2010
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glial response ,nervous system ,[SDV]Life Sciences [q-bio] ,neurodegeneration ,Parkinson’s disease ,oligodendrocytes ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,MPTP - Abstract
International audience; Aims: Mice and non-human primates administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) represent elective experimental models of Parkinsonism, in which degeneration of the nigro-striatal dopaminergic pathway is associated with prominent neuroinflammation, characterized by activated microglia and astrocytes in both substantia nigra (SN) and striatum. To date, it is unknown whether oligodendrocytes play a role in these events. Methods: We performed a detailed qualitative and quantitative analysis of oligodendrocyte-associated changes induced by acute and chronic MPTP treatment, in the SN and striatum of mice and macaques, respectively. Oligodendrocytes were immunolabeled by cell-specific markers and analyzed by confocal microscopy. Results: In both experimental models, MPTP treatment induces an increase in oligodendrocyte cell number and average size, as well as in the total area occupied by this cell type per tissue section, accompanied by evident morphological changes. This multifaceted array of changes, herein referred to as oligodendrogliosis, significantly correlate with the reduction in the level of dopaminergic innervation to the striatum. Conclusions: This event, associated with early damage of the dopaminergic neuron axons and of the complex striatal circuits of which they are part, may result in an important, although neglected, aspect in the onset and progression of Parkinsonism. © 2012 The Authors. Neuropathology and Applied Neurobiology © 2012 British Neuropathological Society.
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- 2012
14. Erratum: IFN-γ signaling, with the synergistic contribution of TNF-α, mediates cell specific microglial and astroglial activation in experimental models of Parkinson’s disease
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Barcia, C, primary, Ros, C M, additional, Annese, V, additional, Gómez, A, additional, Ros-Bernal, F, additional, Aguado-Llera, D, additional, Martínez-Pagán, M E, additional, de Pablos, V, additional, Fernandez-Villalba, E, additional, and Herrero, M T, additional
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- 2012
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15. IFN-γ signaling, with the synergistic contribution of TNF-α, mediates cell specific microglial and astroglial activation in experimental models of Parkinson's disease
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Barcia, C, primary, Ros, C M, additional, Annese, V, additional, Gómez, A, additional, Ros-Bernal, F, additional, Aguado-Llera, D, additional, Martínez-Pagán, M E, additional, de Pablos, V, additional, Fernandez-Villalba, E, additional, and Herrero, M T, additional
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- 2011
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16. MPTP administration increases plasma levels of acute phase proteins in non-human primates (Macaca fascicularis)
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De Pablos, V., primary, Barcia, C., additional, Martínez, S., additional, Gomez, A., additional, Ros-Bernal, F., additional, Zamarro-Parra, J., additional, Soria-Torrecillas, J.J., additional, Hernández, J., additional, Ceron, J.J., additional, and Herrero, M.T., additional
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- 2009
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17. Neuroinflammation in Parkinson's disease: A role for matrix metalloproteinases?
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Stefano, M. E., Valentina Annese, Barcia, C., Ros-Bernal, F., Fernández-Villalba, E., and Herrero, M. T.
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parkinson's disease ,metalloproteinases ,neurodegeneration ,neuroinflammation
18. NOS inhibitors improve L-DOPA-induced dyskinesias in experimental models of parkinsonism
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Yuste, J. E., Bermudez, M., Ros Bernal, F., Carlos Barcia, Martin, J., Del Bel, E., Fernandez Villalba, E., and Herrero, M-T
19. Nigral degeneration correlates with persistent activation of cerebellar Purkinje cells in MPTP-treated monkeys
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Heman P, Carlos Barcia, Gómez A, Cm, Ros, Ros-Bernal F, Je, Yuste, de Pablos V, Fernandez-Villalba E, Toledo-Cárdenas MR, and Mt, Herrero
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Male ,c-Fos ,Dopamine ,MPTP Poisoning ,Organ Size ,6 - Ciencias aplicadas::61 - Medicina::616 - Patología. Medicina clínica. Oncología::616.8 - Neurología. Neuropatología. Sistema nervioso [CDU] ,Parkinson´s disease ,nervous system diseases ,Substantia Nigra ,Disease Models, Animal ,Purkinje Cells ,nervous system ,Purkinje cells ,Cerebellum ,Chronic Disease ,Parkinson’s disease ,Animals ,Macaca ,Female ,Proto-Oncogene Proteins c-fos ,MPTP - Abstract
In the present work we analyze the cerebellum of chronic parkinsonian monkeys in order to clarify whether chronic mesencephalic depletion is associated with long term activation of the cerebellar neurons in chronic Parkinsonism. In our study, we observed a persistent activation of Purkinje cells in the cerebellum of chronic parkinsonian macaques, characterized by the expression of c-Fos, which correlated with dopaminergic degeneration. These results are compatible with the results observed in fMRI in Parkinson’s disease patients, and may contribute to the understanding of additional alterations in the brain circuitry in Parkinsonism.
20. Nucleus incertus projections to rat medial septum and entorhinal cortex: rare collateralization and septal-gating of temporal lobe theta rhythm activity.
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Gil-Miravet I, Núñez-Molina Á, Navarro-Sánchez M, Castillo-Gómez E, Ros-Bernal F, Gundlach AL, and Olucha-Bordonau FE
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- Rats, Animals, Raphe Nuclei, Temporal Lobe, Spatial Memory physiology, Receptors, Peptide, Receptors, G-Protein-Coupled, Entorhinal Cortex, Theta Rhythm
- Abstract
Nucleus incertus (NI) neurons in the pontine tegmentum give rise to ascending forebrain projections and express the neuropeptide relaxin-3 (RLN3) which acts via the relaxin-family peptide 3 receptor (RXFP3). Activity in the hippocampus and entorhinal cortex can be driven from the medial septum (MS), and the NI projects to all these centers, where a prominent pattern of activity is theta rhythm, which is related to spatial memory processing. Therefore, we examined the degree of collateralization of NI projections to the MS and the medial temporal lobe (MTL), comprising medial and lateral entorhinal cortex (MEnt, LEnt) and dentate gyrus (DG), and the ability of the MS to drive entorhinal theta in the adult rat. We injected fluorogold and cholera toxin-B into the MS septum and either MEnt, LEnt or DG, to determine the percentage of retrogradely labeled neurons in the NI projecting to both or single targets, and the relative proportion of these neurons that were RLN3-positive ( +). The projection to the MS was threefold stronger than that to the MTL. Moreover, a majority of NI neurons projected independently to either MS or the MTL. However, RLN3 + neurons collateralize significantly more than RLN3-negative (-) neurons. In in vivo studies, electrical stimulation of the NI induced theta activity in the MS and the entorhinal cortex, which was impaired by intraseptal infusion of an RXFP3 antagonist, R3(BΔ23-27)R/I5, particularly at ~ 20 min post-injection. These findings suggest that the MS plays an important relay function in the NI-induced generation of theta within the entorhinal cortex., (© 2023. The Author(s).)
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- 2023
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21. Postnatal development of the relaxin-3 innervation of the rat medial septum.
- Author
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Ros-Bernal F, Gil-Miravet I, Lucerón J, Navarro-Sánchez M, Castillo-Gómez E, Gundlach AL, and Olucha-Bordonau FE
- Abstract
Introduction: The septal area provides a rich innervation to the hippocampus regulating hippocampal excitability to different behavioral states and modulating theta rhythmogenesis. However, little is known about the neurodevelopmental consequences of its alterations during postnatal development. The activity of the septohippocampal system is driven and/or modulated by ascending inputs, including those arising from the nucleus incertus (NI), many of which contain the neuropeptide, relaxin-3 (RLN3)., Methods: We examined at the molecular and cellular level the ontogeny of RLN3 innervation of the septal area in postnatal rat brains., Results: Up until P13-15 there were only scattered fibers in the septal area, but a dense plexus had appeared by P17 that was extended and consolidated throughout the septal complex by P20. There was a decrease in the level of colocalization of RLN3 and synaptophysin between P15 and P20 that was reversed between P20 and adulthood. Biotinylated 3-kD dextran amine injections into the septum, revealed retrograde labeling present in the brainstem at P10-P13, but a decrease in anterograde fibers in the NI between P10-20. Simultaneously, a differentiation process began during P10-17, resulting in fewer NI neurons double-labeled for serotonin and RLN3., Discussion: The onset of the RLN3 innervation of the septum complex between P17-20 is correlated with the onset of hippocampal theta rhythm and several learning processes associated with hippocampal function. Together, these data highlight the relevance and need for further analysis of this stage for normal and pathological septohippocampal development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ros-Bernal, Gil-Miravet, Lucerón, Navarro-Sánchez, Castillo-Gómez, Gundlach and Olucha-Bordonau.)
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- 2023
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22. Becoming Stressed: Does the Age Matter? Reviewing the Neurobiological and Socio-Affective Effects of Stress throughout the Lifespan.
- Author
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Mañas-Ojeda A, Ros-Bernal F, Olucha-Bordonau FE, and Castillo-Gómez E
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- Animals, Humans, Models, Biological, Stress, Psychological genetics, Longevity physiology, Social Behavior, Stress, Psychological psychology
- Abstract
Social and affective relations occur at every stage of our lives. Impairments in the quality of this "social world" can be exceptionally detrimental and lead to psychopathology or pathological behavior, including schizophrenia, autism spectrum disorder, affective disorders, social phobia or violence, among other things. Exposure to highly stressful or traumatic events, depending on the stage of life in which stress exposure occurs, could severely affect limbic structures, including the amygdala, and lead to alterations in social and affective behaviors. This review summarizes recent findings from stress research and provides an overview of its age-dependent effects on the structure and function of the amygdala, which includes molecular and cellular changes, and how they can trigger deviant social and affective behaviors. It is important to highlight that discoveries in this field may represent a breakthrough both for medical science and for society, as they may help in the development of new therapeutic approaches and prevention strategies in neuropsychiatric disorders and pathological behaviors.
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- 2020
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23. Fernando de Castro: Cajal's Man on the Peripheral Nervous System.
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Ros-Bernal F and de Castro F
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- History, 19th Century, History, 20th Century, Humans, Spain, Neurosciences history, Peripheral Nervous System
- Abstract
Santiago Ramón y Cajal developed his initial scientific career working alone. After the publication of his opus magna ("Textura del sistema nervioso del hombre y los vertebrados") and the general recognition of the scientific environments that crystallized with the concession of the International Moscow Prize (1900), the Spanish Government decided to officially support Cajal with a laboratory and the first salaries to pay collaborators. Is then when the Spanish Neurological School births: in 1902, Francisco Tello is the first one to be incorporated. With new additions, Cajal's work is complimented in new aspects, including Neuropathologies. Fernando de Castro is one of his youngest direct disciples, one of the closest and more beloved. Fernando de Castro worked from 1916 in Cajal's lab, until the death of El Maestro. He was specially committed by Cajal to unravel different aspects of the structure of the peripheral ganglia: sensitive and vegetative. Afterward, Fernando de Castro described by first time the nature of arterial chemoreceptors in the carotid body. While trying to confirm his anatomical description with physiological demonstrations, and accumulating delays because of scientific decision and the sociopolitical circumstances in Spain, Corneille Heymans was awarded with the Nobel Prize in Physiology or Medicine 1938 for his contributions to the knowledge of cardiorespiratory reflexes. The Karolinska Institutet forgot Heinrich Hering and Fernando de Castro in their decision. Undoubtedly, Fernando de Castro was the most important disciple of Cajal working in the different structures of the peripheral nervous system, and this work is now reviewed here. Anat Rec, 303:1206-1214, 2020. © 2019 American Association for Anatomy., (© 2019 American Association for Anatomy.)
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- 2020
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24. Corrigendum to "Early intervention with ABA prevents neuroinflammation and memory impairment in a triple transgenic mice model of Alzheimer´s disease" [Behav. Brain Res. 374 (2019) 112106].
- Author
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Espinosa-Fernández V, Mañas-Ojeda A, Pacheco-Herrero M, Castro-Salazar E, Ros-Bernal F, and Sánchez-Pérez AM
- Published
- 2020
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25. Early intervention with ABA prevents neuroinflammation and memory impairment in a triple transgenic mice model of Alzheimer´s disease.
- Author
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Espinosa-Fernández V, Mañas-Ojeda A, Pacheco-Herrero M, Castro-Salazar E, Ros-Bernal F, and Sánchez-Pérez AM
- Subjects
- Abscisic Acid metabolism, Alzheimer Disease genetics, Alzheimer Disease physiopathology, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor genetics, Animals, Brain metabolism, Cerebral Cortex metabolism, Cognitive Dysfunction drug therapy, Disease Models, Animal, Hippocampus metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neuroimmunomodulation physiology, Neuroprotective Agents therapeutic use, Plaque, Amyloid metabolism, tau Proteins metabolism, Abscisic Acid pharmacology, Alzheimer Disease drug therapy, Memory Disorders drug therapy
- Abstract
Neuroinflammation and insulin resistance in the brain are intimately linked to neurodegenerative disorders, including Alzheimer's disease. Even though traditionally Alzheimer´s disease has been associated to Aβ deposits and hyperphosphorylated Tau intracellular tangles, several studies show that neuroinflammation may be the initial cause that triggers degeneration. Accordingly, a number of natural supplements that improves brain insulin sensitivity and reduce neuroinflammation have been proposed as good choices in the therapeutic prevention of cognitive decline. Further supporting this evidence, we show that phytohormone Abscisic Acid, can prevent memory impairment and neuroinflammation markers in a triple transgenic mouse model, where no peripheral inflammatory changes have occurred. Moreover, our data strongly suggests that early intervention is critical for good prognosis, and that cognitive improvement requires longer treatment than recovering neuroinflammation markers., (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Published
- 2019
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26. Modulation of forebrain function by nucleus incertus and relaxin-3/RXFP3 signaling.
- Author
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Olucha-Bordonau FE, Albert-Gascó H, Ros-Bernal F, Rytova V, Ong-Pålsson EKE, Ma S, Sánchez-Pérez AM, and Gundlach AL
- Subjects
- Animals, Humans, Neural Pathways physiology, Prosencephalon physiology, Raphe Nuclei physiology, Receptors, G-Protein-Coupled metabolism, Relaxin metabolism, Signal Transduction physiology
- Abstract
The nucleus incertus (NI) in the pontine tegmentum sends ascending projections to the midbrain, hypothalamus, amygdala, basal forebrain, hippocampus, and prefrontal cortex, and has a postulated role in modulating several forebrain functions. A substantial population of GABAergic NI neurons expresses the neuropeptide, relaxin-3, which acts via the G
i/o -protein-coupled receptor, RXFP3, present throughout the forebrain target regions. Broad and specific manipulations of these systems by activation or inhibition of the NI or modulating RXFP3 signaling have revealed key insights into the likely influence of the NI/relaxin-3/RXFP3 system on modalities including arousal, feeding, stress responses, anxiety and addiction, and attention and memory. This range of actions corresponds to a likely impact of NI/(relaxin-3) projections on multiple integrated circuits, but makes it difficult to draw conclusions about a generalized function for this network. This review will focus on the key physiological process of oscillatory theta rhythm and the neural circuits that promote it during behavioral activation, highlighting the ability of NI and relaxin-3/RXFP3 signaling systems to modulate these circuits. A better understanding of these mechanisms may provide a way to therapeutically adjust malfunction of forebrain activity present in several pathological conditions., (© 2018 John Wiley & Sons Ltd.)- Published
- 2018
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27. GABAergic Neurons in the Rat Medial Septal Complex Express Relaxin-3 Receptor (RXFP3) mRNA.
- Author
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Albert-Gascó H, Ma S, Ros-Bernal F, Sánchez-Pérez AM, Gundlach AL, and Olucha-Bordonau FE
- Abstract
The medial septum (MS) complex modulates hippocampal function and related behaviors. Septohippocampal projections promote and control different forms of hippocampal synchronization. Specifically, GABAergic and cholinergic projections targeting the hippocampal formation from the MS provide bursting discharges to promote theta rhythm, or tonic activity to promote gamma oscillations. In turn, the MS is targeted by ascending projections from the hypothalamus and brainstem. One of these projections arises from the nucleus incertus in the pontine tegmentum, which contains GABA neurons that co-express the neuropeptide relaxin-3 (Rln3). Both stimulation of the nucleus incertus and septal infusion of Rln3 receptor agonist peptides promotes hippocampal theta rhythm. The G
i/o -protein-coupled receptor, relaxin-family peptide receptor 3 (RXFP3), is the cognate receptor for Rln3 and identification of the transmitter phenotype of neurons expressing RXFP3 in the septohippocampal system can provide further insights into the role of Rln3 transmission in the promotion of septohippocampal theta rhythm. Therefore, we used RNAscope multiplex in situ hybridization to characterize the septal neurons expressing Rxfp3 mRNA in the rat. Our results demonstrate that Rxfp3 mRNA is abundantly expressed in vesicular GABA transporter ( vGAT ) mRNA- and parvalbumin ( PV ) mRNA-positive GABA neurons in MS, whereas ChAT mRNA-positive acetylcholine neurons lack Rxfp3 mRNA. Approximately 75% of Rxfp3 mRNA-positive neurons expressed vGAT mRNA (and 22% were PV mRNA-positive), while the remaining 25% expressed Rxfp3 mRNA only, consistent with a potential glutamatergic phenotype. Similar proportions were observed in the posterior septum. The occurrence of RXFP3 in PV-positive GABAergic neurons gives support to a role for the Rln3-RXFP3 system in septohippocampal theta rhythm.- Published
- 2018
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28. Implications of glial nitric oxide in neurodegenerative diseases.
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Yuste JE, Tarragon E, Campuzano CM, and Ros-Bernal F
- Abstract
Nitric oxide (NO) is a pleiotropic janus-faced molecule synthesized by nitric oxide synthases (NOS) which plays a critical role in a number of physiological and pathological processes in humans. The physiological roles of NO depend on its local concentrations, as well as its availability and the nature of downstream target molecules. Its double-edged sword action has been linked to neurodegenerative disorders. Excessive NO production, as the evoked by inflammatory signals, has been identified as one of the major causative reasons for the pathogenesis of several neurodegenerative diseases. Moreover, excessive NO synthesis under neuroinflammation leads to the formation of reactive nitrogen species and neuronal cell death. There is an intimate relation between microglial activation, NO and neuroinflammation in the human brain. The role of NO in neuroinflammation has been defined in animal models where this neurotransmitter can modulate the inflammatory process acting on key regulatory pathways, such as those associated with excitotoxicity processes induced by glutamate accumulation and microglial activation. Activated glia express inducible NOS and produce NO that triggers calcium mobilization from the endoplasmic reticulum, activating the release of vesicular glutamate from astroglial cells resulting in neuronal death. This change in microglia potentially contributes to the increased age-associated susceptibility and neurodegeneration. In the current review, information is provided about the role of NO, glial activation and age-related processes in the central nervous system (CNS) that may be helpful in the isolation of new therapeutic targets for aging and neurodegenerative diseases.
- Published
- 2015
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29. Persistent phagocytic characteristics of microglia in the substantia nigra of long-term Parkinsonian macaques.
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Barcia C, Ros CM, Ros-Bernal F, Gómez A, Annese V, Carrillo-de Sauvage MA, Yuste JE, Campuzano CM, de Pablos V, Fernández-Villalba E, and Herrero MT
- Subjects
- Animals, Female, Macaca fascicularis, Male, Microglia metabolism, Microglia pathology, Parkinson Disease metabolism, Parkinson Disease pathology, Phagocytes metabolism, Phagocytes pathology, Substantia Nigra metabolism, Substantia Nigra pathology, Time Factors, Microglia immunology, Parkinson Disease immunology, Phagocytes immunology, Phagocytosis immunology, Substantia Nigra immunology
- Abstract
Patients with Parkinson's disease show persistent microglial activation in the areas of the brain where the degeneration of dopaminergic neurons takes place. The reason for maintaining this activated state is still unknown, but it is thought that this persistent microglial activation may contribute to the degeneration of dopaminergic neurons. In this study, we report the microanatomical details of microglia and the relationship between microglia and neurons in the substantia nigra pars compacta of Parkinsonian monkeys years after insult with MPTP. We observed that microglial cells appear polarized toward dopaminergic neurons in MPTP-treated macaques compared to untreated animals and present clear phagocytic characteristics, such as engulfing gliaptic contacts, an increase in Golgi apparatus protein machinery and ball-and-chain phagocytic buds. These results demonstrate that activated microglia maintain phagocytic characteristics years after neurotoxin insult, and phagocytosis may be a key contributor to the neurodegenerative process., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
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30. Effects of pharmacological agents, sleep deprivation, hypoxia and transcranial magnetic stimulation on electroencephalographic rhythms in rodents: towards translational challenge models for drug discovery in Alzheimer's disease.
- Author
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Babiloni C, Infarinato F, Aujard F, Bastlund JF, Bentivoglio M, Bertini G, Del Percio C, Fabene PF, Forloni G, Herrero Ezquerro MT, Noè FM, Pifferi F, Ros-Bernal F, Christensen DZ, Dix S, Richardson JC, Lamberty Y, Drinkenburg W, and Rossini PM
- Subjects
- Alzheimer Disease physiopathology, Animals, Electroencephalography, Mice, Rats, Translational Research, Biomedical, Alzheimer Disease drug therapy, Brain physiopathology, Disease Models, Animal, Hypoxia physiopathology, Sleep Deprivation physiopathology, Transcranial Magnetic Stimulation
- Abstract
Different kinds of challenge can alter spontaneous ongoing electroencephalographic (EEG) rhythms in animal models, thus providing paradigms to evaluate treatment effects in drug discovery. The effects of challenges represented by pharmacological agents, hypoxia, sleep deprivation and transcranial magnetic stimulation (TMS) on EEG rhythms are here reviewed to build a knowledge platform for innovative translational models for drug discovery in Alzheimer's disease (AD). It has been reported that antagonists of cholinergic neurotransmission cause synchronisation of spontaneous ongoing EEG rhythms in terms of enhanced power of EEG low frequencies and decreased power of EEG high frequencies. Acetylcholinesterase inhibitors and serotonergic drugs may restore a normal pattern of EEG desynchronisation. Sleep deprivation and hypoxia challenges have also been reported to elicit abnormal synchronisation of spontaneous ongoing EEG rhythms in rodents. The feasibility and reproducibility of TMS have been demonstrated in rodents but information on a consistent modulation of EEG after TMS manipulation is very limited. Transgenic mice over-expressing human amyloid precursor protein complementary DNAs (cDNAs) harbouring the 'Swedish' mutation and PS-1 cDNAs harbouring the A264E mutation, which recapitulate some of the pathological features of AD, exhibit alterations of spontaneous ongoing EEG rhythms at several low and high frequencies. This does not appear, however, to be a consequence of beta-amyloid deposition in the brain. The present review provides a critical evaluation of changes of spontaneous ongoing EEG rhythms due to the experimental manipulations described above, in order to stimulate the promote more adherent models fitting dynamics in humans., (Copyright © 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2013
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31. IFN-γ signaling, with the synergistic contribution of TNF-α, mediates cell specific microglial and astroglial activation in experimental models of Parkinson's disease.
- Author
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Barcia C, Ros CM, Annese V, Gómez A, Ros-Bernal F, Aguado-Llera D, Martínez-Pagán ME, de Pablos V, Fernandez-Villalba E, and Herrero MT
- Abstract
To through light on the mechanisms underlying the stimulation and persistence of glial cell activation in Parkinsonism, we investigate the function of IFN-γ and TNF-α in experimental models of Parkinson’s disease and analyze their relation with local glial cell activation. It was found that IFN-γ and TNF-α remained higher over the years in the serum and CNS of chronic Parkinsonian macaques than in untreated animals, accompanied by sustained glial activation (microglia and astroglia) in the substantia nigra pars compacta. Importantly, Parkinsonian monkeys showed persistent and increasing levels of IFN-γR signaling in both microglial and astroglial cells. In addition, experiments performed in IFN-γ and TNF-α KO mice treated with MPTP revealed that, even before dopaminergic cell death can be observed, the presence of IFN-γ and TNF-α is crucial for microglial and astroglial activation, and, together, they have an important synergistic role. Both cytokines were necessary for the full level of activation to be attained in both microglial and astroglial cells. These results demonstrate that IFN-γ signaling, together with the contribution of TNF-α, have a critical and cell-specific role in stimulating and maintaining glial cell activation in Parkinsonism.
- Published
- 2012
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32. Dopamine modulation affects the performance of parkinsonian patients in a precision motor task measured by an antropomorphic device.
- Author
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Nombela C, Pedreño-Molina JL, Ros-Bernal F, Molina-Vilaplana J, Fdez-Villalba E, López-Coronado J, and Herrero MT
- Subjects
- Aged, Cholinergic Antagonists adverse effects, Cholinergic Antagonists therapeutic use, Disability Evaluation, Dopamine Agents adverse effects, Dopamine Agents therapeutic use, Female, Humans, Levodopa adverse effects, Levodopa therapeutic use, Male, Middle Aged, Parkinson Disease drug therapy, Psychomotor Performance drug effects, Reaction Time drug effects, Reaction Time physiology, Reference Values, Weight Perception drug effects, Weight Perception physiology, Anthropometry instrumentation, Antiparkinson Agents therapeutic use, Dopamine physiology, Hand Strength physiology, Parkinson Disease physiopathology, Pinch Strength physiology, Psychomotor Performance physiology, Signal Processing, Computer-Assisted instrumentation
- Abstract
Several parameters related to the timing, grip force and load force involved in a precision grasping task were studied in patients with Parkinson's disease (PD) at different moments of medication and healthy controls, using a sensorized anthropomorphic device which was totally adapted to the human hand. The aim of this work was to carry out an accurate study of the reach-load-grip-hold-place-release subtasks to identify any physical motor impairment, its relation to medication and Parkinsonian strategies. Twenty seven patients in ON and OFF-like medication moments, and twenty seven age-matched controls took part in the experiment, which consisted of using the index finger and the thumb to perform a precision motor task involving different experimental objects. Visual cues were used as distracting elements. Results showed several motor parameters impaired in OFF-like medication moment but attenuated in ON state, suggesting a medication effect on the performance of the task., (Copyright © 2011 Elsevier B.V. All rights reserved.)
- Published
- 2012
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33. Nigral degeneration correlates with persistent activation of cerebellar Purkinje cells in MPTP-treated monkeys.
- Author
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Heman P, Barcia C, Gómez A, Ros CM, Ros-Bernal F, Yuste JE, de Pablos V, Fernandez-Villalba E, Toledo-Cárdenas MR, and Herrero MT
- Subjects
- Animals, Cerebellum metabolism, Chronic Disease, Disease Models, Animal, Dopamine deficiency, Female, Macaca, Male, Organ Size, Proto-Oncogene Proteins c-fos metabolism, Purkinje Cells metabolism, Substantia Nigra metabolism, Cerebellum pathology, MPTP Poisoning pathology, Purkinje Cells pathology, Substantia Nigra pathology
- Abstract
In the present work we analyze the cerebellum of chronic parkinsonian monkeys in order to clarify whether chronic mesencephalic depletion is associated with long term activation of the cerebellar neurons in chronic Parkinsonism. In our study, we observed a persistent activation of Purkinje cells in the cerebellum of chronic parkinsonian macaques, characterized by the expression of c-Fos, which correlated with dopaminergic degeneration. These results are compatible with the results observed in fMRI in Parkinson's disease patients, and may contribute to the understanding of additional alterations in the brain circuitry in Parkinsonism.
- Published
- 2012
- Full Text
- View/download PDF
34. CCL2-expressing astrocytes mediate the extravasation of T lymphocytes in the brain. Evidence from patients with glioma and experimental models in vivo.
- Author
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Carrillo-de Sauvage MA, Gómez A, Ros CM, Ros-Bernal F, Martín ED, Perez-Vallés A, Gallego-Sanchez JM, Fernández-Villalba E, Barcia C Sr, Barcia C Jr, and Herrero MT
- Subjects
- Astrocytes physiology, Chemokine CCL2 metabolism, Diagnostic Imaging, Humans, Neuroimaging, Astrocytes metabolism, Brain cytology, Chemokine CCL2 physiology, Chemotaxis, Leukocyte physiology, Glioma pathology, T-Lymphocytes cytology
- Abstract
CCL2 is a chemokine involved in brain inflammation, but the way in which it contributes to the entrance of lymphocytes in the parenchyma is unclear. Imaging of the cell type responsible for this task and details on how the process takes place in vivo remain elusive. Herein, we analyze the cell type that overexpresses CCL2 in multiple scenarios of T-cell infiltration in the brain and in three different species. We observe that CCL2+ astrocytes play a part in the infiltration of T-cells in the brain and our analysis shows that the contact of T-cells with perivascular astrocytes occurs, suggesting that may be an important event for lymphocyte extravasation.
- Published
- 2012
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35. ROCK/Cdc42-mediated microglial motility and gliapse formation lead to phagocytosis of degenerating dopaminergic neurons in vivo.
- Author
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Barcia C, Ros CM, Annese V, Carrillo-de Sauvage MA, Ros-Bernal F, Gómez A, Yuste JE, Campuzano CM, de Pablos V, Fernandez-Villalba E, and Herrero MT
- Subjects
- 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine analogs & derivatives, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine pharmacology, Actin Cytoskeleton physiology, Animals, Cell Size, Dopaminergic Neurons drug effects, Golgi Apparatus physiology, MPTP Poisoning chemically induced, MPTP Poisoning metabolism, MPTP Poisoning pathology, Mice, Mice, Inbred C57BL, Microglia drug effects, Phagocytosis drug effects, cdc42 GTP-Binding Protein metabolism, rho-Associated Kinases metabolism, Dopaminergic Neurons physiology, Microglia physiology, cdc42 GTP-Binding Protein antagonists & inhibitors, rho-Associated Kinases antagonists & inhibitors
- Abstract
The role of microglial motility in the context of adult neurodegeneration is poorly understood. In the present work, we investigated the microanatomical details of microglia-neuron interactions in an experimental mouse model of Parkinson's disease following the intraperitoneal injection of MPTP. The specific intoxication of dopaminergic neurons induces the cellular polarization of microglia, leading to the formation of body-to-body neuron-glia contacts, called gliapses, which precede neuron elimination. Inhibiting ROCK/Cdc42-mediated microglial motility in vivo blocks the activating features of microglia, such as increased cell size and number of filopodia and diminishes their phagocyting/secreting domains, as the reduction of the Golgi apparatus and the number of microglia-neuron contacts has shown. High-resolution confocal images and three-dimensional rendering demonstrate that microglia engulf entire neurons at one-to-one ratio, and the microglial cell body participates in the formation of the phagocytic cup, engulfing and eliminating neurons in areas of dopaminergic degeneration in adult mammals.
- Published
- 2012
- Full Text
- View/download PDF
36. Microglial glucocorticoid receptors play a pivotal role in regulating dopaminergic neurodegeneration in parkinsonism.
- Author
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Ros-Bernal F, Hunot S, Herrero MT, Parnadeau S, Corvol JC, Lu L, Alvarez-Fischer D, Carrillo-de Sauvage MA, Saurini F, Coussieu C, Kinugawa K, Prigent A, Höglinger G, Hamon M, Tronche F, Hirsch EC, and Vyas S
- Subjects
- Aged, Aged, 80 and over, Animals, Cell Nucleus genetics, Cell Nucleus metabolism, Cell Nucleus pathology, Female, Humans, Inflammation chemically induced, Inflammation genetics, Inflammation metabolism, Inflammation pathology, MPTP Poisoning genetics, MPTP Poisoning pathology, Male, Mice, Mice, Transgenic, Microglia pathology, Parkinson Disease genetics, Parkinson Disease pathology, Receptors, Glucocorticoid genetics, Substantia Nigra pathology, Toll-Like Receptors genetics, Toll-Like Receptors metabolism, Up-Regulation drug effects, Up-Regulation genetics, MPTP Poisoning metabolism, Microglia metabolism, Parkinson Disease metabolism, Receptors, Glucocorticoid metabolism, Substantia Nigra metabolism
- Abstract
Among the pathogenic processes contributing to dopaminergic neuron (DN) death in Parkinson disease (PD), evidence points to non-cell-autonomous mechanisms, particularly chronic inflammation mounted by activated microglia. Yet little is known about endogenous regulatory processes that determine microglial actions in pathological states. We examined the role of glucocorticoid receptors (GRs), activated by glucocorticoids released in response to stress and known to regulate inflammation, in DN survival. Overall GR level was decreased in substantia nigra of PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. GR changes, specifically in the microglia after MPTP treatment, revealed a rapid augmentation in the number of microglia displaying nuclear localization of GR. Mice with selective inactivation of the GR gene in macrophages/microglia (GR(LysMCre)) but not in DNs (GR(DATCre)) showed increased loss of DNs after MPTP intoxication. This DN loss in GR(LysMCre) mice was not prevented by corticosterone treatment, in contrast to the protection observed in control littermates. Moreover, absence of microglial GRs augmented microglial reactivity and led to their persistent activation. Analysis of inflammatory genes revealed an up-regulation of Toll-like receptors (TLRs) by MPTP treatment, particularly TLR9, the level of which was high in postmortem parkinsonian brains. The regulatory control of GR was reflected by higher expression of proinflammatory genes (e.g., TNF-α) with a concomitant decrease in anti-inflammatory genes (e.g., IL-1R2) in GR(LysMCre) mice. Indeed, in GR(LysMCre) mice, alterations in phosphorylated NF-κB levels indicated its protracted activation. Together, our data indicate that GR is important in curtailing microglial reactivity, and its deregulation in PD could lead to sustained inflammation-mediated DN injury.
- Published
- 2011
- Full Text
- View/download PDF
37. No Lewy pathology in monkeys with over 10 years of severe MPTP Parkinsonism.
- Author
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Halliday G, Herrero MT, Murphy K, McCann H, Ros-Bernal F, Barcia C, Mori H, Blesa FJ, and Obeso JA
- Subjects
- Animals, Disease Models, Animal, Disease Progression, Longitudinal Studies, MPTP Poisoning metabolism, Macaca fascicularis, Tyrosine 3-Monooxygenase metabolism, alpha-Synuclein metabolism, Lewy Bodies pathology, MPTP Poisoning pathology
- Abstract
The recent knowledge that 10 years after transplantation surviving human fetal neurons adopt the histopathology of Parkinson's disease suggests that Lewy body formation takes a decade to achieve. To determine whether similar histopathology occurs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-primate models over a similar timeframe, the brains of two adult monkeys made parkinsonian in their youth with intermittent injections of MPTP were studied. Despite substantial nigral degeneration and increased alpha-synuclein immunoreactivity within surviving neurons, there was no evidence of Lewy body formation. This suggests that MPTP-induced oxidative stress and inflammation per se are not sufficient for Lewy body formation, or Lewy bodies are human specific., (Copyright 2009 Movement Disorder Society.)
- Published
- 2009
- Full Text
- View/download PDF
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