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1.
Front Neurosci ; 15: 659853, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33958986

RESUMEN

Increasing evidence has demonstrated that in addition to dysfunction of neuronal circuitry, oligodendroglial dysfunction and/or disruption of white matter integrity are found in the brains of patients with schizophrenia. DNA methylation, a well-established risk factor for schizophrenia, has been demonstrated to cause neuronal dysfunction; however, whether dysregulation of DNA methylation contributes to oligodendroglial/myelin deficits in the pathogenesis of schizophrenia remains unclear. In the present study, by using L-methionine-treated mice, we confirmed that mice with DNA hypermethylation exhibited an anxious phenotype, impaired sociability, and sensorimotor gating deficits. Notably, DNA hypermethylation in oligodendroglial cells led to dysregulation of multiple oligodendroglia-specific transcription factors, which indicated disruption of the transcriptional architecture. Furthermore, DNA hypermethylation caused a reduction of oligodendroglial lineage cells and myelin integrity in the frontal white matter of mice. Taken together, these results indicate that DNA hypermethylation leads to oligodendroglial and/or myelin deficits, which may, at least in part, contribute to schizophrenia-like behaviors in mice. This study provides new insights into the possibility that precise modulation of DNA methylation status in oligodendroglia could be beneficial for the white matter pathology in schizophrenia.

3.
PLoS One ; 8(1): e54590, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23359803

RESUMEN

Demyelination occurs widely in neurodegenerative diseases. Progesterone has neuroprotective effects, is known to reduce the clinical scores and the inflammatory response. Progesterone also promotes remyelination in experimental autoimmune encephalomyelitis and cuprizone-induced demyelinating brain. However, it still remains unclear whether progesterone can alleviate neural behavioral deficits and demyelination with degeneration of oligodendroglial cells in cuprizone-induced mice. In this study, mice were fed with 0.2% cuprizone to induce demyelination, and treated with progesterone to test its potential protective effect on neural behavioral deficits, demyelination and degeneration of oligodendroglial cells. Our results showed noticeable alleviation of neural behavioral deficits following progesterone treatment as assessed by changes in average body weight, and activity during the open field and Rota-rod tests when compared with the vehicle treated cuprizone group. Progesterone treatment alleviated demyelination as shown by Luxol fast blue staining, MBP immunohistochemical staining, and electron microscopy. There was an obvious decrease in TUNEL and Caspase-3-positive apoptotic cells, and an increase in the number of oligodendroglial cells staining positive for PDGFRα, Olig2, Sox10 and CC-1 antibody in the brains of cuprizone-induced mice after progesterone administration. These results indicate that progesterone can alleviate neural behavioral deficits and demyelination against oligodendroglial cell degeneration in cuprizone-induced mice.


Asunto(s)
Conducta Animal/efectos de los fármacos , Cuprizona/farmacología , Enfermedades Desmielinizantes/prevención & control , Oligodendroglía/efectos de los fármacos , Progesterona/farmacología , Animales , Apoptosis , Peso Corporal/efectos de los fármacos , Caspasa 3/metabolismo , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Electrónica de Transmisión , Oligodendroglía/patología , Oligodendroglía/ultraestructura , Progesterona/administración & dosificación , Prueba de Desempeño de Rotación con Aceleración Constante
4.
J Neurosci Res ; 90(5): 925-32, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22253220

RESUMEN

Remyelination of the central nervous system in multiple sclerosis patients is often incomplete. Remyelination depends on normal oligodendrogenesis and the differentiation of oligodendrocyte precursor cells (OPC) into mature oligodendrocytes (OL). Inhibitor of DNA binding (ID), a transcription factor, is thought to inhibit oligodendrogenesis and the differentiation of OPC. This Mini-Review aims to reveal the roles of and mechanisms used by IDs (mainly ID2) in this process. An interaction between ID2 and retinoblastoma tumor suppressor is responsible for the cell cycle transition from G1 to S. The translocation of ID2 between the nucleus and cytoplasm is regulated by E47 and OLIG. An interaction between ID2 and OLIG mediates the inhibitory effects of bone morphogenic proteins and G protein-coupled receptor 17 on oligodendroglia differentiation. ID2 expression is regulated by Wnt and histone deacetylases during the differentiation of OPC. ID4, another member of the ID family, functions similarly to ID2 in regulating the differentiation of OPC. The main difference is that ID4 is essential for oligodendrogenesis, whereas ID2 is nonessential. This could have important implications for demyelinating diseases, and interfering with these pathways might represent a viable therapeutic approach for these diseases.


Asunto(s)
Diferenciación Celular/fisiología , Proteína 2 Inhibidora de la Diferenciación/fisiología , Oligodendroglía/metabolismo , Animales , Proteínas Morfogenéticas Óseas/metabolismo , Ciclo Celular/fisiología , Proliferación Celular , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/patología , Regulación de la Expresión Génica/fisiología , Humanos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Transporte de Proteínas , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal
5.
Acta Histochem ; 114(7): 653-8, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22172709

RESUMEN

The mechanisms underlying oligodendrocyte differentiation and myelination are still unclear, but understanding them will be critical for the development of therapies for multiple sclerosis. Inhibitor of DNA binding 2 (Id2) is a transcription factor thought to inhibit oligodendrocyte differentiation, however, it is not known whether the developmental changes and subcellular localization of Id2 are related to myelination. Therefore, we investigated the developmental changes in and the subcellular localization of Id2 immunoreactivity in the rat Corpus callosum, at post-natal developmental stages P0, P7, P14, P21, P42 and P90, by immunohistochemistry. Id2 expression increased from P0 to a peak at P42, the late stage of myelination in the Corpus callosum. Id2 immunostaining decreased slightly, but still remained high at P90. Subcellular localization of Id2 changed from presence in cytoplasm at P14 to the nuclei at P42. Moreover, Id2 was mainly co-localized with CC-1-immunopositive mature oligodendrocytes at P42. These results may be consistent with Id2 inhibitory function in oligodendrocyte differentiation, at the end of myelination or in compaction of myelin in the Corpus callosum of postnatal rat brain.


Asunto(s)
Cuerpo Calloso/crecimiento & desarrollo , Cuerpo Calloso/metabolismo , Proteína 2 Inhibidora de la Diferenciación/metabolismo , Animales , Diferenciación Celular , Cuerpo Calloso/citología , Regulación del Desarrollo de la Expresión Génica , Proteína 2 Inhibidora de la Diferenciación/genética , Fibras Nerviosas Mielínicas/metabolismo , Fibras Nerviosas Mielínicas/fisiología , Oligodendroglía/metabolismo , Oligodendroglía/fisiología , Transporte de Proteínas , Ratas , Ratas Sprague-Dawley
6.
Neurosci Lett ; 497(1): 22-6, 2011 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-21524686

RESUMEN

Chronic cerebral hypoperfusion is thought to induce white matter lesions (WMLs) with oligodendrocyte (OLG) death and myelin breakdown. Although apoptosis is believed to be involved in the pathologic process of WMLs, effective therapies for such remain lacking. In the present study, we investigated whether catalpol, an iridoid glycoside, could act on oligodendrocytes (OLGs) and myelin sheaths in a rat chronic hypoperfusion model, and whether transcription factor cAMP-responsive element binding protein (CREB) phosphorylation is involved in the resulting neuroprotection. A rat model of chronic cerebral hypoperfusion was prepared by bilateral common carotid artery ligation. On the 30th day after hypoperfusion, OLG loss and myelin disruption in the ischemic white matter were more severe and evident than in the sham control. Spatial memory was also more seriously impaired in rats after hypoperfusion. Treatment with catalpol significantly suppressed diminished OLGs and myelin breakdown, and promoted the recovery of cognitive decline. The expression of Bcl-2 and phosphorylated CREB (p-CREB) was also significantly increased by catalpol treatment. In conclusion, catalpol could protect against hypoperfusion-induced WMLs and cognitive impairment through the p-CREB signaling pathway leading to downstream upregulation of Bcl-2. Our results suggest that catalpol may be a useful approach for treating cerebrovascular WMLs.


Asunto(s)
Apoptosis/efectos de los fármacos , Isquemia Encefálica/patología , Encéfalo/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Oligodendroglía/efectos de los fármacos , Compuestos de Amonio Cuaternario/farmacología , Animales , Western Blotting , Encéfalo/patología , Proteína de Unión a CREB/metabolismo , Modelos Animales de Enfermedad , Inmunohistoquímica , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Vaina de Mielina/efectos de los fármacos , Vaina de Mielina/patología , Oligodendroglía/patología , Fosforilación , Ratas , Ratas Wistar , Recuperación de la Función/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
7.
Neurosci Lett ; 476(1): 42-5, 2010 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-20381586

RESUMEN

Multiple sclerosis (MS) is the most common demyelination disease of central nervous system (CNS). The deterioration of the disease is characterized by the axonal loss with defective remyelination. Progesterone can promote the remyelination, but whether it exerts beneficial effect on treatment of MS still remains unclear. Olig1 protein is a key regulator in the remyelination, when the intracellular sublocalization plays an import role too. We observed the effect of progesterone on experimental autoimmune encephalomyelitis (EAE) in rats by injecting the progesterone after the neurological behavioral deficits were shown up. The results showed no continuous increase of the nervous function score from day 10 after injection (p<0.05). Electron microscopy and LFB staining found prominent increase of OD value of normal myelin in the brain from day 6 after injection (p<0.05). Olig1 protein was localized almost completely in the cytoplasm of Olig1-positive cells from normal rats' brain. In EAE rats, the Olig1 protein has been translocated to the nucleus of 32.17% of Olig1-positive cells, which was increased to 68.52% after injection with progesterone at day 6 after injection (p<0.01). The results indicate that the progesterone is beneficial to attenuating neurological behavioral deficits, for it can promote more successful remyelination of EAE with aid of the nucleus-sublocalized Olig1 protein.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Conducta Animal/efectos de los fármacos , Núcleo Celular/metabolismo , Encefalomielitis Autoinmune Experimental/prevención & control , Vaina de Mielina/metabolismo , Proteínas del Tejido Nervioso/fisiología , Progesterona/uso terapéutico , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encefalomielitis Autoinmune Experimental/fisiopatología , Encefalomielitis Autoinmune Experimental/psicología , Masculino , Ratas , Ratas Wistar
8.
Cell Mol Neurobiol ; 30(3): 469-82, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19885730

RESUMEN

Alpha-synuclein (alpha-SYN) is one of the major components of intracellular fibrillary aggregates in the brains of a subset of neurodegenerative disorders. Although alpha-SYN expression has been found in developing mouse brain, a detailed distribution during mouse-embryonic development has not been made. Here we describe the expression pattern of alpha-SYN during the development of mice from E9.5 to P0 by immunohistochemistry (IHC). As a result, alpha-SYN was detected as early as E9.5. During the embryonic stages, alpha-SYN was dynamically expressed in several regions of the brain. In the neocortex, expression was detected in the marginal zone (MZ) in the early stages and was later condensed in the MZ and in the subplate (SP); in the cerebellum, expression was initially detected in the deep cerebellar nuclei (DCN) and was later condensed in the Purkinje cells. These spatio-temporal expression patterns matched the neuronal migratory pathways and the formation of the synapse connections. Additionally, alpha-SYN was detected in the sensory systems, including the nasal mucosa, the optic cup, the sensory ganglia, and their dominating nerve fibers. Furthermore, the nuclear location of alpha-SYN protein was found in developing neurons in the early stages, and later it was mostly found in the non-nuclear compartments. This finding was further confirmed by Western blot analysis. These results suggest that alpha-SYN may be involved not only in the migration of neurons and in the synaptogenesis of the central nervous system (CNS) but also in the establishment of the sensory systems. The nuclear location of alpha-SYN may hint at an important function in these events.


Asunto(s)
Encéfalo/embriología , Encéfalo/metabolismo , Compartimento Celular/fisiología , Neuronas/metabolismo , Organogénesis/fisiología , alfa-Sinucleína/metabolismo , Vías Aferentes/citología , Vías Aferentes/embriología , Vías Aferentes/metabolismo , Animales , Encéfalo/citología , Mapeo Encefálico , Diferenciación Celular/fisiología , Movimiento Celular/fisiología , Núcleo Celular/metabolismo , Núcleo Celular/ultraestructura , Cerebelo/citología , Cerebelo/embriología , Cerebelo/metabolismo , Citoplasma/metabolismo , Citoplasma/ultraestructura , Inmunohistoquímica , Ratones , Ratones Endogámicos BALB C , Neurogénesis/fisiología , Neuronas/citología , Células Receptoras Sensoriales/citología , Células Receptoras Sensoriales/metabolismo , Sinapsis/metabolismo , Sinapsis/ultraestructura
9.
Cells Tissues Organs ; 191(4): 289-300, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-19940436

RESUMEN

Engrailed-1 (En-1) is a transcription factor involved in the development of the midbrain/hindbrain during mouse early embryogenesis. Although En-1 is expressed from embryogenesis to adulthood, there has been no detailed description of its expression during late mouse embryonic development. Here we report the expression pattern of En-1 in the mouse embryo from E10.5 to the neonatal state. With immunohistochemistry we found that En-1 was expressed in the central nervous system (CNS) from E10.5 to the neonatal state, mostly restricted to the midbrain/hindbrain junction. Outside the CNS, En-1 is dynamically expressed in several neural crest-associated structures including the cranial mesenchyme, the mandibular arches, the vagus nerve, the dorsal root ganglia, the sympathetic ganglia, the somites, the heart and the cloaca. Additionally, we found that in the CNS, most of the En-1 was located in the nuclei, while outside the CNS, En-1 was mainly expressed in the cytoplasm. These findings provided additional evidence that En-1 may be involved in the development of neural crest cells.


Asunto(s)
Sistema Nervioso Central/embriología , Embrión de Mamíferos/metabolismo , Desarrollo Embrionario , Proteínas de Homeodominio/metabolismo , Animales , Desarrollo Embrionario/genética , Proteínas de Homeodominio/genética , Ratones , Ratones Endogámicos BALB C , Cresta Neural/citología , Cresta Neural/metabolismo
10.
Anat Rec (Hoboken) ; 292(4): 498-512, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19142997

RESUMEN

The tumor suppressor phosphatase and tensin homologue (PTEN) is a protein and lipid phosphatase. PTEN mutations have been associated with a large number of human cancers. To understand the physiological role of PTEN in the brain and its relationship to Akt in ischemic injury, we first investigated the localization of PTEN immunoreactivity in the brains of normal adult rats using immunohistochemistry. We then detected the modulation of PTEN and p-Akt following transient global ischemia by Western blot and immunohistochemistry analyses. Our observation of normal brains showed that PTEN was heterogeneously distributed in the cytoplasm, nuclei, and processes in different regions. It was shown immunohistochemically that PTEN was distributed differentially in rat brain, with the highest levels in the anterior olfactory nucleus, cerebral cortex, amygdaloid nucleus, hippocampus, Purkinje's cells, and several nuclei in the basal ganglia, thalamus, midbrain, and pons. After global cerebral ischemia, PTEN and p-Akt immunoreactivities were increased in the cerebral cortex. This was accompanied by the nuclear translocation of p-Akt. Double-labeling experiments revealed that PTEN and p-Akt were most likely localized to neurons. These results suggest a role for PTEN in normal adult brain and that the PTEN/Akt pathway may be involved in neuronal survival or plasticity after ischemic injury.


Asunto(s)
Isquemia Encefálica/metabolismo , Encéfalo/anatomía & histología , Encéfalo/metabolismo , Corteza Cerebral/metabolismo , Fosfohidrolasa PTEN/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transporte Activo de Núcleo Celular/fisiología , Animales , Isquemia Encefálica/fisiopatología , Mapeo Encefálico , Supervivencia Celular/fisiología , Corteza Cerebral/fisiopatología , Modelos Animales de Enfermedad , Inmunohistoquímica , Masculino , Plasticidad Neuronal/fisiología , Neuronas/citología , Neuronas/metabolismo , Fosfohidrolasa PTEN/análisis , Proteínas Proto-Oncogénicas c-akt/análisis , Ratas , Ratas Sprague-Dawley , Regulación hacia Arriba/fisiología
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