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1.
Cell ; 138(6): 1222-35, 2009 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-19766573

RESUMEN

Plasticity related gene-1 (PRG-1) is a brain-specific membrane protein related to lipid phosphate phosphatases, which acts in the hippocampus specifically at the excitatory synapse terminating on glutamatergic neurons. Deletion of prg-1 in mice leads to epileptic seizures and augmentation of EPSCs, but not IPSCs. In utero electroporation of PRG-1 into deficient animals revealed that PRG-1 modulates excitation at the synaptic junction. Mutation of the extracellular domain of PRG-1 crucial for its interaction with lysophosphatidic acid (LPA) abolished the ability to prevent hyperexcitability. As LPA application in vitro induced hyperexcitability in wild-type but not in LPA(2) receptor-deficient animals, and uptake of phospholipids is reduced in PRG-1-deficient neurons, we assessed PRG-1/LPA(2) receptor-deficient animals, and found that the pathophysiology observed in the PRG-1-deficient mice was fully reverted. Thus, we propose PRG-1 as an important player in the modulatory control of hippocampal excitability dependent on presynaptic LPA(2) receptor signaling.


Asunto(s)
Proteoglicanos/metabolismo , Sinapsis/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Animales , Electroencefalografía , Hipocampo/química , Hipocampo/citología , Hipocampo/metabolismo , Lisofosfolípidos/metabolismo , Ratones , Ratones Noqueados , Proteoglicanos/análisis , Proteoglicanos/genética , Receptores AMPA/metabolismo , Receptores del Ácido Lisofosfatídico/metabolismo , Transducción de Señal , Proteínas de Transporte Vesicular/análisis , Proteínas de Transporte Vesicular/genética
2.
Cell Mol Life Sci ; 69(7): 1179-91, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22068610

RESUMEN

During development, axonal projections have a remarkable ability to innervate correct dendritic subcompartments of their target neurons and to form regular neuronal circuits. Altered axonal targeting with formation of synapses on inappropriate neurons may result in neurodevelopmental sequelae, leading to psychiatric disorders. Here we show that altering the expression level of the polysialic acid moiety, which is a developmentally regulated, posttranslational modification of the neural cell adhesion molecule NCAM, critically affects correct circuit formation. Using a chemically modified sialic acid precursor (N-propyl-D: -mannosamine), we inhibited the polysialyltransferase ST8SiaII, the principal enzyme involved in polysialylation during development, at selected developmental time-points. This treatment altered NCAM polysialylation while NCAM expression was not affected. Altered polysialylation resulted in an aberrant mossy fiber projection that formed glutamatergic terminals on pyramidal neurons of the CA1 region in organotypic slice cultures and in vivo. Electrophysiological recordings revealed that the ectopic terminals on CA1 pyramids were functional and displayed characteristics of mossy fiber synapses. Moreover, ultrastructural examination indicated a "mossy fiber synapse"-like morphology. We thus conclude that homeostatic regulation of the amount of synthesized polysialic acid at specific developmental stages is essential for correct synaptic targeting and circuit formation during hippocampal development.


Asunto(s)
Homeostasis , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Ácidos Siálicos/metabolismo , Sinapsis/metabolismo , Animales , Ratones , Ratones Endogámicos C57BL
3.
Cancer Sci ; 100(10): 1856-62, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19681905

RESUMEN

Brain edema is a hallmark of human malignant brain tumors and contributes to the clinical course and outcome of brain tumor patients. The so-called perifocal edema or brain swelling imposes in T2-weighted MR scans as high intensity areas surrounding the bulk tumor mass. The mechanisms of this increased fluid attraction and the cellular composition of the microenvironment are only partially understood. In this study, we focus on imaging perifocal edema in orthotopically implanted gliomas in rodents and correlate perifocal edema with immunohistochemical markers. We identified that areas of perifocal edema not only include the tumor invasion zone, but also are associated with increased glial fibrillary acidic protein (GFAP) and aquaporin-4 expression surrounding the bulk tumor mass. Moreover, a high number of activated microglial cells expressing CD11b and macrophage migration inhibitory factor (MIF) accumulate at the tumor border. Thus, the area of perifocal edema is mainly dominated by reactive changes of vital brain tissue. These data corroborate that perifocal edema identified in T2-weighted MR scans are characterized with alterations in glial cell distribution and marker expression forming an inflammatory tumor microenvironment.


Asunto(s)
Edema Encefálico/patología , Neoplasias Encefálicas/patología , Glioma/patología , Animales , Acuaporina 4/biosíntesis , Edema Encefálico/etiología , Neoplasias Encefálicas/complicaciones , Proteína Ácida Fibrilar de la Glía/biosíntesis , Glioma/complicaciones , Inmunohistoquímica , Inflamación/etiología , Inflamación/patología , Oxidorreductasas Intramoleculares/biosíntesis , Factores Inhibidores de la Migración de Macrófagos/biosíntesis , Imagen por Resonancia Magnética , Microglía/metabolismo , Microscopía Fluorescente , Trasplante de Neoplasias , Neoplasias Experimentales/complicaciones , Neoplasias Experimentales/patología , Ratas
4.
Cell Tissue Res ; 337(2): 213-21, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19513756

RESUMEN

Myelin is a multilamellar membrane structure primarily composed of lipids and myelin proteins essential for proper neuronal function. Since myelin is a target structure involved in many pathophysiological conditions such as metabolic, viral, and autoimmune diseases and genetic myelin disorders, a reliable myelin detection technique is required that is equally suitable for light- and electron-microscopic analysis. Here, we report that single myelinated fibers are specifically stained by the gold phosphate complex, Black gold, which stains myelin in the brain, spinal cord, and peripheral nerve fibers in a reliable manner. Electron-microscopic and morphometric analyses have revealed that gold particles are equally distributed in the inner, compact, and outer myelin layers. In contrast to Luxol fast blue, the gold dye stains proteinase-sensitive myelin structures, indicating its selective labeling of myelin-specific proteins. Aiming at defining the target of gold staining, we performed staining in several mouse myelin mutants. Gold complex distribution and myelin staining in MBP(-/-)/shiverer mouse mutants was comparable with that seen in wild-type mice but revealed a more clustered Black gold distribution. This gold staining method thus provides a sensitive and specific high-resolution marker for both central and peripheral myelin sheaths; it also allows the quantitative analysis of myelinated fibers at the light- and electron-microscopic level suitable for investigations of myelin and axonal disorders.


Asunto(s)
Sistema Nervioso Central/metabolismo , Inmunohistoquímica/métodos , Vaina de Mielina/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Sistema Nervioso Periférico/metabolismo , Receptores de Superficie Celular/metabolismo , Factores de Transcripción/metabolismo , Animales , Sistema Nervioso Central/citología , Sistema Nervioso Central/ultraestructura , Oro/química , Masculino , Ratones , Ratones Mutantes , Microscopía Electrónica de Transmisión , Proteína Básica de Mielina , Vaina de Mielina/ultraestructura , Glicoproteína Asociada a Mielina , Proteínas del Tejido Nervioso/genética , Sistema Nervioso Periférico/citología , Sistema Nervioso Periférico/ultraestructura , Ratas , Receptores de Superficie Celular/genética , Factores de Transcripción/genética
6.
Biol Trace Elem Res ; 161(3): 246-54, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25164034

RESUMEN

The trace element selenium and selenocysteine-carrying selenoproteins play a pivotal role in the brain. Beside the essential function during development and maintenance of brain action, selenium has also been associated with several neurological and neuro-oncological conditions. Reliable supply of selenium is important since selenium compounds can affect tumor microenvironment and neoangiogenesis in malignant gliomas (WHO grade III and IV [glioblastoma, GBM]) via induction of apoptosis and alteration of matrix metalloproteinases expression. Here, we summarize recent findings focusing on the anti-toxicity and cancer-preventive properties of selenium and their implication in current multimodal therapies including temozolomide (Temodal), cyclophosphamide (Endoxan), and cisplatin (DDP, Platiblastin, and Platinol). We shed light on unintended side effects in chemotherapy and the developments of novel combinatorial chemotherapeutics with selenium compounds. We found that selenium and selenium compounds have dual action profiles with direct anti-cancer and chemotherapy-intensifier effects as well as neuroprotective and cytoprotective agents. Current selenium trials and selenium supplementation with focus on neuro-oncology will be discussed with regard to low-adequate-to-high/toxic selenium status.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Selenio/uso terapéutico , Selenoproteínas/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Selenio/administración & dosificación , Selenio/efectos adversos , Selenio/deficiencia
7.
Sci Rep ; 4: 6226, 2014 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-25228443

RESUMEN

Malignant gliomas are characterized by neurodegenerative actions leading to the destruction of surrounding brain parenchyma. The disturbance in glutamate homeostasis caused by increased expression of the glutamate transporter xCT plays a key role in glioma progression. We demonstrate that the HDAC-inhibitor SAHA specifically inhibits the xCT-transporter expression. Thereby, tumor cell stress is engendered, marked by increase in ROS. Moreover, SAHA dependent xCT-reduction correlates with the inhibition of ATF4-expression, a factor known to foster xCT expression. Since xCT/system Xc- is pivotal for the brain tumor microenvironment, normalization of this system is a key in the management of malignant gliomas. To date, the problem lay in the inability to specifically target xCT due to the ubiquitous expression of the xCT-transporter--i.e. in non-cancerously transformed cells too--as well as its essential role in physiological CNS processes. Here, we show xCT-transporter equilibration through SAHA is specific for malignant brain tumors whereas SAHA does not affect the physiological xCT levels in healthy brain parenchyma. Our data indicate that SAHA operates on gliomas specifically via normalizing xCT expression which in consequence leads to reduced extracellular glutamate levels. This in turn causes a marked reduction in neuronal cell death and normalized tumor microenvironment.


Asunto(s)
Sistema de Transporte de Aminoácidos y+/metabolismo , Glioma/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/química , Ácidos Hidroxámicos/farmacología , Microambiente Tumoral/efectos de los fármacos , Sistema de Transporte de Aminoácidos y+/genética , Apoptosis/efectos de los fármacos , Western Blotting , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Glioma/metabolismo , Glioma/patología , Humanos , Técnicas para Inmunoenzimas , ARN Mensajero/genética , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas , Vorinostat
8.
Cancer Med ; 3(4): 865-77, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24898306

RESUMEN

Poor prognosis and limited therapeutic options render malignant brain tumors one of the most devastating diseases in clinical medicine. Current treatment strategies attempt to expand the therapeutic repertoire through the use of multimodal treatment regimens. It is here that dietary fibers have been recently recognized as a supportive natural therapy in augmenting the body's response to tumor growth. Here, we investigated the impact of isoflavonoids on primary brain tumor cells. First, we treated glioma cell lines and primary astrocytes with various isoflavonoids and phytoestrogens. Cell viability in a dose-dependent manner was measured for biochanin A (BCA), genistein (GST), and secoisolariciresinol diglucoside (SDG). Dose-response action for the different isoflavonoids showed that BCA is highly effective on glioma cells and nontoxic for normal differentiated brain tissues. We further investigated BCA in ex vivo and in vivo experimentations. Organotypic brain slice cultures were performed and treated with BCA. For in vivo experiments, BCA was intraperitoneal injected in tumor-implanted Fisher rats. Tumor size and edema were measured and quantified by magnetic resonance imaging (MRI) scans. In vascular organotypic glioma brain slice cultures (VOGIM) we found that BCA operates antiangiogenic and neuroprotective. In vivo MRI scans demonstrated that administered BCA as a monotherapy was effective in reducing significantly tumor-induced brain edema and showed a trend for prolonged survival. Our results revealed that dietary isoflavonoids, in particular BCA, execute toxicity toward glioma cells, antiangiogenic, and coevally neuroprotective properties, and therefore augment the range of state-of-the-art multimodal treatment approach.


Asunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Genisteína/administración & dosificación , Glioma/tratamiento farmacológico , Administración Oral , Inhibidores de la Angiogénesis/farmacología , Animales , Astrocitos/efectos de los fármacos , Astrocitos/fisiología , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular/efectos de los fármacos , Dieta , Ensayos de Selección de Medicamentos Antitumorales , Genisteína/farmacología , Humanos , Masculino , Trasplante de Neoplasias , Ratas Endogámicas F344 , Ratas Wistar
9.
Nat Rev Neurol ; 9(3): 141-51, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23358480

RESUMEN

Malignant gliomas represent one of the most devastating human diseases. Primary treatment of these tumours involves surgery to achieve tumour debulking, followed by a multimodal regimen of radiotherapy and chemotherapy. Survival time in patients with malignant glioma has modestly increased in recent years owing to advances in surgical and intraoperative imaging techniques, as well as the systematic implementation of randomized trial-based protocols and biomarker-based stratification of patients. The role and importance of several clinical and molecular factors-such as age, Karnofsky score, and genetic and epigenetic status-that have predictive value with regard to postsurgical outcome has also been identified. By contrast, the effect of the extent of glioma resection on patient outcome has received little attention, with an 'all or nothing' approach to tumour removal still taken in surgical practice. Recent studies, however, reveal that maximal possible cytoreduction without incurring neurological deficits has critical prognostic value for patient outcome and survival. Here, we evaluate state-of-the-art surgical procedures that are used in management of malignant glioma, with a focus on assessment criteria and value of tumour reduction. We highlight key surgical factors that enable optimization of adjuvant treatment to enhance patient quality of life and improve life expectancy.


Asunto(s)
Neoplasias Encefálicas/cirugía , Glioma/cirugía , Procedimientos Neuroquirúrgicos/métodos , Resultado del Tratamiento , Neoplasias Encefálicas/mortalidad , Glioma/mortalidad , Humanos , Estado de Ejecución de Karnofsky
10.
Int J Cell Biol ; 2012: 139573, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22973314

RESUMEN

Macrophage migration inhibitory factor (MIF) is a cytokine which also exhibits enzymatic properties like oxidoreductase and tautomerase. MIF plays a pivotal role in innate and acquired immunity as well as in the neuroendocrine axis. Since it is involved in the pathogenesis of acute and chronic inflammation, neoangiogenesis, and cancer, MIF and its signaling components are considered suitable targets for therapeutic intervention in several fields of medicine. In neurodegenerative and neurooncological diseases, MIF is a highly relevant, but still a hardly investigated mediator. MIF operates via intracellular protein-protein interaction as well as in CD74/CXCR2/CXCR4 receptor-mediated pathways to regulate essential cellular systems such as redox balance, HIF-1, and p53-mediated senescence and apoptosis as well as multiple signaling pathways. Acting as an endogenous glucocorticoid antagonist, MIF thus represents a relevant resistance gene in brain tumor therapies. Alongside this dual action, a functional homolog-annotated D-dopachrome tautomerase/MIF-2 has been uncovered utilizing the same cell surface receptor signaling cascade as MIF. Here we review MIF actions with respect to redox regulation in apoptosis and in tumor growth as well as its extracellular function with a focus on its potential role in brain diseases. We consider the possibility of MIF targeting in neurodegenerative processes and brain tumors by novel MIF-neutralizing approaches.

11.
PLoS One ; 7(9): e44885, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23049761

RESUMEN

Despite continuing debates around cytoreductive surgery in malignant gliomas, there is broad consensus that increased extent of tumor reduction improves overall survival. However, maximization of the extent of tumor resection is hampered by difficulty in intraoperative discrimination between normal and pathological tissue. In this context, two established methods for tumor visualization, fluorescence guided surgery with 5-ALA and intraoperative MRI (iMRI) with integrated functional neuronavigation were investigated as a dual intraoperative visualization (DIV) approach. Thirty seven patients presumably suffering from malignant gliomas (WHO grade III or IV) according to radiological appearance were included. Twenty-one experimental sequences showing complete resection according to the 5-ALA technique were confirmed by iMRI. Fourteen sequences showing complete resection according to the 5-ALA technique could not be confirmed by iMRI, which detected residual tumor. Further analysis revealed that these sequences could be classified as functional grade II tumors (adjacent to eloquent brain areas). The combination of fluorescence guided resection and intraoperative evaluation by high field MRI significantly increased the extent of tumor resection in this subgroup of malignant gliomas located adjacent to eloquent areas from 61.7% to 100%; 5-ALA alone proved to be insufficient in attaining gross total resection without the danger of incurring postoperative neurological deterioration. Furthermore, in the case of functional grade III gliomas, iMRI in combination with functional neuronavigation was significantly superior to the 5-ALA resection technique. The extent of resection could be increased from 57.1% to 71.2% without incurring postoperative neurological deficits.


Asunto(s)
Neoplasias Encefálicas/cirugía , Encéfalo/cirugía , Glioma/cirugía , Neuronavegación/métodos , Adulto , Anciano , Ácido Aminolevulínico , Encéfalo/patología , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patología , Femenino , Colorantes Fluorescentes , Glioma/diagnóstico , Glioma/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Neoplasia Residual , Neuronavegación/instrumentación
12.
Ann Anat ; 192(5): 309-13, 2010 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-20801625

RESUMEN

Several nutrient transporters impacting the glutathione/redox cycle regulation and cell proliferation have been identified in cancer, which render these transporters potential prime targets for cytotoxic anticancer therapy. One promising transporter is system X(c)(-), also known as xCT (SLC7a11), which is expressed in various cancers including primary malignant brain tumors (gliomas). An important biological feature of these transporters, and in particular of xCT is its specific modulation of the tumor microenvironment leading to growth advantage for cancer. Thus, tumor microenvironment shaping by xCT inhibition revealed a so far neglected hallmark of gliomas, i.e. tumor-induced neurotoxicity and its impact on the development of peritumoral brain swelling. This review here discusses available pharmacological tools for the tumor microenvironment normalization, in the context of perifocal edema and the Warburg effect and highlights the implications of such metabolic normalization approach in the design of new therapies.


Asunto(s)
Sistema de Transporte de Aminoácidos y+/antagonistas & inhibidores , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Edema Encefálico/etiología , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/metabolismo , Metabolismo Energético , Glioma/complicaciones , Glioma/metabolismo , Humanos
13.
Mol Biol Cell ; 21(4): 521-37, 2010 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-20032306

RESUMEN

Members of the plasticity-related gene (PRG1-4) family are brain-specific integral membrane proteins and implicated in neuronal plasticity, such as filopodia formation and axon growth after brain lesion. Here we report on the cloning of a novel member of the PRG family, PRG5, with high homologies to PRG3. PRG5 is regulated during brain and spinal cord development and is exclusively allocated within the nervous system. When introduced in neurons, PRG5 is distributed in the plasma membrane and induces filopodia as well as axon elongation and growth. Conversely, siRNA mediated knockdown of PRG5 impedes axon growth and disturbs filopodia formation. Here we show that PRG5 induces filopodia growth independently of Cdc42. Moreover, axon collapse and RhoA activation induced by LPA and myelin-associated neurite inhibitor Nogo-A is attenuated in the presence of PRG5, although direct activation of the RhoA-Rho-PIP5K kinase pathway abolishes PRG5 -formed neurites. Thus, we describe here the identification of a novel member of the PRG family that induces filopodia and axon elongation in a Cdc42-independent manner. In addition, PRG5 impedes brain injury-associated growth inhibitory signals upstream of the RhoA-Rho kinase pathway.


Asunto(s)
Axones , Lisofosfolípidos/farmacología , Proteínas de la Membrana/metabolismo , Proteínas de la Mielina/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuritas , Monoéster Fosfórico Hidrolasas/metabolismo , Seudópodos , Secuencia de Aminoácidos , Animales , Axones/efectos de los fármacos , Axones/metabolismo , Axones/ultraestructura , Encéfalo/citología , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Células Cultivadas , Proteínas de la Membrana/genética , Ratones , Datos de Secuencia Molecular , Proteínas de la Mielina/genética , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Neuritas/efectos de los fármacos , Neuritas/fisiología , Neuritas/ultraestructura , Neuronas/citología , Neuronas/fisiología , Proteínas Nogo , Monoéster Fosfórico Hidrolasas/química , Monoéster Fosfórico Hidrolasas/genética , Conformación Proteica , Seudópodos/efectos de los fármacos , Seudópodos/metabolismo , Seudópodos/ultraestructura , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Ratas , Ratas Wistar , Alineación de Secuencia , Transducción de Señal/fisiología , Médula Espinal/citología , Médula Espinal/crecimiento & desarrollo , Médula Espinal/metabolismo , Proteína de Unión al GTP cdc42/genética , Proteína de Unión al GTP cdc42/metabolismo , Quinasas Asociadas a rho/genética , Quinasas Asociadas a rho/metabolismo , Proteína de Unión al GTP rhoA/genética , Proteína de Unión al GTP rhoA/metabolismo
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