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Hospital de Órbigo, Spain

Yunta M.,Experimental Neurology Unit
PloS one | Year: 2012

Spinal cord injury (SCI) triggers a multitude of pathophysiological events that are tightly regulated by the expression levels of specific genes. Recent studies suggest that changes in gene expression following neural injury can result from the dysregulation of microRNAs, short non-coding RNA molecules that repress the translation of target mRNA. To understand the mechanisms underlying gene alterations following SCI, we analyzed the microRNA expression patterns at different time points following rat spinal cord injury.The microarray data reveal the induction of a specific microRNA expression pattern following moderate contusive SCI that is characterized by a marked increase in the number of down-regulated microRNAs, especially at 7 days after injury. MicroRNA downregulation is paralleled by mRNA upregulation, strongly suggesting that microRNAs regulate transcriptional changes following injury. Bioinformatic analyses indicate that changes in microRNA expression affect key processes in SCI physiopathology, including inflammation and apoptosis. MicroRNA expression changes appear to be influenced by an invasion of immune cells at the injury area and, more importantly, by changes in microRNA expression specific to spinal cord cells. Comparisons with previous data suggest that although microRNA expression patterns in the spinal cord are broadly similar among vertebrates, the results of studies assessing SCI are much less congruent and may depend on injury severity. The results of the present study demonstrate that moderate spinal cord injury induces an extended microRNA downregulation paralleled by an increase in mRNA expression that affects key processes in the pathophysiology of this injury.

Valle-Argos B.,Cajal Institute CSIC | Gomez-Nicola D.,Cajal Institute CSIC | Gomez-Nicola D.,Experimental Neurology Unit | Nieto-Sampedro M.,Cajal Institute CSIC | Nieto-Sampedro M.,Experimental Neurology Unit
European Journal of Medicinal Chemistry | Year: 2010

O-acetyl-ganglioside neurostatin, (Galβ1 → 3GalNAcβ1 → 4[9-O-Ac Neu5Acα2 → 8Neu5Acα2 → 3]Galβ1 → 4Glcβ1 → 1′-ceramide), is a natural GD1b-derived inhibitor of astroblast and astrocytoma division, whose structure and purification method limits its availability and stability. Therefore, we set-up the reaction to obtain O-acetylated and O-butyrylated neurostatin analogs by chemical synthesis, in order to improve its availability and stability. The compounds antitumoral activity was evaluated on U373MG and C6 glioblastoma cells, observing that the O-acetylation-dependent increase in the inhibitory activity was enhanced by O-butyrylation, with no further improvement with the multi-substitution, pointing to the initial conformational change and the stability change as responsible of its function. These results open the possibility for the application of the neurostatin-related compounds to in-vivo tumoral models. © 2010 Elsevier Masson SAS. All rights reserved.

Valle-Argos B.,Instituto Cajal | Gomez-Nicola D.,Instituto Cajal | Gomez-Nicola D.,Experimental Neurology Unit | Nieto-Sampedro M.,Instituto Cajal | Nieto-Sampedro M.,Experimental Neurology Unit
Neuro-Oncology | Year: 2010

In spite of their low incidence, central nervous system tumors have elevated morbidity and mortality, being responsible for 2.3% of total cancer deaths. The ganglioside O-acetylated GD1b (O-Ac GD1b; neurostatin), present in the mammalian brain, and the semi-synthetic O-butyrylated GD1b (O-But GD1b) are potent glioma proliferation inhibitors, appearing as possible candidates for the treatment of nervous system tumors. Tumoral cell division inhibitory activity in culture correlated with growth inhibition of glioma xenotransplants in Foxn 1nu nude mice and intracranial glioma allotransplants. Both O-Ac GD1b and O-But GD1b inhibited in vivo cell proliferation, induced cell cycle arrest, and potentiated immune cell response to the tumor. Furthermore, the increased stability of the butyrylated compound (O-But GD1b) enhanced its activity with respect to the acetylated ganglioside (neurostatin). These results are the first report of the antitumoral activity of neurostatin and a neurostatin-like compound in vivo and indicate that semi-synthetic O-acetylated and O-butyrylated gangliosides are potent antitumoral compounds that should be considered in strategies for brain tumor treatment. © The Author(s) 2010.

Valle-Argos B.,Cajal Institute | Gomez-Nicola D.,Cajal Institute | Gomez-Nicola D.,Experimental Neurology Unit | Nieto-Sampedro M.,Cajal Institute | Nieto-Sampedro M.,Experimental Neurology Unit
Molecular and Cellular Neuroscience | Year: 2011

The high frequency and malignancy of human glioblastomas has stimulated the search for potential therapeutic approaches. The control of the glioma cell proliferation in response to mitogenic signals is one of the most promising antitumoral strategies, and the main target of several therapies.Neurostatin, an O-acetylated derivative of the ganglioside GD1b, has potent antiproliferative activity over the in vitro and in vivo growth of glioma cells. The mechanism of its antitumoral action is the focus of the present study. Using a combined in vitro-in vivo approach, we observed that neurostatin arrested glioma proliferation by inhibiting the expression of cell cycle promoters (i.e. cyclins and CDKs) and promoting the expression of cell cycle inhibitors (i.e. p21 and p27). Neurostatin inhibits epidermal growth factor receptor (EGFR) signaling pathways, blocking the activation of the main promitogenic MAPKs and PI3K pathways. Neurostatin action not only interferes in the cell cycle progression, but also in the protection from apoptosis, and the generation of angiogenic and invasive responses.The antitumoral actions described here point to neurostatin as a novel and promising chemotherapeutic agent for glioma treatment. © 2010.

Martin-Lopez E.,Cajal Institute | Nieto-Diaz M.,Experimental Neurology Unit | Nieto-Sampedro M.,Cajal Institute | Nieto-Sampedro M.,Experimental Neurology Unit
Journal of Biomaterials Applications | Year: 2012

Chitosan (Ch) and some of its derivatives have been proposed as good biomaterials for tissue engineering, to construct scaffolds promoting tissue regeneration. In this work we made composite films from Ch and mixtures of Ch with gelatin (G) and poly-l-lysine (PLL), and evaluated the growth on these films of PC12 and C6 lines as well as neurons and glial cells derived from cerebral tissue and dorsal root ganglia (DRG). C6 glioma cells proliferated on Ch, G, and Ch-+-G films, although metabolic activity was decreased by the presence of the G in the mixtures. NGF-differentiated PC12 cells, adhered preferentially on Ch and films containing PLL. Unlike NGF-treated PC12 cells, cortical and hippocampal neurons showed good adhesion to Ch and Ch-+-G films, where they extended neurites. Astrocytes adhered on Ch, Ch-+-G, and Ch-+-PLL mixtures, although viability decreased during the culture time. Olfactory ensheathing cells (OEC) adhered and proliferated to confluency on the wells covered with Ch-+-G films. Neurites from DRGs exhibited high extension on these films. These results demonstrate that Ch-+-G films have excellent adhesive properties for both neurons and regeneration-promoting glia (OEC). These films also promoted neurite extension from DRG, making them good candidates for tissue engineering of nerve repair. © The Author(s), 2010.

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