Glicolípidos neuronales regulan negativamente la división glial durante el desarrollo y tras una lesión / Neuronal glycolipids regulate glial cell division negatively during development and following a lesion

En el sistema nervioso central de los mamíferos, las células gliales superan diez veces en número a las neuronas. Su número permanente estacionario durante la edad adulta, controlado por la presencia simultánea de mitógenos gliales e inhibidores de esos mitógenos. El inhibidor más abundante, la neurostatina, es el gangliósido GD1b O-acetilado en el grupo 9 del ácido siálico más externo. La neurostatina y los oligosacáridos sintéticos inhiben la proliferación de astroblastos en cultivo primario (citostáticos) y de células de gliomas (citotóxicos), tanto de roedores como de humanos, en concentración nanomolar. A esas concentraciones, la neurostatina no tuvo efecto sobre células de linaje no glial ni sobre glía madura. La neurostatina y sus análogos mostraron actividad antimitótica directa sobre las células tumorales, interfiriendo con la progresión del ciclo celular en múltiples sitios, pero también actuaron indirectamente, haciendo visibles las células tumorales al sistema inmune del huésped y activando linfocitos CD4+ y CD8+. Análogos de neurostatina podrían generar nuevos fármacos antiinflamatorios, con múltiples acciones directas e indirectas contra el crecimiento de gliomas, una patología todavía sin tratamiento clínico satisfactorio. La neurostatina es producida por las neuronas, pero el contacto de éstas con astrocitos estimula notablemente su expresión. La acción de la neurostatina puede estar mediada por numerosas proteínas receptoras, incluyendo integrinas, siglecs y receptores Toll-like (AU)

Glial cells in the central nervous system of adult mammals outnumber neurons 10-fold. Their number remains stationary throughout adulthood, controlled by the concomitant presence of mitogens and mitogen inhibitors. The most abundant inhibitor, neurostatin, is ganglioside GD1b O-acetylated on hydroxyl 9 of its outermost sialic acid. Neurostatin inhibited the proliferation of primary microglia and astroblasts in culture (cytostatic) as well as both rodent and human glioma cells (cytotoxic) at nanomolar concentrations. At those concentrations neurostatin had no effect on non-glial lineage cells or differentiated glia. Neurostatin shows direct antimitotic activity on tumoral cells, interfering with multiple signals regulating cell cycle progression. But it also promotes indirectly total destruction of experimental rat brain glioma, presumably by making it visible to the host immune system and activating CD4+ and CD8+ lymphocytes. Neurostatin could be a new anti-inflammatory agent, with multiple convergent direct and indirect actions on glioma growth, a pathology without satisfactory clinical treatment. Neurostatin is produced by neurons but its expression is up-regulated by neuron-astrocyte contact. The action of neurostatin could be mediated by a number of receptor proteins, including integrins, Toll-like receptors and siglecs (AU)

Neural differentiation of transplanted neural stem cells in a rat model of striatal lacunar infarction: light and electron microscopic observations.

The increased risk and prevalence of lacunar stroke and Parkinson's disease (PD) makes the search for better experimental models an important requirement for translational research. In this study we assess ischemic damage of the nigrostriatal pathway in a model of lacunar stroke evoked by damaging the perforating arteries in the territory of the substantia nigra (SN) of the rat after stereotaxic administration of endothelin-1 (ET-1), a potent vasoconstrictor peptide. We hypothesized that transplantation of neural stem cells (NSCs) with the capacity of differentiating into diverse cell types such as neurons and glia, but with limited proliferation potential, would constitute an alternative and/or adjuvant therapy for lacunar stroke. These cells showed neuritogenic activity in vitro and a high potential for neural differentiation. Light and electron microscopy immunocytochemistry was used to characterize GFP-positive neurons derived from the transplants. 48 h after ET-1 injection, we characterized an area of selective degeneration of dopaminergic neurons within the nigrostriatal pathway characterized with tissue necrosis and glial scar formation, with subsequent behavioral signs of Parkinsonism. Light microscopy showed that grafted cells within the striatal infarction zone differentiated with a high yield into mature glial cells (GFAP-positive) and neuron types present in the normal striatum. Electron microscopy revealed that NSCs-derived neurons integrated into the host circuitry establishing synaptic contacts, mostly of the asymmetric type. Astrocytes were closely associated with normal small-sized blood vessels in the area of infarct, suggesting a possible role in the regulation of the blood brain barrier and angiogenesis. Our results encourage the use of NSCs as a cell-replacement therapy for the treatment of human vascular Parkinsonism.

Tyrosine hydroxylase cells appearing in the mouse striatum after dopamine denervation are likely to be projection neurones regulated by L-DOPA.

Tyrosine hydroxylase (TH)-immunoreactive (ir) neurones are detected in the striatum of animals after dopamine depletion and also in human parkinsonian patients. Although there is extensive evidence for TH-ir neurones in the lesioned rodent striatum, there are few details regarding the molecular phenotype of these neurones, regulation of their TH expression after l-3,4-dihydroxyphenylalanine (L-DOPA) treatment and their function. In the present study, we examined the time-course of appearance of TH-ir neurones in the mouse striatum after 6-hydroxydopamine (6-OHDA) lesion and determined their molecular phenotype. We found that TH-ir neurones appeared in the striatum as early as 3 days after a 6-OHDA lesion. By 1 week after the lesion, the number of TH-ir neurones started to decrease and this decrease progressed significantly over time. Treatment with L-DOPA increased both the number of TH-ir neurones and the intensity of their immunolabelling. The TH-ir neurones that appear after the 6-OHDA lesion in the striatum are not newly generated cells as they did not incorporate 5-bromo-2-deoxyuridine. We found that the vast majority of TH-ir neurones colocalized with dynorphin and enkephalin, suggesting that they are projection neurones of the direct and indirect striatal output pathways. TH-ir neurones did not express the dopamine transporter but half of them expressed amino acid decarboxylase, an enzyme required for dopamine synthesis. Finally, striatal TH-ir neurones are functionally active, expressing the neuronal activation marker FosB in response to L-DOPA treatment. Promotion of these striatal TH-ir neurones may be beneficial in Parkinson's disease, particularly in the early stages when dopamine denervation is incomplete.

Olfactory glia transplantation into cervical spinal cord contusion injuries.

OBJECT: The results of olfactory ensheathing cell (OEC) transplantation have raised great expectations as a potential treatment for spinal cord injury (SCI). Its capacity to promote functional neural repair, however, remains unclear. The authors studied axonal growth and locomotor recovery after C-7 contusion injury and OEC transplantation in adult rats. METHODS: Twenty-four male Wistar rats underwent a mild C-7 contusion injury that completely disrupted the dorsal corticospinal tract (DCST). In 14 rats OECs were transplanted into the lesion, and 10 were used as controls. At 3 months postcontusion, the kinematics of locomotion were assessed, and the CST was traced by injecting dextran tetramethylrhodamine bilaterally into the cerebral cortex. The animals were killed 2 weeks after tracer injection, and their spinal cords were studied immunohistochemically. Although the survival of transplanted cells varied, they were present in all cases. The authors observed neither OEC migration nor DCST axon regeneration in any of the cell transplant-treated rats. Corticospinal axons ended in retraction bulbs at the proximal edge of the lesion or, exceptionally, a few micrometers inside the transplant. The results of neurofilament immunohistochemical analysis provided evidence of neurites from systems other than the DCST growing into the transplant, but in some cases these neurites formed loops of pathological appearance. Contusion injury of C-7 caused chronic locomotor deficits that did not improve after OEC transplants. CONCLUSIONS: The findings in this study indicate that OEC transplants alone are not sufficient for neural repair and functional recovery after SCI. In addition, OECs can induce abnormal axonal growth, making further studies necessary before considering their clinical use.

Mecanismos involucrados en la promoción de crecimiento axonal por la glia envolvente del bulbo olfatorio / Mechanism involved in axonal growth promotion by olfactory bulb ensheathing cells

La actividad que promueve el crecimiento de axones por la glia envolvente (GE) del bulbo olfatorio depemde de la expresión de diversas moléculas durante el desarrollo, la vida adulta y la reparación de lesiones nerviosas. Diversas moléculas tales como las neurotrofinas y sus receptores, los factores de crecimiento, las moléculas de adhesión celular, las moléculas de matriz extracelular y las moleculas asociadas con la mielinización son producidas por la glia del sistema olfatorio durante el desarrollo. Su expresion sostenida durante la vida adulta parece estar asociada con el reemplazo celular y la alta plasticidad de este sistema. A su vez, su expresión se involucra en procesos de reparación de lesiones mediados por trasplantes de glia. La migración de la GE, que acompaña axones en crecimiento, se observa durante el desarrollo y en procesos de regeneración luego de una lesión. Los trasplantes de GE permiten la navegación de brotes regenerantes a través del tejido gliótico inhbidor formado luego de una lesión del sistema nervioso central. El propósito de esta revisión es profundizar en los mecanismos de actividad promotora de crecimiento axonal