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Background: Massive expression in rats of the mutated human superoxide dismutase-1 gene (mhSOD1G93A) causes an incurable, fast-progressing fatal illness that is an established model of fALS. We showed earlier that CDPch can slightly but signifi cantly defer the onset of neurologic symptoms and extend life of the carriers. Here we report effects of the drug on some biochemical indices. Methods: Transgenic mhSOD1G93A(+) (Tg+) rats were randomized by gender and litter between study groups. The treatments began on postnatal day (PD) 61, consisted of a daily ip dose of CDPch (0.5 g/kg) or isotonic NaCl, and continued for a preset time or until an arbitrary (the rats were euthanized when unable to feed voluntarily) death point. Untreated Tg+ rats (PD 50ñ60, 94 and 108ñ129) and their Tg-siblings were used for additional controls. After decapitation, blood serum and CNS were harvested and stored at −80°C till analyzed. Results: ANOVA showed signifi cant (P<0.001) age-related elevation of serum immunoreactive mhSOD1 (s-ir-mhSOD1) in NaCl-treated Tg+ rats, signifi cantly (P=0.011) higher s-ir-mhSOD1 level in NaCl-treated terminal stage Tg+ rats than in their CDPch-treated counterparts, and a signifi cant interaction (P=0.02) between these factorsí effects on s-ir-mhSOD1 level; no such effect was found in serum VEGF or spinal cord ir-mhSOD1 level. There was signifi cant (P<0.01) lowering effect of CDPch treatment, a tendency (P=0.09) for agerelated lowering and a tendency (P=0.10) for interaction between these factorsí effects on serum total thiol (sTT) level; post-hoc analysis showed signifi cantly lower sTT level in CDPch-treated terminal stage rats than in their NaCl-treated counterparts. Western blots showed the existence of multiple oligomeric forms of s-ir-mhSOD1 in Tg+ rats.
Because of their potential for self-renewal and the ability for generating many differentiated cell types, progenitor cells are a key player in regenerative and repair processes. In the central nervous system, pools of these cells have been identified in two regions: the subgranular zone of hippocampal gyrus dentatus and the subventricular zone. Neural stem cells that reside in these regions are subject to a specific neurogenesis-stimulating and -regulating environment called ‘niche’. Our model of surgical brain injury (SBI) opens the avenues for studying the mechanisms of repair and reconstruction of brain cortex and enables demonstrating the presence of possible vascular niches in the peri-lesion zone. The present studies were aimed at characterizing of the immune phenotype of the cells that populate this region. The peri-lesion area of the brain cortex showed the presence of dying neurons and glial cells since the first postlesion day. Simultaneously, activated microglial cells and astrocytes appeared, and part of the latter formed a scar on the surface of the damaged cortex. Another fractions of the cells that appeared following the SBI in both the lumen and the vicinity of blood vessels expressed either the macrophagal/monocytic marker CD14, or the marker of hematopoietic progenitor cells and small vessel endothelium CD34. Beginning on the first post-SBI day, the peri-lesion area showed also the presence and accumulation of a variety of cells with immature phenotypes. These included immature endothelial cells building new blood vessels (angiogenesis) and cells with phenotypes of other brain parenchyma-forming cell subpopulations: (1) nestin-positive astroglial and non-glial cells, (2) cells expressing the marker of juvenile astrocytes vimentin-positive, and (3) cells showing doublecortin immunoreactivity (the marker of early differentiated neurons). These results clearly indicate that during the early post-SBI period the peri-lesion zone is being populated by a heterogenic pool of morphologically immature cells that most likely herald the advent of reconstruction and/or repair of the injured brain region. Supported by the Polish Ministry of Science and Higher Education grant No N N404 522838
Adult mammalian brain contains a number of specialized neurovascular structures termed “niches” that act as sources of neuronal cells throughout the individual’s life. Some of the niches generate neurons to satisfy the need for ‘replacement’ neurons within the same or closely located brain structures, whereas the other can provide such cells for more distant destinations in the brain. A common characteristic of known neurovascular niches is the presence of a complex 3-dimensional network of basal lamina processes, called fractones. It apparently plays a major role in communication between the various niche-populating cell types as well as in niche activity and output. We hypothesized that similar niches may form ad hoc after a mechanical brain trauma, and tested this possibility in a rat model of surgical brain injury. Four days after removing a small fragment of sensorimotor cortex, the peri-wound region showed numerous symptoms of active repair and remodeling of brain parenchyma, including the presence of multiple cell types of immature phenotypes. The latter, as shown by a variety of light and electron microscopy techniques, included endothelial cell precursors as well as nestin-positive immature neural cells of astrocytic or non-glial characteristics. However, there was no evidence of in situ neurogenesis or a considerable migration of cells from SVZ. The centers of the said repair processes were capillary blood vessels connected with basal lamina-formed fractones. These results indicate that surgical brain trauma causes the formation of a vascular niche with no apparent neurogenic potential.
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