| 1. |
- Grabowski, Martin, et al.
(författare)
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Fetal neocortical grafts implanted in adult hypertensive rats with cortical infarcts following a middle cerebral artery occlusion: ingrowth of afferent fibers from the host brain
- 1992
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Ingår i: Experimental Neurology. - 0014-4886. ; 116:2, s. 105-121
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Tidskriftsartikel (refereegranskat)abstract
- This study is focused on the survival of fetal neocortical grafts placed in the infarcted adult host cortex of the spontaneously hypertensive rat and describes the ability of host axonal regeneration into the graft after a focal ischaemic lesion. Five to seven days following ligation of the right middle cerebral artery, dissociated neocortical primordium from fetuses of gestational age 12-18 days was implanted into the infarcted cortical area. Surviving transplants were seen in all rats, although grafts derived from gestational age 12-14 days displayed an irregular morphology rich in sinusoid-like cavities and containing fewer cells of apparently mature neuronal morphology. Grafts from older donors contained perikarya of neuronal appearance; however, they lacked normal cortical lamination. Ten days postgrafting, fibers stained by acetylcholinesterase histochemistry, dopamine-beta-hydroxylase, and 5-hydroxytryptamine immunohistochemistry were found in the grafts, and by 10-23 weeks after transplantation the fiber density had increased substantially. When the retrograde tracer Fluoro-Gold was injected into the grafted tissue, labeled cells were found in several subcortical nuclei of the host, including the nucleus basalis of Meynert, ventral pallidum, thalamus, dorsal raphe, locus coeruleus, as well as the ipsilateral and contralateral neocortex. This study shows that grafts of dissociated neocortical tissue exhibit good survival and growth potential when implanted into infarcted neocortex and that several nerve fiber systems of the adult host have a regenerative capacity sufficient to innervate the grafted tissue.
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| 2. |
- Maciel, EN, et al.
(författare)
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Cyclosporin A and Bcl-2 do not inhibit quinolinic acid-induced striatal excitotoxicity in rodents
- 2003
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Ingår i: Experimental Neurology. - 0014-4886. ; 183:2, s. 430-437
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial permeability transition (MPT) is a nonselective inner membrane permeabilization that contributes to neuronal cell death under circumstances such as brain trauma, ischemia, and hypoglycemia. Here we study the participation of MPT and the Bcl-2-sensitive apoptotic cell death pathway in glutamate receptor-mediated excitotoxicity. Intrastriatal infusions of the N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid caused massive striatal neurodegeneration in both rats and mice. Interestingly, transgenic mice overexpressing human Bcl-2 and rats systemically treated with cyclosporin A did not exhibit reduced sensitivity to quinolinic acid-induced striatal toxicity. Both Bcl-2 and cyclosporin A are inhibitors of MPT; in addition Bcl-2 also inhibits apoptotic stimuli-mediated release of mitochondrial apoptogenic factors. Isolated brain mitochondria from cyclosporin A-treated rats showed resistance to Ca2+-induced dissipation of the membrane potential, indicating protection against MPT. We conclude that quinolinic acid-mediated striatal excitotoxicity is not dependent on MPT and Bcl-2-sensitive apoptotic cell death pathways. (C) 2003 Elsevier Science (USA). All rights reserved.
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| 3. |
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| 4. |
- Castilho, Roger F, et al.
(författare)
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FK506 and cyclosporin A enhance the survival of cultured and grafted rat embryonic dopamine neurons
- 2000
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 164:1, s. 94-101
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Tidskriftsartikel (refereegranskat)abstract
- We examined the effects of the immunophilin ligands and calcineurin inhibitors FK506 and cyclosporin A on the survival of rat embryonic dopamine (tyrosine hydroxylase (TH)-immunoreactive) neurons. The protective effects of FK506 and cyclosporin A were first studied in dissociated mesencephalic cell cultures subjected to serum deprivation. Significant increases in both the total number of surviving mesencephalic cells and the number of surviving TH-immunoreactive neurons were observed when FK506 or cyclosporin A was present following withdrawal of serum from the culture medium. In a second series of experiments, FK506 increased the survival of dopamine neurons when added only to a hibernation medium in which donor tissue pieces were stored for 7 days prior to preparation of the cultures. In a third set of experiments, we investigated the effects of FK506 and cyclosporin A on the survival of grafted rat embryonic dopamine neurons. When FK506 or cyclosporin A was present during tissue preparation and in the final mesencephalic cell suspension used for grafting, the survival of TH-immunoreactive neurons implanted in the striatum increased to around 185% of control values. In contrast, treatment of graft recipient rats, but not the graft suspension itself, with immunosuppressive doses of FK506 or cyclosporin A did not augment the survival of grafted TH-immunoreactive neurons. We conclude that administration of FK506 during storage of embryonic mesencephalic tissue and FK506 or cyclosporin A during preparation of nigral cell suspensions used for grafting can increase the survival of grafted embryonic dopamine neurons.
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| 5. |
- Christophersen, Nicolaj, et al.
(författare)
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Midbrain expression of Delta-like 1 homologue is regulated by GDNF and is associated with dopaminergic differentiation.
- 2007
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 204:2, s. 791-801
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Tidskriftsartikel (refereegranskat)abstract
- Affymetrix GeneChip technology and quantitative real-time PCR (Q-PCR) were used to examine changes in gene expression in the adult murine substantia nigra pars compacta (SNc) following lentiviral glial cell line-derived neurotrophic factor (GDNF) delivery in adult striatum. We identified several genes that were upregulated after GDNF treatment. Among these, the gene encoding the transmembrane protein Delta-like 1 homologue (Dlk1) was upregulated with a greater than 4-fold increase in mRNA encoding this protein. Immunohistochemistry with a Dlk1-specific antibody confirmed the observed upregulation with increased positive staining of cell bodies in the SNc and fibers in the striatum. Analysis of the developmental regulation of Dlk1 in the murine ventral midbrain showed that the upregulation of Dlk1 mRNA correlated with the generation of tyrosine hydroxylase (TH)-positive neurons. Furthermore, Dlk1 expression was analyzed in MesC2.10 cells, which are derived from embryonic human mesencephalon and capable of undergoing differentiation into dopaminergic neurons. We detected upregulation of Dlk1 mRNA and protein under conditions where MesC2.10 cells differentiate into a dopaminergic phenotype (41.7+/-7.1% Dlk1+ cells). In contrast, control cultures subjected to default differentiation into non-dopaminergic neurons only expressed very few (3.7+/-1.3%) Dlk1-immunopositive cells. The expression of Dlk1 in MesC2.10 cells was specifically upregulated by the addition of GDNF. Thus, our data suggest that Dlk1 expression precedes the appearance of TH in mesencephalic cells and that levels of Dlk1 are regulated by GDNF.
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| 6. |
- Deierborg, Tomas, et al.
(författare)
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Absence of striatal newborn neurons with mature phenotype following defined striatal and cortical excitotoxic brain injuries.
- 2009
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 219, s. 363-367
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Tidskriftsartikel (refereegranskat)abstract
- Experimental stroke and excitotoxic brain lesion to the striatum or cortex increase the proliferation of cells residing within the ventricular wall and cause subsequent migration of newborn neuroblasts into the lesioned brain parenchyma. In this study, we clarify the different events of neurogenesis following striatal or cortical excitotoxic brain lesions in adult rats. Newborn cells were labeled by intraperitoneal injection of bromo-deoxy-uridine (BrdU), or by green fluorescent protein (GFP)-expressing lentiviral vectors injected into the subventricular zone (SVZ). We show that only neural progenitors born the first 5 days in the SVZ reside and expand within this neurogenic niche over time, and that these early labeled cells are more prone to migrate towards the striatum as neuroblasts. However, these neuroblasts could not mature into NeuN(+) neurons in the striatum. Furthermore, we found that cortical lesions, close or distant from the SVZ, could not upregulate SVZ cell proliferation nor promote neurogenesis. Our study demonstrates that both the time window for labeling proliferating cells and the site of lesion are crucial when assessing neurogenesis following brain injury.
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| 7. |
- Duarte, Ane, et al.
(författare)
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IGF-1 protects against diabetic features in an in vivo model of Huntington's disease.
- 2011
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 231, s. 314-319
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is the most prevalent polyglutamine expansion disorder. HD is caused by an expansion of CAG triplet in the huntingtin (HTT) gene, associated with striatal and cortical neuronal loss. Central and peripheral metabolic abnormalities and altered insulin-like growth factor-1 (IGF-1) levels have been described in HD. Thus, we hypothesized that restoration of IGF-1-mediated signaling pathways could rescue R6/2 mice from metabolic stress and behavioral changes induced by polyglutamine expansion. We analyzed the in vivo effect of continuous peripheral IGF-1 administration on diabetic parameters, body weight and motor behavior in the hemizygous R6/2 mouse model of HD. We used 9week-old and age-matched wild-type mice, subjected to continuously infused recombinant IGF-I or vehicle, for 14days. IGF-1 treatment prevented the age-related decrease in body weight in R6/2 mice. Although blood glucose levels were higher in R6/2 mice, they did not reach a diabetic state. Even though, IGF-1 ameliorated poor glycemic control in HD mice. This seemed to be associated with a decrease in blood insulin levels in R6/2 mice, which was increased following IGF-1 infusion. Similarly, blood IGF-1 levels decreased during aging in both wild-type and R6/2 mice, being significantly improved upon its continuous infusion. Although no significant differences were found in motor function in R6/2-treated mice, IGF-1 treatment highly improved paw clasping scores. In summary, these results suggest that IGF-1 has a protective role against HD-associated impaired glucose tolerance, by enhancing blood insulin levels.
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| 8. |
- Emgård-Mattson, Mia, et al.
(författare)
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Patterns of cell death and dopaminergic neuron survival in intrastriatal nigral grafts
- 1999
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 160:1, s. 88-279
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies indicate that 80-95% of grafted dopamine neurons die following implantation of embryonic ventral mesencephalic tissue into the striatum. It is believed that the majority die within the first 1-3 weeks after surgery. The aim of this study was to study when and where the implanted neurons die, using the novel fluorescent stain Fluoro-Jade. Fluoro-Jade has recently been shown to stain cell bodies, dendrites, axons, and terminals of degenerating neurons. We transplanted dissociated ventral mesencephalic tissue from embryonic day 14 rat embryos into intact adult rat striatum. After perfusion and sectioning of the implanted rat brains, the number and distribution of Fluoro-Jade and tyrosine hydroxylase-positive neurons were evaluated at 6, 10, 14, and 42 days posttransplantation. Intensely Fluoro-Jade stained neurons were numerous in the grafts at 6 and 10 days after graft surgery; appeared in reduced numbers at 14 days; and had disappeared by the 42-day time point. The number of surviving tyrosine hydroxylase-positive, dopaminergic neurons in the grafts did not change between 6 and 42 days and the low survival rate confirmed that over 90% of these neurons had died during the first week. Assessment of the distribution of neurons positive for Fluoro-Jade or tyrosine hydroxylase revealed higher numbers of neurons stained for these markers located at the periphery than the center of the grafts, and this pattern did not change over time. This study indicates that transplanted neurons continue to die up to 14 days after grafting. Since the majority of transplanted tyrosine hydroxylase-positive neurons most probably die before 6 days after transplantation, neuroprotective strategies should primarily focus on the transplantation procedure and the first week after implantation.
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| 9. |
- Grabowski, Martin, et al.
(författare)
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Neocortical grafts placed in the infarcted brain of adult rats: few or no efferent fibers grow from transplant to host
- 1995
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 134:2, s. 273-276
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Tidskriftsartikel (refereegranskat)abstract
- The present study examines the capacity of fetal neocortical grafts placed in a brain infarct to exchange axonal projections with the host brain. Five to 7 days after a middle cerebral artery occlusion in adult spontaneously hypertensive rats, dissociated neocortical primordium from fetuses of gestational age 15-16 days was implanted into the infarcted area. Four to 11 months later, the neural tracers Phaseolus vulgaris-leucoagglutinin and Fluoro-Gold were injected in the grafts and host neocortex. An extensive axonal network was present in the transplants but only one of eight rats with appropriate placed injections displayed efferent connections from transplant to host. The sparse axonal outgrowth indicates major limitations for fetal rat cortical grafts to form connections with host neural circuitries after an ischemic insult.
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| 10. |
- Grabowski, Martin, et al.
(författare)
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Survival of fetal neocortical grafts implanted in brain infarcts of adult rats: the influence of postlesion time and age of donor tissue
- 1994
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 127:1, s. 126-136
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Tidskriftsartikel (refereegranskat)abstract
- We have previously found that fetal cortex taken from 16- to 18-day-old donors survives grafting to the infarcted cortex 5-7 days after middle cerebral artery occlusion. The present study was undertaken to examine the effect on graft survival of varying the age of the fetal donor tissue and the time between vessel occlusion and graft implantation. First, a cell suspension of neocortical tissue was grafted from fetuses aged 15, 17, or 20 gestational days to the infarcted cortex of hypertensive rats which had undergone arterial occlusion 5-7 days earlier. There were no significant differences in the mean size or general morphology assessed in Nissl- and acetylcholinesterase-stained sections between the groups. Second, neocortical tissue was grafted from fetuses aged 15 gestational days to the infarcted cortex at different times following arterial occlusion. When surgery was delayed until 5-7 days, 3 weeks, or 8 weeks postocclusion, graft survival was significantly better than when implanted 1 day postocclusion. Implantation after 3 weeks yielded grafts that also were significantly larger than those in rats grafted 5-7 days after cortical infarction. The results indicate that there is no crucial upper donor age limit for dissociated fetal neocortical grafts in terms of graft survival and volume. Furthermore, a delay between lesion and transplantation is desirable in this stroke model. The host brain environment seems to be most hospitable around 3 weeks after arterial occlusion.
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