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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Journal of neurology 242 (1994), S. S54 
    ISSN: 1432-1459
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Fetal neural grafts, rich in dopamine neurons, taken from the ventral mesencephalon and implanted into the dopamine-denervated striatum, can reinnervate the striatum, form synaptic contacts with host neurons, release dopamine and improve motor function. In animal models of Parkinson's disease, the improvement resulting from transplantation is dependent on the number of surviving grafted dopamine neurons and the density and extent of graft-derived reinnervation. The major unresolved scientific question at present is not whether neural grafting is better than established drug treatments but if survival and function of such grafts are at all possible in patients with Parkinson's disease. A more general problem is that if cell transplantation is to become clinically useful for a large number of Parkinsonian patients and also be applied in other neurological disorders, alternative sources of donor tissue must be found; several have been proposed, including adrenal medulla cells and sympathetic ganglia but perhaps the most exciting strategy is to implant cells that have been genetically engineered to synthesize and release L-dopa or dopamine.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-1106
    Keywords: Platelet-derived growth factor ; Brain-derived neurotrophic factor ; Dopaminergic neurons ; Cell culture ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The neurotrophic effects of the BB isoform of platelet-derived growth factor (PDGF) on rat and human fetal mesencephalic dopaminergic neurons have been characterized in vitro. A dose-response analysis demonstrated maximal responses at 30 ng/ml of PDGF-BB. This concentration resulted in a marked increase in the survival and neurite outgrowth from rat and human tyrosine hydroxylase-(TH) positive, presumed dopaminergic neurons after 7 days in vitro. The effects of PDGF-BB on survival of TH-positive neurons were comparable to those of brain-derived neurotrophic factor (BDNF), whereas neurite outgrowth was more pronounced after addition of BDNF. The combination of BDNF and PDGF-BB yielded no additive effects. Double immunohistochemical staining of rat cultures demonstrated PDGF β-receptors on about 90% of the TH-positive neurons. PDGF-BB treatment of rat mesencephalic cultures induced an upregulation of c-fos and TH mRNA with maximal levels after 0.5–2 h as assessed by quantitative PCR analysis. An increased number of Fos protein-positive cells was detected immunohistochemically after 4 h of PDGF-BB treatment. The present results provide further evidence for specific and direct effects of PDGF-BB on gene expression, survival and neurite outgrowth of mesencephalic dopaminergic neurons of rat and human origin.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-1106
    Keywords: Nerve growth factors ; Neuronal plasticity ; Substantia nigra ; Tyrosine hydroxylase ; Image analysis ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Brain-derived neurotrophic factor (BDNF) has been shown to promote the survival of cultured fetal mesencephalic dopaminergic neurons of rat and human origin. In the present study, BDNF was tested for its ability to influence neuronal structure of dopaminergic neurons in dissociated cultures of human fetal ventral mesencephalon after 7 days in vitro. Following immunocytochemical staining for tyrosine hydroxylase, all surviving dopaminergic neurons were counted. Computer-assisted three-dimensional reconstructions of uniform randomly selected neurons cultured with 50 ng/ml BDNF (n=120) or without BDNF (n=80) were made. BDNF increased the number of surviving human dopaminergic neurons by 76%. Mean soma profile area was significantly enlarged by 18% in BDNF-treated neurons as compared to controls. Analysis of parameters of neuritic size and complexity in these cultures revealed that combined neuritic length, combined neuritic volume, and neuritic field area were increased by 60%, 125% and 129%, respectively, and the mean number of segments per cell was increased by 41%. A change in neurite complexity in BDNF-treated cultures was further confirmed by the Sholl's concentric sphere analysis. These results demonstrate that BDNF promotes development and differentiation of human fetal dopaminergic neurons in vitro.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature Publishing Group
    Nature 441 (2006), S. 1094-1096 
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Many common neurological disorders, such as Parkinson's disease, stroke and multiple sclerosis, are caused by a loss of neurons and glial cells. In recent years, neurons and glia have been generated successfully from stem cells in culture, fuelling efforts to develop stem-cell-based transplantation ...
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    [s.l.] : Macmillan Magazines Ltd.
    Nature 405 (2000), S. 892-895 
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] In tissues that can repair themselves, such as skin and liver, dead cells can be replaced either by the proliferation of nearby cells or by the activation of resident stem cells — undifferentiated cells with the potential to generate many different cell types. The brain apparently lacks ...
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Noradrenaline (NA) metabolism tn the neocortex and hippocampus was examined in rats atl 1, 24, and 48 h following 15 min of reversible forebrain ischemia. As assessed by the ratio of accumulated 3,4-dihydroxyphenylalanine (DOPA) to the tissue NA level after inhibition of DOPA decarboxylase, the NA turnover rates were markedly increased (120-148% above the control) at 1 h postischemia in both the neocortex and hippocampal formation (CA1 and CA3 plus dentate gyrus). The DOPA:NA ratio went back to control levels after longer postischemic survival times. The ratio between levels of the deaminated NA metabolite, 3,4-dihy-droxyphenylethyleneglycol (DOPEG), and NA, which gives another measure of NA turnover rate, Showed similar changes. In the neocortex and the CA3 plus dentate gyrus, the DOPEG:NA ratio was markedly increased (89-118%) 1 h after the ischemia, but this change had disappeared at 24 and 48 h. Thus, both the DOPA accumulation experiments and the NA and DOPEG measurements indicate that following transient forebrain ischemia, there is an increased NA turnover in the hippocampus and cortex only in the early recirculation period and not after longer postischemic survival times. The degree of neuronal necrosis in ihe CA1 region was examined light microscopically on celestine blue-acid fuchsin-stained sections at 24, 48, and 96 h following the ischemic insult. The neuronal damage in CA1 was sparse after 24 h of recovery, had increased markedly after 48 h. and was very pronounced at 96 h. Our data show that the changes in NA turnover in the neocortex and hippocampus follow a different time course than the development of neuronal damage in the hippocampal CA 1 region. The activation of the NA system occurs during and immediately after the period of high extracellular levels of glutamate. Excitatory amino acids have been proposed to be of major importance for the development of ischemic brain damage, whereas the NA afferents to the hippocampus and cortex (originating in the locus coeruleus) seem to have a protective role. We hypothesize that the increased activity of the locus coeruleus system, observed early postischemically in the present study, mitigates the detrimental effects evoked by excessive glutamate receptor stimulation, thereby reducing the degree of neuronal necrosis.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Dopaminergic innervation of the caudate nucleus in adult rats can be partially restored by the grafting of embryonic substantia nigra into the overlying parietal cortex with concomitant compensation of certain behavioral abnormalities. In this study the function of such grafts was investigated neurochemically by quantification of transmitter metabolism and glucose utilization in the reinnervated target. Rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal bundle received a single graft to the dorsal caudateputamen and were screened for rotational behavior following 5 mg/kg methamphetamine. The grafts restored dopamine concentrations in the caudateputamen from initially less than 0.5% to an average of 13.6% of normal in rats with behavioral compensation. The ratio of 3,4-dihydroxyphenylacetic acid to dopamine, which is a measure of the rate of transmitter turnover, were equivalent in transplanted and normal control rats. Moreover, measurements of DOPA accumulation for a 30-min period after DOPA decarboxylase inhibition indicated similar fractional dopamine turnover rates in normal and transplantreinnervated tissues. Correlations between rotational behavior and dopamine concentrations showed that reinnervation to only 3% of normal was sufficient to counterbalance the motor asymmetry. Measurements of glucose utilization by [14C]deoxyglucose autoradiography indicated equivalent metabolic rates for the grafted tissue and the intact substantia nigra. 6-Hydroxydopamine denervation of the caudate-putamen had no significant effect on neuronal metabolism in that region, nor did subsequent reinnervation from a graft. Grafts, however, were associated with a 16% reduction of glucose uptake in the ipsilateral globus pallidus, indicating a significant transsynaptic influence of the nigral transplants on neuronal metabolism in the host brain. Overall the results indicate that behaviorally functional neuronal grafts spontaneously metabolize dopamine and utilize glucose at rates characteristic of the intact nigrostriatal system. This provides further evidence that ectopic intracortical nigral trans-plants can reinstate dopaminergic neurotransmission in regions of the host brain initially denervated by the 6-hydroxydopamine lesion.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Hippocampal extracellular levels of noradrenaline (NA), 5-hydroxytryptamine (5-HT), and 5-hydroxyindole-acetic acid (5-HIAA) were monitored with the microdialysis technique in freely moving rats. In one experiment 30 min samples were collected during 24 h of continuous perfusion, and the monoamine output was compared to the behavioural activity state, as arbitrarily classified in three categories: sleep/rest, drowsiness and full alertness associated with complex behaviours. In the individual animal the hippocampal NA and 5-HT output showed pronounced fluctuations during the 24 h period, but the 30 min sampling times did not allow for a clear-cut correlation to behavioural activity state. However, the mean NA and 5-HT output for all animals during the dark period of the day was 43 and 38% higher, respectively, than during the light period, and the average NA and 5-HT levels in samples collected during periods of high behavioural activity was 34 and 45% higher, respectively, than during periods of rest or sleep. In contrast, there were no detectable changes in extracellular 5-HIAA. The selective serotonin uptake blocker indalpine, added to the perfusion fluid at 1 μM, increased the extracellular 5-HT levels 6-fold, with a similar correlation to behavioural activity state as without indalpine.In a second experiment the effect of handling and tail-pinch was studied in 15 min sample fractions. Gentle handling of the animals during the sampling period increased the hippocampal NA and 5-HT output by 32 and 72%, respectively, and a similar increase (63 and 48%) was obtained by application of tail-pinch. Maximum NA output was reached during the handling or tail-pinch period, whereas maximal 5-HT levels were detected in the subsequent 15 min sample fraction. No changes in extracellular 5-HIAA was observed.It is concluded (1) that intracerebral microdialysis provides a useful method for the study of extracellular NA and 5-HT in the hippocampal formation of conscious rats during active behaviour; (2) that there are substantial fluctuations in hippocampal NA and 5-HT output in freely moving rats which correlate with the light-dark cycle as well as with the activity state of the animals; (3) that the spontaneous variations in 5-HT output are maintained during reuptake blockade; and (4) that behavioural activation through gentle handling or tail-pinch elicits NA and 5-HT release. The present data support a role of the forebrain NA and 5-HT systems in behavioural state control and highlights the necessity of experimental designs in which the spontaneous fluctuations in transmitter release are controlled for in studies of, for example, drug effects on NA and 5-HT release in conscious animals.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The rat brain-derived neurotrophic factor (BDNF) gene consists of four short 5-exons linked to separate promoters and one 3′-exon encoding the mature BDNF protein. Using in situ hybridization we demonstrate here that kindling-induced seizures, cerebral ischaemia and insulin-induced hypoglycaemic coma increase BDNF mRNA levels through insult- and region-specific usage of three promoters within the BDNF gene. Both brief (2 min) and longer (10 min) periods of forebrain ischaemia induced significant and major increases only of exon III mRNA in the dentate gyrus. Following hypoglycaemic coma (1 and 30 min), exon III mRNA was markedly elevated in the dentate gyrus and, in addition, exon I mRNA showed a moderate increase. Single and recurrent (n= 40) hippocampal seizures significantly increased expression of exon I, II and III mRNAs in the dentate gyrus granule cells. After recurrent seizures, including generalized convulsions, there were also major increases of both exon I and III mRNAs in the CA3 region, amygdala, piriform cortex and neocortex, whereas in the hippocampal CA1 sector marked elevations were detected only for exon III mRNA. The insults had no effect on the level of exon IV mRNA in the brain. The region- and insult-specific pattern of promoter activation might be of importance for the effectiveness of protective responses as well as for the regulation of plastic changes following brain insults.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    European journal of neuroscience 4 (1992), S. 0 
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: In vivo microdialysis was used to monitor noradrenalin (NA) release in the rat hippocampus, sensorimotor cortex and amygdala in response to seizures induced by electrical kindling stimulation in the hippocampus. Generalized seizures increased NA output in the hippocampus five-fold above baseline level (as assessed with 2-min sampling periods). The peak value was seen 2–4 min after onset of seizure activity and baseline was reached after another 6–8 min. In the sensorimotor cortex, there was a seven-fold increase showing a similar time-course. Focal hippocampal seizures gave rise to three-fold and 80% increases above baseline in the hippocampus and sensorimotor cortex, respectively. A unilateral knife transection of the dorsal noradrenergic bundle reduced hippocampal NA release induced by focal seizures by 53%. In animals subjected to 30 stimulus-evoked seizures with 5-min intervals (‘rapid kindling’), maximal NA output was observed after the third seizure in both hippocampus (237% increase) and amygdala (122% increase). NA levels tapered off with repeated stimulation and reached baseline after nine stimulations in the hippocampus; in the amygdala, the NA output was still slightly elevated at the end of the stimulation period. These results indicate that there is a general activation of the locus coeruleus system during focal as well as generalized seizures, as evidenced by marked increases in transmitter release from noradrenergic terminals in all forebrain areas studied. NA output in areas exhibiting seizure activity is dependent on impulse flow in locus coeruleus neurons and probably also on local regulatory mechanisms active at the noradrenergic terminal level. The increase in inhibitory noradrenergic transmission in both epileptic and non-epileptic brain regions may dampen ongoing seizure activity as well as lessen its spread and generalization.
    Type of Medium: Electronic Resource
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