1.
Archer, Trevor, 1949, et al.
(author)
Influence of noradrenaline denervation on MPTP-induced deficits in mice
2006
In: Journal of neural transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 113:9, s. 1119-1129
Journal article (peer-reviewed) abstract
C57/BL6 mice were administered either DSP4 (50 mg/kg, s.c., 30 min after injection of zimeldine, 20 Cemg/kg, s.c.) or vehicle (saline) at 63 days of age. Three weeks later, one group (n = 10) of DSP4-treated and one group of vehicle-treated mice were administered MPTP (2 x 40 mg/kg, s.c., 24 hours between injections; the High dose groups), one group (n = 10) of DSP4-treated and one group of vehicle-treated mice were administered MPTP (2 x 20 mg/kg, s.c., 24 hours between injections; the Low dose groups), and one group (n = 10) of DSP4-treated and one group of vehicle-treated mice were administered vehicle. Three weeks later, all six groups were tested in motor activity test chambers, followed by injections of L-Dopa (20 mg/kg, s.c.), and then tested over a further 360 min in the activity test chambers. It was found that pretreatment with the selective NA neurotoxin, DSP4, deteriorated markedly the dose-dependent motor activity deficits observed in the vehicle pretreated MPTP treated mice. These 'ultra-deficits' in the spontaneous motor behaviour of MPTP-treated mice were observed over all three parameters: locomotion, rearing and total activity, and were restricted to the 1(st) and 2(nd) 20-min periods. Administration of L-Dopa (20 mg/kg) following the 60-min testing of spontaneous behaviour restored the motor activity of Vehicle + MPTP treated mice (neither the Vehicle + MPTP-Low nor the Vehicle + MPTP-High groups differed from the Vehicle-Vehicle group, here) but failed to do so in the DSP4 pretreated mice. Here, a dose-dependent deficit of L-Dopa-induced motor activity (over all three parameters) was obtained thereby offering further evidence of an 'ultra-deficit' of function due to previous denervation of the NA terminals. The present findings support the notion that severe damage to the locus coeruleus noradrenergic system, through systemic DSP4, disrupts the facilitatory influence on the nigrostriatal DA system, and interferes with the ability of the nigrostriatal pathway to compensate for or recover from marked injury, MPTP treatment.
2.
Christophersen, Nicolaj, et al.
(author)
Induction of dopaminergic neurons from growth factor expanded neural stem/progenitor cell cultures derived from human first trimester forebrain.
2006
In: Brain Research Bulletin. - : Elsevier BV. - 0361-9230 .- 1873-2747. ; 70:4-6, s. 457-466
Journal article (peer-reviewed) abstract
Multipotent stem/progenitor cells derived from human first trimester forebrain can be expanded as free-floating aggregates, so called neurospheres. These cells can differentiate into neurons, astrocytes and oligodendrocytes. In vitro differentiation protocols normally yield γ-aminobutyric acid-immunoreactive neurons, whereas only few tyrosine hydroxylase (TH) expressing neurons are found. The present report describes conditions under which 4–10% of the cells in the culture become TH immunoreactive (ir) neurons within 24 h. Factors including acidic fibroblast growth factor (aFGF) in combination with agents that increase intracellular cyclic AMP and activate protein kinase C, in addition to a substrate that promotes neuronal differentiation appear critical for efficient TH induction. The cells remain THir after trypsinization and replating, even when their subsequent culturing takes place in the absence of inducing factors. Consistent with a dopaminergic phenotype, mRNAs encoding aromatic acid decarboxylase, but not dopamine-β-hydroxylase were detected by quantitative real time RT-PCR. Ten weeks after the cells had been grafted into the striatum of adult rats with unilateral nigrostriatal lesions, only very few of the surviving human neurons expressed TH. Our data suggest that a significant proportion of expandable human neural progenitors can differentiate into TH-expressing cells in vitro and that they could be useful for drug and gene discovery. Additional experiments, however, are required to improve the survival and phenotypic stability of these cells before they can be considered useful for cell replacement therapy in Parkinson's disease.
3.
4.
Liljekvist-Soltic, Ingela, et al.
(author)
Progenitor cell-derived factors enhance photorecepto survival in rat retinal explants.
2008
In: Brain Research. - : Elsevier BV. - 0006-8993 .- 1872-6240. ; 1227, s. 226-233
Journal article (peer-reviewed) abstract
Explantation of postnatal rat retinas is associated with degenerative events that show morphological similarities to human retinal degenerative disorders. The most evident morphological features are photoreceptor apoptosis involving caspase-3 and Müller cell activation. The purpose of the present study was to determine the content of protective factors in rat retinal progenitor cells and analyze the influence of the identified factors on the survival of photoreceptor cells and retinal gliosis. Tissue inhibitors of matrix metalloproteinase-1 (TIMP-1) and vascular endothelial growth factor (VEGF) were identified as putative beneficial factors, and their combined effect was examined in rat retinal explant cultures. Photoreceptor apoptosis was estimated by cell counts of cleaved caspase-3 and caspase-12 immunolabeled as well as TUNEL labeled cells. TIMP-1 and VEGF in combination significantly suppressed photoreceptor apoptosis involving caspase-3 activation. Cell counts of caspase-12 and TUNEL labeled photoreceptors showed no significant difference between the experiment and control retinas. TIMP-1 and VEGF appeared to have no effect on Müller cell activation as measured by GFAP and Ki-67 immunohistochemistry. Our data suggest that TIMP-1 and VEGF in combination promote the survival of photoreceptor cells in rat retinal explants, possibly by affecting a caspase-3 signaling pathway.
5.
Marcussen, A B, et al.
(author)
Increase in neurogenesis and behavioural benefit after chronic fluoxetine treatment in Wistar rats
2008
In: Acta Neurologica Scandinavica. - : Hindawi Limited. - 1600-0404 .- 0001-6314. ; 117:2, s. 94-100
Journal article (peer-reviewed) abstract
Objective - Disturbances in hippocampal neurogenesis may be involved in the pathophysiology of depression and it has been argued that an increase in the generation of new nerve cells in the hippocampus is involved in the mechanism of action of antidepressants. Materials and Methods - Adult Wistar rats were treated with fluoxetine (10 mg/kg) 1 h, daily for 5 (subchronic) or 28 days (chronic) before the Novelty Suppressed Feeding test was performed. Cell proliferation and neurogenesis were analysed using the markers 5-bromo-deoxy-2'-uridine, Ki-67, and doublecortin. Results - A significant behavioural effect was found after 28 days of fluoxetine administration. However, no behavioural improvement was demonstrated after acute and subchronic treatment with fluoxetine. We further demonstrate that chronic antidepressant treatment increases cell proliferation as well as neurogenesis in the dentate gyrus, here using Wistar rats. Conclusions - In further development of antidepressants, neurogenesis may serve as an important parameter to examine the efficacy and mechanism of action of novel drugs.
6.
Persson, M L, et al.
(author)
Aberrant amino acid transport in fibroblasts from patients with bipolar disorder
2009
In: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 457:1, s. 49-52
Journal article (peer-reviewed) abstract
Aberrant tyrosine transport is a repeated finding in fibroblasts from schizophrenic patients. The transport aberration could lead to disturbances in the dopaminergic and noradrenergic neurotransmitter systems. Tyrosine and tryptophan are the precursors of the neurotransmitters dopamine and serotonin. Disturbed dopaminergic, noradrenergic and serotoninergic systems are implicated as causes of bipolar disorder. Hence, the aim of this study was to explore whether patients with bipolar disorder have an aberrant transport of tyrosine and/or tryptophan. Fibroblast cell lines from patients with bipolar type-1 disorder (n=10) and healthy controls (n=10) were included in this study. All patients fulfilled the DSM-IV diagnostic criteria. The transport of amino acids across the cell membranes was measured by the cluster tray method. The kinetic parameters, maximal transport velocity (V(max)) and affinity constant (K(m)) were determined. A significantly lower V(max) for tyrosine (p=0.027) was found in patients with bipolar type-1 disorder in comparison to healthy controls. No significant differences in K(m) for tyrosine and in the kinetic parameters of tryptophan between patients with bipolar type-1 disorder and healthy controls were observed. The decreased tyrosine transport (low V(max)) found in this study may indicate less access of dopamine in the brain, resulting in disturbed dopaminergic and/or noradrenergic neurotransmission, that secondarily could lead to disturbances in other central neurotransmitter systems, such as the serotoninergic system. However, as sample size was small in this study and an age difference between patients and controls existed, the present findings should be considered as pilot data. Further studies with larger sample number are needed to elucidate the transport aberration and the significance of these findings.
7.
Pierri, Mette, et al.
(author)
KW-6002 protects from MPTP induced dopaminergic toxicity in the mouse
2005
In: Neuropharmacology. - : Elsevier. - 0028-3908 .- 1873-7064. ; 48:4, s. 517-524
Journal article (peer-reviewed) abstract
The risk of Parkinson's disease (PD) is associated with a lower intake of caffeine, a non-selective adenosine A2A antagonist. In agreement, genetic or pharmacological inactivation of adenosine A2A receptors in animal models of PD has demonstrated both symptomatic and neuroprotective effects. These findings and the lack of disease modifying therapies have led to intense research on adenosine A2A antagonists as a novel treatment for PD. In the present study the neuroprotective effect of the A2A receptor antagonist KW-6002 was investigated using different models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice, which induced dopaminergic terminal and or dopaminergic cell loss and inflammation. Treatment with KW-6002 prevented the loss of dopaminergic striatal terminals and nigral cell bodies and inhibited the nigral microglia activation. Our results confirm previous findings that pharmacological inactivation of A2A receptors inhibits MPTP-induced dopaminergic damage at the level of striatum. In addition, we demonstrate for the first time that, after MPTP treatment in mice, an A 2A antagonist is neuroprotective, and has anti-inflammatory effects, at the level of the substantia nigra. Thus, our data further support the use of A2A receptor antagonists as a novel neuroprotective therapy for PD
8.
Vumma, Ravi, et al.
(author)
Functional characterization of tyrosine transport in fibroblast cells from healthy controls
2008
In: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 434:1, s. 56-60
Journal article (peer-reviewed) abstract
Human fibroblast cells are an advantageous model to study the transport of amino acids across cell membranes, since one can control the environmental factors. A major problem in all earlier studies is the lack of precise and detailed knowledge regarding the expression and functionality of tyrosine transporters in human fibroblasts. This motivated us to perform a systematic functional characterization of the tyrosine transport in fibroblast cells with respect to the isoforms of system-L (LAT1, LAT2, LAT3, LAT4), which is the major transporter of tyrosine. Ten (n=10) fibroblast cell lines from healthy volunteers were included in the study. Uptake of L-[U-14C] tyrosine in fibroblasts was measured using the cluster tray method in the presence and absence of excess concentrations of various combinations of inhibitors. This study demonstrated that LAT1 is involved in 90% of total uptake of tyrosine and also around 51% of alanine. Not more than 10% can be accounted for by LAT2, LAT3 and LAT4 isoforms. LAT2 seems to be functionally weak in uptake of tyrosine while LAT3 and LAT4 contributed around 7%. 10% could be contributed by system-A (ATA2 isoform). Alanine consequently inhibited the tyrosine transport by up to 60%. Tyrosine transport through the LAT1 isoform has a higher affinity compared to system-L. In conclusion, the LAT1 isoform is the major transporter of tyrosine in human fibroblast cells. Competition between tyrosine and alanine for transport is shown to exist, probably between LAT1 and LAT2 isoforms. This study established fibroblast cells as a suitable experimental model for studying amino acid transport defects in humans.
