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Christine Winter

Publications and source records attributed to Christine Winter.

15 recordsLinked to original sources
PubMed2006

Subthalamic nucleus lesioning inhibits expression and phosphorylation of c-Jun in nigral neurons in the rat's 6-OHDA model of Parkinson's disease.

Parkinson's Disease (PD) is characterized by a loss of nigral dopamine (DA) neurons, followed by a striatal DA deficit. Inhibition of the subthalamic nucleus (STN) reverses L-DOPA sensitive motor symptoms and improves efficacy of pharmacotherapy in PD-patients. The underlying mechanism of these effects, however, remains largely unknown. Previously, we could show in the rat's 6-hydroxyDA (6-OHDA) model of PD that ablative STN-lesioning exerts functionally neuroprotective effects on the DAergic nigrostriatal pathway against 6-OHDA toxicity, in terms of elevating the number of tyrosine hydroxylase (TH)-expressing neurons rather than enhancing the total number of cells surviving 2 and 6 weeks post lesioning, as assessed via fluorogold staining. These data were correlated with increased functional recovery of 6-OHDA-lesioned rats with preceding STN-lesioning. Here, we extend the previous study design to observation periods of up to 12 weeks to assess long-term effects. Furthermore, to elucidate cellular mechanisms underlying potential neuroprotective effects, we explore the regulation of cellular markers involved in neurodegenerative cascades via immunocytochemistry. We show that preceding STN-lesioning significantly inhibits 6-OHDA induced expression/phosphorylation of the transcription factor c-Jun in surviving nigral neurons in comparison with controls. However, we also demonstrate that functionally neuroprotective effects of preceding STN-lesioning subside after 12 weeks, as assessed with TH immunostaining. We therefore conclude that c-Jun induction/phosphorylation is involved in 6-OHDA toxicity and that STN-lesioning transiently preserves of dopaminergic phenotype of nigral neurons partially via delaying the induction and attenuating the expression and phosphorylation of c-Jun.

Adrenergic Agents↗
PubMed2006

Sialic acid is a receptor determinant for infection of cells by avian Infectious bronchitis virus.

The importance of sialic acid for infection by avian Infectious bronchitis virus (IBV) has been analysed. Neuraminidase treatment rendered Vero, baby hamster kidney and primary chicken kidney cells resistant to infection by the IBV-Beaudette strain. Sialic acid-dependent infection was also observed with strain M41 of IBV, which infects primary chicken kidney cells but not cells from other species. In comparison with Influenza A virus and Sendai virus, IBV was most sensitive to pre-treatment of cells with neuraminidase. This finding suggests that IBV requires a greater amount of sialic acid on the cell surface to initiate an infection compared with the other two viruses. In previous studies, with respect to the haemagglutinating activity of IBV, it has been shown that the virus preferentially recognizes alpha2,3-linked sialic acid. In agreement with this finding, susceptibility to infection by IBV was connected to the expression of alpha2,3-linked sialic acid as indicated by the reactivity with the lectin Maackia amurensis agglutinin. Here, it is discussed that binding to sialic acid may be used by IBV for primary attachment to the cell surface; tighter binding and subsequent fusion between the viral and the cellular membrane may require interaction with a second receptor.

Animals↗
PubMed2005

Enriched environment induces cellular plasticity in the adult substantia nigra and improves motor behavior function in the 6-OHDA rat model of Parkinson's disease.

The adult substantia nigra bears the capacity to generate new neural cells throughout adulthood. The mechanisms of cellular plasticity in this brain region remain unknown. In the adult dentate gyrus, dopamine was suggested to be one of the key players in neurogenesis. We therefore investigated nigral cellular plasticity in the 6-OHDA rat model of Parkinson's disease. The absolute numbers of newborn cells in the SN were not affected by dopamine depletion. Interestingly, we found a specific downregulation of generation of newborn nigral astrocytic cells. As enriched environment with physical activity are robust inducers of neuro- and gliogenesis in the adult DG, we investigated the role of these physiological stimuli in nigral cellular plasticity and in motor behavior of 6-OHDA lesioned rats. We describe a significant increase in numbers of newborn NG2-positive and GFAP-positive cells in the SN. Moreover, 6-OHDA lesioned animals living in enriched environment with physical activity for 7 weeks showed improved motor behavior compared to controls under standard conditions. Thus, physiological neurogenic and gliogenic stimuli induce significant microenvironmental changes in the adult SN and improve motor behavior in the 6-OHDA lesion model of PD.

Adrenergic Agents↗
PubMed2004

The effects of electrode material, charge density and stimulation duration on the safety of high-frequency stimulation of the subthalamic nucleus in rats.

High-frequency stimulation (HFS) of deep brain structures is a powerful therapeutic tool for the treatment of various movement disorders in patients. However, the pathophysiological mechanisms of this therapeutic approach on basal ganglia network function are still largely unknown. Hitherto, experimental studies have focused on short-term stimulation. Since patients receive HFS for many years, animal studies which reproduce the conditions of long-term stimulation will be necessary to accurately investigate the effects of HFS. However, stimulation parameters of acute HFS cannot be easily transferred to long-term conditions. Accordingly, for this purpose we studied the influence of different charge densities (0, 3, 6.5, 13 and 26 microC/cm2/phase) and duration (4 h or 3 days) of subthalamic nucleus (STN)-HFS using stainless-steel and platinum-iridium (Pt/Ir) electrodes on neuronal tissue damage in rats. Our data demonstrate the advantage of Pt/Ir over stainless-steel electrodes when used in short-term HFS (frequency 130 Hz, pulse width 60 micros) and indicate that HFS using Pt/Ir-electrodes pulsed with 3 microC/cm2/phase over 3 days did not produce any relevant tissue damage in the STN.

Animals↗
PubMed2004

Subthalamic high frequency stimulation induced rotations are differentially mediated by D1 and D2 receptors.

High frequency stimulation (HFS) of the subthalamic nucleus (STN) has clinically emerged as a promising approach in the treatment of Parkinson's disease, epilepsy, dystonia as well as compulsive and possibly other mood disorders. The underlying mechanisms are incompletely understood, but are definitely related to high frequency and likely to involve the dopamine (DA)-system. To further test this hypothesis the present study investigated the modulation of STN-HFS-induced circling by systemic and intracerebral injection of drugs acting on DA receptors in naive freely moving rats. Within this experimental setup, unilateral STN-HFS alone induced intensity-dependent circling. Systemic injections of selective D1- (SCH-23390) and D2-((-)-sulpiride) antagonists as well as the mixed D1 and D2 agonist apomorphine dose-dependently reduced STN-HFS-induced rotational behavior. Intracerebral microinjections of (-)-sulpiride but not SCH-23390 decreased circling when injected intrastriatally and increased the number of rotations when injected intranigrally (pars reticulata (SNr)). These data reveal that STN-HFS-induced contralateral circling is differentially modulated by D1 and D2 receptors. While D2 receptor-mediated effects involve the dorso-/ventrolateral striatum and the SNr, D1 receptors probably exert their actions via brain areas outside the striatum and SNr. These findings suggest the nigrostriatal DA-system to be specifically involved in the mediation of STN-HFS-induced motor effects.

Animals↗
PubMed2004

Ablation of the subthalamic nucleus protects dopaminergic phenotype but not cell survival in a rat model of Parkinson's disease.

Inhibition or ablation of the hyperactive subthalamic nucleus (STN) in Parkinson's disease (PD) does not only reverse motor deficits, silencing the glutamatergic output of the subthalamic nucleus, but has also been implicated to have neuroprotective effects on nigral neurons in animal models of Parkinson's disease. Ablation of the subthalamic nucleus has been shown to increase the number of tyrosinhydroxylase-immunopositive cells and partially restores behavioral deficits in animal models of Parkinson's disease. However, it is unclear whether subthalamic nucleus ablation indeed prevents cell death or whether the effect is due to the rescue of the dopaminergic (DA) phenotype of impaired cells by upregulating tyrosine hydroxylase (TH). We therefore investigated the potential neuroprotective effects of a preceding subthalamic nucleus lesion on 6-hydroxydopamine (6-OHDA)-induced nigral cell death and compared the retrograde tracer fluorogold (FG) as a marker of cell survival with tyrosinhydroxylase immunoreactivity as a marker of the dopaminergic phenotype. In the present study, we show that ablation of the subthalamic nucleus does not affect the number of fluorogold-labeled cells but increases the number of tyrosinhydroxylase-positive neurons in subthalamic nucleus-lesioned hemiparkinsonian animals and leads to partial behavioral recovery of the rats. We conclude that subthalamic nucleus ablation exerts neuroprotective properties on the dopaminergic nigrostriatal pathway against 6-hydroxydopamine toxicity in terms of rescuing the neurotransmitter phenotype in the remaining neurons rather than enhancing the total number of nigral cells.

Animals↗
PubMed2004

High frequency stimulation of the entopeduncular nucleus has no effect on striatal dopaminergic transmission.

High frequency stimulation (HFS) of the subthalamic nucleus (STN) is thought to be superior to stimulation of the internal pallidum (GPi) in alleviating symptoms of Parkinson's disease (PD). However, preliminary controlled studies comparing the effectiveness of both targets have not found significant differences in the improvement of parkinsonian symptoms, but have shown that STN stimulation allows a dramatic decrease in dopaminergic medication. We have previously shown that STN-HFS increases striatal extracellular dopamine (DA) metabolites, but not DA, in both naive and 6-hydroxydopamine (6-OHDA)-lesioned rats, whereas stimulation of the entopeduncular nucleus (EP), the rodent equivalent of the internal pallidum, does not affect DA or metabolite levels. Intriguingly, STN-HFS increases striatal DA release after inhibition of DA reuptake or metabolism, suggesting that this observation may have been obscured in non-drug treated animals by rapid and effective DA reuptake. Since STN-HFS further enhances DA metabolism after DA reuptake inhibition or depletion it has been proposed that STN-HFS increases both, striatal DA release and metabolism, independently. Therefore, the present study assesses the impact of EP-HFS on striatal DA release and metabolism in normal rats after inhibition of DA reuptake or metabolism, using microdialysis. In summary, our data demonstrate that, contrary to STN stimulation, EP-HFS has no effect on striatal DA release and metabolism. Thus, the present study provides a partial explanation for the reported clinical differences, and experimental evidence for differential mechanisms of action between HFS of the internal pallidum and the STN, that are most likely related to differences in functional anatomy.

Animals↗
PubMed2003

Deep brain stimulation in dystonia.

Renewed interest in stereotaxy for dystonia followed the introduction of deep brain stimulation (DBS) in Parkinson's disease and essential tremor in the 1990s. DBS evolved from ablative surgery, which was applied with varying results in the 1950s in patients with movement disorders such as Parkinson's disease, essential tremor and dystonia. The present review summarizes the current knowledge on clinical aspects of DBS in dystonia (Dec. 2002). Excellent results have been achieved in dystonic patients carrying a mutation in the DYT1 gene with improvements up to 90 %. Similar results may also be obtained in patients with idiopathic generalized dystonia, myoclonus-dystonia syndrome, and tardive dystonia. Substantial improvement has been observed in patients with focal dystonia (for instance cervical dystonia). Patients with secondary dystonia often display a lesser and more variable degree of improvement. Long-term studies are warranted to assess both motor and neuropsychological sequelae of DBS in dystonia. Furthermore, the optimal target for different dystonic disorders remains to be determined, although the globus pallidus internus has currently emerged as the most promising target for dystonia.

Dystonia↗
PubMed2003

High-frequency stimulation of the subthalamic nucleus enhances striatal dopamine release and metabolism in rats.

High-frequency stimulation of the subthalamic nucleus is believed to exert its main effects via the basal ganglia output structures. Previously, we have shown a concomitant increase in striatal dopamine (DA) metabolites in normal and 6-hydroxydopamine-lesioned rats. The present study was designed to determine whether this increase in striatal DA metabolites reflects enhanced intraneuronal DA turnover or, alternatively, is due to increased DA release with subsequent rapid and efficient reuptake and/or metabolism. Thus, high-frequency stimulation of the subthalamic nucleus was performed in normal rats after inhibition of DA reuptake, metabolism or DA depletion. Extracellular levels of striatal DA and its metabolites were assessed using microdialysis. Our data suggest that subthalamic high-frequency stimulation increases striatal DA release and activates independent striatal DA metabolism. Since such changes could be triggered by modification of either the activity or the gene expression of the rate-limiting enzyme tyrosine hydroxylase, an activity assay and RT-PCR of striatal and nigral samples were performed. Subthalamic stimulation increased striatal tyrosine hydroxylase activity without affecting gene expression. We, therefore, conclude that the application of subthalamic high-frequency stimulation could partially compensate for the DA deficit by inducing increased striatal DA release and metabolism.

Animals↗
PubMed2002

JunB and Bcl-2 overexpression results in protection against cell death of nigral neurons following axotomy.

Transection of the medial forebrain bundle is a well established approach to investigate neuronal cell body response in the derived neuronal populations of the substantia nigra pars compacta (SNC). This model of central axotomy leads in mouse within 50 days post transection to degeneration of up to 70% of the affected SNC neurons. A central component of the axotomy induced alterations leading to neuronal degeneration is the rapid induction, lasting expression and activation of the c-Jun transcription factor. However, the role of c-Jun in the process of neuronal degeneration is not fully understood. Since null mutations of c-Jun cause embryonic lethality, this study was designed to investigate the impact of two c-Jun modulating proteins on neuronal survival after axotomy in transgenic mice: JunB, a Jun family member affecting c-Jun expression, and Bcl-2, an antiapoptotic protooncogene interacting among others with the c-Jun N-terminal kinases. In JunB as well as in Bcl-2 transgenic mice the long term survival rate of transected SNC neurons was remarkably increased when compared to wildtype controls. These effects were obviously achieved by cellular modulations directly following axotomy: Whereas JunB overexpression attenuated c-Jun induction and simultaneously led to a higher phosphorylation rate of c-Jun in SNC neurons, Bcl-2 overexpression did not influence c-Jun expression, but resulted in a reduced phosphorylation state of c-Jun in transected SNC neurons. We therefore conclude that the early phosphorylation rate of c-Jun might play an important role for the long term fate of transected neurons.

Animals↗
PubMed2002

Human immunodeficiency virus type 1 neutralization measured by flow cytometric quantitation of single-round infection of primary human T cells.

There is currently intensive research on the design of novel human immunodeficiency virus type 1 (HIV-1) vaccine immunogens that can elicit potent neutralizing antibodies. A prerequisite for comparing and optimizing these strategies is the ability to precisely measure neutralizing antibody responses. To this end, we sought to develop an assay that directly quantifies single-round HIV-1 infection of peripheral blood mononuclear cells (PBMC). Initial experiments demonstrated that essentially all productively infected PBMC could be identified by flow cytometric detection of intracellular p24 antigen (p24-Ag). After infection of PBMC with HIV-1, p24(+) lymphocytes could be distinguished beginning 1 day postinfection, and the majority of CD8(-) T cells were p24-Ag positive by 3 to 4 days postinfection. To directly quantify first-round infection, we included a protease inhibitor in PBMC cultures. The resulting 2-day assay was highly sensitive and specific for the detection of HIV-1-infected PBMC. Serial dilutions of virus stocks demonstrated that the number of target cells infected was directly related to the amount of infectious virus input into the assay. In neutralization assays, the flow cytometric enumeration of first-round infection of PBMC provided quantitative data on the number of target cells infected and on the inactivation of infectious virus due to reaction with antibody. We also used this single-round assay to compare the percentage of cells expressing p24-Ag to the number of copies of HIV-1 gag per 100 PBMC. The precision and reproducibility of this assay will facilitate the measurement of HIV-1 neutralization, particularly incrementally improved neutralizing antibody responses generated by new candidate vaccines.

Cells, Cultured↗