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Biomedical subjects

Jörg B Schulz

Publications and source records attributed to Jörg B Schulz.

At least 19 recordsLinked to original sources
PubMed2007

Transient expression of Nxf, a bHLH-PAS transactivator induced by neuronal preconditioning, confers neuroprotection in cultured cells.

Cortical spreading depression (CSD) induces waves of neuronal depolarization that confer neuroprotection to subsequent ischemic events in the rat brain. To gain insights into the molecular mechanisms elicited by CSD, we used representational difference analysis (RDA) to identify mRNAs induced by potassium depolarization in vivo. Using this approach, we have isolated a cDNA encoding the SIM2-related bHLH-PAS protein Nxf. Our results confirm that Nxf mRNA and protein are rapidly and transiently expressed in cortical neurons following CSD. Reporter assays show that Nxf is a transcriptional activator that associates with the bHLH-PAS sub-class co-factor ARNT2. Adenovirus-mediated expression of epitope-tagged Nxf results in cell death and the direct activation of the Bax gene in cultured cells. However, RNA interference studies show that endogenous Nxf is required for optimal neuroprotection by preconditioning in cultured F-11 cells. Together, our data indicate that Nxf is a novel bHLH-PAS transactivator transiently induced by preconditioning and that its sustained expression is detrimental. The identification of Nxf may represent an important step in our understanding of the molecular mechanisms of brain preconditioning and injury.

Animals↗
PubMed2007

Extracellular domain splice variants of a transforming protein tyrosine phosphatase alpha mutant differentially activate Src-kinase dependent focus formation.

The extracellular domains of receptor-type protein-tyrosine phosphatases (PTPs) contain a diverse range of protein modules like fibronectin- or immunoglobulin-like structures. These are frequently expressed in a tissue- and development specific manner as splice variants. The extracellular domain of PTPalpha is rather short and heavily glycosylated. Two splice variants are known, which it differs by an exon encoding nine amino acids within the extracellular domain. We have analyzed the expression pattern of both variants and found that the smaller form is ubiquitously expressed while the larger form was found at an increased level only in brain, some skeletal muscle and differentiating cells like granule neurons, adipocytes and myotubes. The phosphatase activity of both forms was similar when tested in vitro using para-nitrophenylphosphate as a substrate and in a transient expression system with the substrates c-Fyn or c-Src. In a quantitative focus formation assay the capability of the larger form to activate Src-dependent focus formation in intact cells was increased more than twofold whereas the capability to dephosphorylate the insulin receptor in a BHK cell system was similar. We conclude that the two splice variants of PTPalpha are expressed differentially and regulate c-Src activity in different ways.

3T3-L1 Cells↗
PubMed2006

Cortical stimulation mapping using epidurally implanted thin-film microelectrode arrays.

Stimulation mapping of motor cortex is an important tool for assessing motor cortex physiology. Existing techniques include intracortical microstimulation (ICMS) which has high spatial resolution but damages cortical integrity by needle penetrations, and transcranial stimulation which is non-invasive but lacks focality and spatial resolution. A minimally invasive epidural microstimulation (EMS) technique using chronically implanted polyimide-based thin-film microelectrode arrays (72 contacts) was tested in rat motor cortex and compared to ICMS within individual animals. Results demonstrate reliable mapping with high reproducibility and validity with respect to ICMS. No histological evidence of cortical damage and the absence of motor deficits as determined by performance of a motor skill reaching task, demonstrate the safety of the method. EMS is specifically suitable for experiments integrating electrophysiology with behavioral and molecular biology techniques.

Analysis of Variance↗
PubMed2006

Cholesterol depletion reduces aggregation of amyloid-beta peptide in hippocampal neurons.

A key event in the pathogenesis of Alzheimer's disease is the conversion of soluble amyloid Abeta-peptide into toxic aggregates. Here, we studied the effect of cholesterol depletion on the formation of insoluble Abeta. We found that reduction of neuronal cholesterol by approximately 25% reduced the neuronal formation of insoluble Abeta without affecting the secretion of soluble Abeta. Moreover, we demonstrate that Abeta-oligomers from Alzheimer's disease brains associate with a detergent-resistant membrane fraction in a cholesterol-dependent manner. These results suggest a key role for cholesterol in aggregation of Abeta.

Adult↗
PubMed2006

Granulocyte-colony stimulating factor is neuroprotective in a model of Parkinson's disease.

We have recently shown that the hematopoietic Granulocyte-Colony Stimulating Factor (G-CSF) is neuroprotective in rodent stroke models, and that this action appears to be mediated via a neuronal G-CSF receptor. Here, we report that the G-CSF receptor is expressed in rodent dopaminergic substantia nigra neurons, suggesting that G-CSF might be neuroprotective for dopaminergic neurons and a candidate molecule for the treatment of Parkinson's disease. Thus, we investigated protective effects of G-CSF in 1-methyl-4-phenylpyridinium (MPP+)-challenged PC12 cells and primary neuronal midbrain cultures, as well as in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Substantial protection was found against MPP+-induced dopaminergic cell death in vitro. Moreover, subcutaneous application of G-CSF at a dose of 40 microg/Kg body weight daily over 13 days rescued dopaminergic substantia nigra neurons from MPTP-induced death in aged mice, as shown by quantification of tyrosine hydroxylase-positive substantia nigra cells. Using HPLC, a corresponding reduction in striatal dopamine depletion after MPTP application was observed in G-CSF-treated mice. Thus our data suggest that G-CSF is a novel therapeutic opportunity for the treatment of Parkinson's disease, because it is well-tolerated and already approved for the treatment of neutropenic conditions in humans.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2006

The multidrug resistance protein 1 (Mrp1), but not Mrp5, mediates export of glutathione and glutathione disulfide from brain astrocytes.

Astrocytes play an important role in the glutathione (GSH) metabolism of the brain. To test for an involvement of multidrug resistance protein (Mrp) 1 and 5 in the release of GSH and glutathione disulfide (GSSG) from astrocytes, we used astrocyte cultures from wild-type, Mrp1-deficient [Mrp1(-/-)] and Mrp5-deficient [Mrp5(-/-)] mice. During incubation of wild-type or Mrp5(-/-) astrocytes, GSH accumulated in the medium at a rate of about 3 nmol/(h.mg), whereas the export of GSH from Mrp1(-/-) astrocytes was only one-third of that. In addition, Mrp1(-/-) astrocytes had a 50% higher specific GSH content than wild-type or Mrp5(-/-) cells. The presence of 50 microm of the Mrp inhibitor MK571 inhibited the rate of GSH release from wild-type and Mrp5(-/-) astrocytes by 60%, but stimulated at the low concentration of 1 microm GSH release by 40%. In contrast, both concentrations of MK571 did not affect GSH export from Mrp1(-/-) astrocytes. Moreover, in contrast to wild-type and Mrp5(-/-) cells, GSSG export during H(2)O(2) stress was not observed for Mrp1(-/-) astrocytes. These data demonstrate that in astrocytes Mrp1 mediates 60% of the GSH export, that Mrp1 is exclusively responsible for GSSG export and that Mrp5 does not contribute to these transport processes.

Animals↗
PubMed2006

Visualization and quantification of disease progression in multiple system atrophy.

To visualize and quantify disease progression in multiple system atrophy (MSA) from cerebellar type (MSA-C), we combined two magnetic resonance imaging (MRI) techniques, voxel-based morphometry (VBM) and 3D-based volumetry. Patients suffering from MSA-C (n = 14) were imaged twice with an interval of 2.0 +/- 0.2 years. We first applied VBM to map brain morphology changes between MSA patients and controls and to identify brain areas that showed a significant amount of atrophy. Using 3D-based volumetry, we confirmed that in MSA-C patients, the brainstem including medulla and pons, vermis and cerebellar hemispheres, caudate nucleus and putamen showed significant atrophy compared with controls. Next, we used 3D-based volumetry to analyze the atrophy rates. Atrophy rates in patients with MSA were significantly different from controls for putamen (-11.4% +/- 2.6%/year), vermis (-12.3% +/- 2.9%/year), and cerebellar hemispheres (-6.6% +/- 1.1%/year). The results show that 3D-based MRI volumetry is a tool that allows the disease progression of MSA to be followed over a time period of 2 years and suggest that it may serve as a surrogate marker in clinical trials to measure disease progression.

Aged↗
PubMed2006

Ergoline and non-ergoline derivatives in the treatment of Parkinson's disease.

There are a large variety of dopamine agonists available. Especially de novo patients are treated with dopamine agonists to avoid dyskinesia. Dopamine agonists can be subdivided into ergoline and non-ergoline derivatives. This distinction raises the question whether there are differences in the effects to treat symptoms, not only in the side effects between the individual dopamine agonists but also between these two groups. Pergolide is now considered a second line drug because of its particularly high tendency towards valvular heart disease. Some authors claim that all ergoline-derivatives may cause this problem, while own results do not necessarily support this view. We recommend performing echocardiography on those patients being treated with an ergot-derivative. New data support the view that all dopaminergic drugs may cause somnolence and that there is no preference for non-ergots. It may be that the number of gamblers is slightly higher among patients treated with pramipexole than in others. Dopamine agonists with a high affinity to D3 receptors have a good anti-anhedonic potency. In cell culture all dopamine agonists studied so far show neuroprotective properties in cell culture. The introduction of a slow-release formulation for ropinirole and the rotigotine and lisuride patches have opened new ways of continuous dopamine receptor stimulation. Taken together, dopamine agonists show individual properties and there are differences between ergot and non-ergot derivatives.

Dopamine Agonists↗
PubMed2006

Statin therapy at carotid angioplasty and stent placement: effect on procedure-related stroke, myocardial infarction, and death.

PURPOSE: To retrospectively determine if preprocedural statin treatment is associated with a reduction of cardiovascular events after carotid angioplasty and stent placement (CAS) in patients with symptomatic carotid stenosis. MATERIALS AND METHODS: A study resulting in a prospective database was approved by the institutional ethics review board; written informed consent was obtained. The approval and informed consent included future retrospective analysis. Consecutive patients (n = 180) from the prospective database underwent CAS for high-grade symptomatic carotid disease. The frequency of cardiovascular complications (composite of stroke, myocardial infarction, and death within 30 days after CAS) between 127 patients without preprocedural statin treatment and that of 53 patients with preprocedural statin treatment at CAS were compared with chi2 and multivariate logistic regression analysis. RESULTS: The overall 30-day myocardial infarction rate was two of 180 (1%) patients, the minor stroke rate was 16 of 180 (9%) patients, the major stroke rate was one of 180 (0.5%) patients, and the death rate was two of 180 (1%) patients. The incidence of cardiovascular events (composite of stroke, myocardial infarction, and death within 30 days after CAS) was significantly different between patients with preprocedural treatment (4%) and those without preprocedural statin treatment (15%) (P < .05). These higher complication rates among patients without preprocedural statin treatment were not mediated by adjustment for age, sex, other baseline characteristics, degree of carotid stenosis, use of cerebral protection devices, or the year in which CAS was performed. CONCLUSION: Preprocedural statin therapy appears to reduce the incidence of stroke, myocardial infarction, and death within 30 days after CAS. Future prospective randomized trials are warranted to further assess this potential protective effect of statin drugs during carotid interventions.

Aged↗
PubMed2005

FasL (CD95L/APO-1L) resistance of neurons mediated by phosphatidylinositol 3-kinase-Akt/protein kinase B-dependent expression of lifeguard/neuronal membrane protein 35.

The contribution of Fas (CD95/APO-1) to cell death mechanisms of differentiated neurons is controversially discussed. Rat cerebellar granule neurons (CGNs) express high levels of Fas in vitro but are resistant to FasL (CD95L/APO-1L/CD178)-induced apoptosis. We here show that this resistance was mediated by a phosphatidylinositol 3-kinase (PI 3-kinase)-Akt/protein kinase B (PKB)-dependent expression of lifeguard (LFG)/neuronal membrane protein 35. Reduction of endogenous LFG expression by antisense oligonucleotides or small interfering RNA lead to increased sensitivity of CGNs to FasL-induced cell death and caspase-8 cleavage. The inhibition of PI 3-kinase activity sensitized CGNs to FasL-induced caspase-8 and caspase-3 processing and caspase-dependent fodrin cleavage. Pharmacological inhibition of PI 3-kinase, overexpression of the inhibitory protein IkappaB, or cotransfection of an LFG reporter plasmid with dominant-negative Akt/PKB inhibited LFG reporter activity, whereas overexpression of constitutively active Akt/PKB increased LFG reporter activity. Overexpression of LFG in CGNs interfered with the sensitization to FasL by PI 3-kinase inhibitors. In contrast to CGNs, 12 glioma cell lines, which are sensitive to FasL, did not express LFG. Gene transfer of LFG into these FasL-susceptible glioma cells protected against FasL-induced apoptosis. These results demonstrate that LFG mediated the FasL resistance of CGNs and that, under certain circumstances, e.g., inhibition of the PI 3-kinase-Akt/PKB pathway, CGNs were sensitized to FasL.

Animals↗
PubMed2005

Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease.

Recently targeted disruption of Omi/HtrA2 has been found to cause neurodegeneration and a parkinsonian phenotype in mice. Using a candidate gene approach, we performed a mutation screening of the Omi/HtrA2 gene in German Parkinson's disease (PD) patients. In four patients, we identified a novel heterozygous G399S mutation, which was absent in healthy controls. Moreover, we identified a novel A141S polymorphism that was associated with PD (P<0.05). Both mutations resulted in defective activation of the protease activity of Omi/HtrA2. Immunohistochemistry and functional analysis in stably transfected cells revealed that S399 mutant Omi/HtrA2 and to a lesser extent, the risk allele of the A141S polymorphism induced mitochondrial dysfunction associated with altered mitochondrial morphology. Cells overexpressing S399 mutant Omi/HtrA2 were more susceptible to stress-induced cell death than wild-type. On the basis of functional genomics, our results provide a novel link between mitochondrial dysfunction and neurodegeneration in PD.

Amino Acid Sequence↗
PubMed2005

Palmitoylation is a sorting determinant for transport to the myelin membrane.

Myelin is a specialized membrane enriched in glycosphingolipids and cholesterol that contains a restricted set of proteins. The mechanisms by which oligodendrocytes target myelin components to myelin are not known. To identify the sorting determinants for protein transport to myelin, we used a primary oligodendrocyte culture system in which terminal differentiation is synchronized and there is excessive deposition of myelin-like membranes (MLMs). Because several myelin proteins are palmitoylated, we explored the role of acylation in protein transport to MLMs. We found that palmitoylation-deficient mutants of a major myelin protein, proteolipid protein (PLP/DM20), were less efficiently targeted to MLMs. The N-terminal 13 amino acids of PLP/DM20, which are palmitoylated at three sites, were sufficient to direct a fluorescent fusion protein to MLMs. Mutagenesis of the N-terminal palmitoylation motif abolished the transport of the fusion protein to MLMs, indicating that palmitoylation is required for sorting to myelin. Similar results were obtained in myelinating co-cultures of oligodendrocytes and neurons. Furthermore, the combined farnesylation/palmitoylation signals from c-Ha-Ras and the N-terminal consensus sequence for dual palmitoylation from neuromodulin were sufficient for the transport of fluorescent fusion proteins to MLMs. Thus, we conclude that palmitoylation is a sorting determinant for transport to the myelin membrane.

Animals↗
PubMed2005

Clinical predictors of transient ischemic attack, stroke, or death within 30 days of carotid angioplasty and stenting.

BACKGROUND AND PURPOSE: Carotid angioplasty and stenting (CAS) is currently being assessed in the treatment of severe carotid stenosis. However, little data are available concerning patient-related factors affecting the risk of CAS. The purpose of this study was to identify potential clinical risk factors for the development of postprocedural deficits after CAS. METHODS: The clinical characteristics of 299 patients (217 men, 82 women; mean age 69+/-9 years) who underwent CAS for asymptomatic (n=129, 43%) or symptomatic (n=170, 57%) stenoses and the combined 30-day complication rates (any transient ischemic attack [TIA], minor stroke, major stroke, or death) were analyzed with logistic regression analysis. RESULTS: The overall 30-day TIA rate was 3.7%; the minor stroke rate was 5.3%, the major stroke rate was 0.7%, and the death rate was 0.7%. Although patients presenting with a hemispherical TIA or minor stroke had a significantly higher risk than asymptomatic patients (odds ratio [OR] 5.69; 95% confidence interval [CI], 2.03 to 19.57; P<0.001), the complication rates between patients presenting with a retinal TIA and asymptomatic patients was comparable (OR, 1.42; 95% CI, 0.13 to 9.09; P=0.6). Multivariate regression analysis revealed advanced age (OR, 1.06; 95% CI, 1 to 1.11; P<0.05), stroke (OR, 8; 95% CI, 2.6 to 24.4; P<0.01) or hemispherical TIA (OR, 4.7; 95% CI, 1.6 to 13.3) as presenting symptoms as independent clinical predictors of the combined 30-day outcome measures any TIA, stroke, or death. CONCLUSIONS: Aside from advanced age and symptom status, the type of presenting event predicts postprocedural complications after CAS. When evaluating the outcome of CAS and comparing this treatment modality to surgery, patients should be stratified according to their presenting event.

Aged↗
PubMed2004

Systematic review of early recurrent stenosis after carotid angioplasty and stenting.

BACKGROUND AND PURPOSE: Carotid angioplasty and stenting (CAS) has emerged as a potential alternative to endarterectomy (CEA) for the treatment of carotid artery disease. Aside from the periprocedural complication rates, the benefits of CAS will be affected by the incidence of recurrent carotid stenosis. METHODS: We conducted a systematic analysis of all peer-reviewed studies reporting on the rate of restenosis (> or =50%) after CAS based on duplex ultrasound or angiography that were published between January 1990 and July 2004. We identified 34 studies that reported on a total of 4185 patients with a follow-up of 3814 arteries over a median of 13 months (range, 6 to 31 months). The ultrasound criteria and the lower thresholds for defining a recurrent stenosis were very heterogeneous. RESULTS: The cumulative restenosis rates after 1 and 2 years were approximately 6% and 7.5% in those studies, which used a lower restenosis threshold > or =50% to 70% and approximately 4% in the first 2 years after CAS in those studies, which used a lower restenosis threshold >70% to 80%. CONCLUSIONS: In reviewing the current literature, the early restenosis rates after CAS compare well with those reported for CEA. However, this analysis of the peer-reviewed literature also indicates that the early restenosis rates after CAS might be higher than previously suggested in observational surveys. Therefore, an active follow-up of all stented arteries seems to be warranted. Moreover, the bulk of endovascular data are derived from small studies with short follow-up periods so that the long-term durability of CAS still needs to be established in large trials. Ideally, these studies should use a clear and uniform definition of restenosis and identical follow-up schedules.

Aged↗
PubMed2004

Characterization of motor skill and instrumental learning time scales in a skilled reaching task in rat.

Successful motor skill learning requires repetitive training interrupted by rest periods. In humans, improvement occurs within and between training sessions reflecting fast and slow components of motor learning [Karni A, Meyer G, Rey-Hipolito C, Jezzard P, Adams MM, Turner R, et al. The acquisition of skilled motor performance: fast and slow experience-driven changes in primary motor cortex. Proc Natl Acad Sci USA 1998;95:861-8]. Here, these components are characterized in male and female rats using a model of skilled forelimb reaching and are compared to time scales of instrumental learning. Twenty female and 14 male adult Long-Evans rats were pre-trained to operate a motorized door (via a sensor in the opposite cage wall) to access a food pellet by tongue. Latencies between pellet removal and door opening were recorded as measures of instrumental learning. After criterion performance was achieved, skilled forelimb reaching was requested by increasing the pellet-window distance to 1.5cm. Reaching success was recorded per trial. Mean latencies decreased exponentially over sessions and no improvement within-session was found. Skill learning over eight training sessions followed an exponential course in females and a sigmoid course in males. Females acquired the skill significantly faster than males starting at higher baseline levels (P < 0.001) but reaching similar plateaus. Within-session improvement was found during the sessions 1-3 in females and 1-4 in males. Performance at the end of session 1 was not carried over to session 2. Learning curves of individual animals were highly variable. These findings confirm in rat that motor skill learning has fast and slow components. No within-session improvement is seen in instrumental learning.

Animals↗
PubMed2004

Repetitive bilateral arm training and motor cortex activation in chronic stroke: a randomized controlled trial.

CONTEXT: Reorganization in central motor networks occurs during early recovery from hemiparetic stroke. In chronic stroke survivors, specific rehabilitation therapy can improve upper extremity function. OBJECTIVE: To test the hypothesis that in patients who have chronic motor impairment following stroke, specific rehabilitation therapy that improves arm function is associated with reorganization of cortical networks. DESIGN, SETTING, AND PATIENTS: A randomized controlled clinical trial conducted in a US ambulatory rehabilitation program with 21 patients (median [IQR], 50.3 [34.8-77.3] months after unilateral stroke). Data were collected between 2001 and 2004. INTERVENTIONS: Patients were randomly assigned to bilateral arm training with rhythmic auditory cueing (BATRAC) (n = 9) or standardized dose-matched therapeutic exercises (DMTE) (n = 12). Both were conducted for 1 hour, 3 times a week, for 6 weeks. MAIN OUTCOME MEASURES: Within 2 weeks before and after the intervention, brain activation during elbow movement assessed by functional magnetic resonance imaging (fMRI) and functional outcome assessed using arm function scores. RESULTS: Patients in the BATRAC group but not in the DMTE group increased hemispheric activation during paretic arm movement (P = .03). Changes in activation were observed in the contralesional cerebrum and ipsilesional cerebellum (P = .009). BATRAC was associated with significant increases in activation in precentral (P<.001) and postcentral gyri (P = .03) and the cerebellum (P<.001), although 3 BATRAC patients showed no fMRI changes. Considering all patients, there were no differences in functional outcome between groups. When only BATRAC patients with fMRI response were included (n = 6), BATRAC improved arm function more than DMTE did (P = .02). CONCLUSIONS: These preliminary findings suggest that BATRAC induces reorganization in contralesional motor networks and provide biological plausibility for repetitive bilateral training as a potential therapy for upper extremity rehabilitation in hemiparetic stroke.

Aged↗