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Wolf-Rüdiger Schäbitz

Publications and source records attributed to Wolf-Rüdiger Schäbitz.

15 recordsLinked to original sources
PubMed2006

Granulocyte-colony stimulating factor (G-CSF) and G-CSF receptor expression in human ischemic stroke.

Granulocyte-colony stimulating factor (G-CSF) receptor signaling counteracts detrimental pathways in ischemic stroke. In rodents, neuroprotection provided by the G-CSF system involves up-regulation of the G-CSF receptor and its ligand, G-CSF, during cerebral ischemia. The confirmation of a similar response in the human brain would be an important rationale for the use of G-CSF in clinical stroke trials. Therefore, the temporal and cellular profile of G-CSF and G-CSF receptor expression was examined in a series of human stroke brains. The median age of the 21 stroke patients was 67 years; median time from death to autopsy was 24 h (range: 10-67 h). In acute ischemic stroke, strong neuronal G-CSF receptor immunoreactivity was encountered in the infarct area and the peri-infarct rim as compared to the contralateral cortex. In subacute infarctions, microglial and macrophage G-CSF receptor immunoreactivity predominated, whereas chronic infarction was characterized by the presence of G-CSF receptor expressing reactive astrocytes. Neuronal G-CSF expression was encountered very early upon ischemic stroke. At later time-points, an up-regulation of vascular G-CSF expression in the peri-infarct area prevailed. In conclusion, the observed up-regulation of G-CSF receptors and G-CSF points towards a role in the pathophysiology of human ischemic stroke.

Aged↗
PubMed2006

An extended window of opportunity for G-CSF treatment in cerebral ischemia.

BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) is known as a powerful regulator of white blood cell proliferation and differentiation in mammals. We, and others, have shown that G-CSF is effective in treating cerebral ischemia in rodents, both relating to infarct size as well as functional recovery. G-CSF and its receptor are expressed by neurons, and G-CSF regulates apoptosis and neurogenesis, providing a rational basis for its beneficial short- and long-term actions in ischemia. In addition, G-CSF may contribute to re-endothelialisation and arteriogenesis in the vasculature of the ischemic penumbra. In addition to these trophic effects, G-CSF is a potent neuroprotective factor reliably reducing infarct size in different stroke models. RESULTS: Here, we have further delayed treatment and studied effects of G-CSF on infarct volume in the middle cerebral artery occlusion (MCAO) model and functional outcome in the cortical photothrombotic model. In the MCAO model, we applied a single dose of 60 microg/kg bodyweight G-CSF in rats 4 h after onset of ischemia. Infarct volume was determined 24 h after onset of ischemia. In the rat photothrombotic model, we applied 10 microg/kg bodyweight G-CSF daily for a period of 10 days starting either 24 or 72 h after induction of ischemia. G-CSF both decreased acute infarct volume in the MCAO model, and improved recovery in the photothrombotic model at delayed timepoints. CONCLUSION: These data further strengthen G-CSF's profile as a unique candidate stroke drug, and provide an experimental basis for application of G-CSF in the post-stroke recovery phase.

Animals↗
PubMed2006

Neuroprotective cannabinoid receptor antagonist SR141716A prevents downregulation of excitotoxic NMDA receptors in the ischemic penumbra.

Whether cannabinoids act as neuroprotectants or, on the contrary, even worsen neuronal damage after cerebral ischemia is currently under discussion. We have previously shown that treatment with the cannabinoid (CB1) receptor antagonist SR141716A reduces infarct volume by approximately 40% after experimental stroke. Since it is suggested that SR141716A may exert neuroprotection besides its cannabinoid receptor-blocking effect, we addressed the question whether SR141716A may act via modulation of postischemic ligand binding to excitatory NMDA and/or alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptors. For this purpose, rats (n = 12) were treated with either intravenous saline (control) or CB1 receptor antagonist SR141716A (1 mg/kg) 30 min after permanent middle cerebral artery occlusion. Five hours after ischemia, quantitative receptor autoradiography was performed using [(3)H]CP 55,940, [(3)H]MK-801, and [(3)H]AMPA for labeling of CB1, NMDA, and AMPA receptors, respectively. Ligand binding was analyzed within the infarct core, cortical penumbra, and corresponding areas of the contralateral hemisphere and compared to that of sham-operated rats (n = 5). Both in ischemic controls and SR141716A-treated rats [(3)H]CP 55,940 ligand binding was not specifically regulated in the cortical penumbra or contralateral cortex. Importantly, reduced infarct volumes in SR141716A-treated rats were associated with maintained [(3)H]MK-801 binding to excitotoxic NMDA receptors in the penumbra, compared to a decrease in the control group. In summary, our data suggest that SR141716A may possess additional intrinsic neuroprotective properties independent of receptor-coupled pathways or due to action as a partial agonist.

Animals↗
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

Long-term gene expression changes in the cortex following cortical ischemia revealed by transcriptional profiling.

Cerebral ischemia evokes changes in gene expression time-dependently after the ischemic event. Most studies on transcriptional changes following ischemia have centered on relatively early postischemic time points, and detected multiple genes relevant to neuronal cell death. However, functional outcome after ischemia depends critically on adaptations of the postischemic brain. Plasticity may derive from network-inherent changes, or from the formation of new nerve cells in the CNS. We have screened for gene expression changes up to 3 weeks following a limited photothrombotic cortical insult in the rat sensorimotor cortex by using the sensitive restriction-mediated differential display (RMDD) technique. A high number of genes were detected as induced at early or intermediate time points in the ipsi- and contralateral cortex (6 and 48 h). Unexpectedly, at the late time point examined (3 weeks), we still detected 40 genes that were changed in their expression. We further characterized the expression of two genes linked to neurogenesis (nestin and stathmin), and two genes likely involved in reconfiguring neuronal networks (semaphorin VIa and synaptotagmin IV). Conclusively, our data highlight the degree of long-term transcriptional changes in the cortex after ischemia, and provide insight into functional pathways of relevance for compensatory recovery mechanisms in neural networks.

Animals↗
PubMed2006

Toward a multimodal neuroprotective treatment of stroke.

BACKGROUND AND PURPOSE: Stroke remains a common medical problem with importance attributable to the demographic changes in industrialized societies. SUMMARY OF REVIEW: After years of setbacks, acute stroke therapy has finally emerged, including thrombolysis with tissue plasminogen activator (t-PA). However, t-PA treatment is limited by a narrow time window and side effects, so that only 3% of all stroke patients receive thrombolysis. Unimodal targeting of key events in stroke pathophysiology was not effective in providing long-term benefits, leading to negative results in previous clinical neuroprotective stroke trials. A successful future stroke therapy should approach multiple pathophysiological mechanisms besides revascularization at once, including reduction of t-PA-related side effects, prevention of cell death, stimulation of neuroregeneration, and plasticity. CONCLUSIONS: Strategies targeting these processes include multiple combination therapies as well as treatment with multimodal drugs that interact with these mechanisms. Here, we review such combination approaches, and outline how this concept could be developed into future stroke treatment.

Animals↗
PubMed2005

The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis.

G-CSF is a potent hematopoietic factor that enhances survival and drives differentiation of myeloid lineage cells, resulting in the generation of neutrophilic granulocytes. Here, we show that G-CSF passes the intact blood-brain barrier and reduces infarct volume in 2 different rat models of acute stroke. G-CSF displays strong anti-apoptotic activity in mature neurons and activates multiple cell survival pathways. Both G-CSF and its receptor are widely expressed by neurons in the CNS, and their expression is induced by ischemia, which suggests an autocrine protective signaling mechanism. Surprisingly, the G-CSF receptor was also expressed by adult neural stem cells, and G-CSF induced neuronal differentiation in vitro. G-CSF markedly improved long-term behavioral outcome after cortical ischemia, while stimulating neural progenitor response in vivo, providing a link to functional recovery. Thus, G-CSF is an endogenous ligand in the CNS that has a dual activity beneficial both in counteracting acute neuronal degeneration and contributing to long-term plasticity after cerebral ischemia. We therefore propose G-CSF as a potential new drug for stroke and neurodegenerative diseases.

Animals↗
PubMed2004

Combination therapy of moderate hypothermia and thrombolysis in experimental thromboembolic stroke--an MRI study.

Thrombolysis (T) is limited by reperfusion-associated injury and the short therapeutic window after stroke onset. The present study investigates whether hypothermia alone or in combination with thrombolysis has beneficial effects after experimental thromboembolic stroke. Wistar rats (n = 60) were subjected to thromboembolic occlusion (TE) of the middle cerebral artery (MCA). Thrombolysis (T) was performed with intravenous recombinant tissue-plasminogen activator (rt-PA) 1 h (early T) or 3 h (late T) after TE. Hypothermia (Hy) was applied for 4 h at 33 degrees C started 1 h after TE. Experimental groups included control (C), early thrombolysis (ET), late thrombolysis (LT), hypothermia (Hy), early thrombolysis plus hypothermia (ET+Hy), and late thrombolysis plus hypothermia (LT+Hy). Animals were investigated by MRI and silver infarct staining (SIS) to assess the cerebral infarct size. All animals of group Hy survived, in contrast to 40% in group C (P < 0.05). ET+HY and LT+Hy showed a trend towards better survival as compared to ET and LT alone. PWI parameters were not significantly different between ET versus ET+HY and LT versus LT+Hy, but rt-PA administration led to improved cerebral perfusion in MRI. Significant differences in infarct volumes (T2/SIS) were found after 24 h in all treatment groups versus the control group (P < 0.05). The lesion volume calculated from T2 was significantly smaller in ET (16% +/- 5%), ET+Hy (10 +/- 4%), and LT+Hy (20% +/- 9%) after 5.5 h (10.8% +/- 4.8%) versus C (42% +/- 15%), (P < 0.05). These data indicate that hypothermia improves survival and decreases infarct volume. However, there were no significant differences between the use of rt-PA alone or in combination with hypothermia. Further studies are needed to confirm these effects, also several days after stroke onset.

Animals↗
PubMed2003

Severe forward flexion of the trunk in Parkinson's disease: focal myopathy of the paraspinal muscles mimicking camptocormia.

Pronounced forward flexion of the trunk, often termed camptocormia, is a typical symptom of patients with Parkinson's disease. In 4 parkinsonian patients with camptocormia, paraspinal muscles were studied by electromyography (EMG) and axial computerized tomography (CT) or magnetic resonance imaging (MRI) scans and muscle biopsy. EMG of the lumbar and thoracic paravertebral muscles showed abundant fibrillations, positive sharp waves, and bizarre high-frequency discharges. Spinal CT and MRI scans revealed variable degrees of atrophy and fatty replacement of the thoracolumbar paraspinal muscles on both sides. No other signs of neuromuscular disease were found. Biopsy of the paraspinal muscles revealed end-stage myopathy with autophagic vacuoles, chronic inflammatory myopathy, unspecific myopathic changes, or mitochondrial myopathy. In parkinsonian patients with pronounced forward flexion of the trunk, myopathy confined to the erector spinae muscles must be considered.

Aged↗
PubMed2002

Early effects of acid-base management during hypothermia on cerebral infarct volume, edema, and cerebral blood flow in acute focal cerebral ischemia in rats.

BACKGROUND: Although the frequency for the use of moderate hypothermia in acute ischemic stroke is increasing, the optimal acid-base management during hypothermia remains unclear. This study investigates the effect of pH- and alpha-stat acid-base management on cerebral blood flow (CBF), infarct volume, and cerebral edema in a model of transient focal cerebral ischemia in rats. METHODS: Twenty Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (MCAO) for 2 h during normothermic conditions followed by 5 h of reperfusion during hypothermia (33 degrees C). Animals were artificially ventilated with either alpha- (n = 10) or pH-stat management (n = 10). CBF was analyzed 7 h after induction of MCAO by iodo[(14)C]antipyrine autoradiography. Cerebral infarct volume and cerebral edema were measured by high-contrast silver infarct staining (SIS). RESULTS: Compared with the alpha-stat regimen, pH-stat management reduced cerebral infarct volume (98.3 +/- 33.2 mm(3) vs. 53.6 +/- 21.6 mm(3); P > or = 0.05 mean +/- SD) and cerebral edema (10.6 +/- 4.0% vs. 3.1 +/- 2.4%; P > or = 0.05). Global CBF during pH-stat management exceeded that of alpha-stat animals (69.5 +/- 12.3 ml x 100 g(-1) x min(-1) vs. 54.7 +/- 13.3 ml x 100 g(-1) x min; P > or = 0.05). The regional CBF of the ischemic hemisphere was 62.1 +/- 11.2 ml x 100 g(-1) x min(-1) in the pH-stat group versus 48.2 +/- 7.2 ml x 100 g(-1) x min(-1) in the alpha-stat group ( P> or = 0.05). CONCLUSIONS: In the very early reperfusion period (5 h), pH-stat management significantly decreases cerebral infarct volume and edema as compared with alpha-stat during moderate hypothermia, probably by increasing CBF.

Acid-Base Equilibrium↗
PubMed2002

Effects of hypothermia on excitatory amino acids and metabolism in stroke patients: a microdialysis study.

BACKGROUND AND PURPOSE: The objective of this study was to assess the effect of therapeutic moderate hypothermia on excitatory amino acids and metabolism by applying cerebral microdialysis in patients suffering from space-occupying middle cerebral artery infarction. METHODS: This was an open, prospective, observational study of 12 patients undergoing moderate hypothermia (33 degrees C) as rescue therapy for large, life-threatening middle cerebral artery infarction. Microdialysis probes were placed concomitantly with intracranial pressure (ICP) measuring devices in the frontal lobe of the infarcted and/or noninfarcted hemisphere. Using the CMA 600 Microdialysis Autoanalyzer, we analyzed glutamate, glycerol, pyruvate, and lactate. RESULTS: According to follow-up cranial CT scans, 3 different compartments of microdialysis measurements could be defined. First, noninfarcted brain tissue had stable dialysate concentrations but a significant effect of hypothermia on glutamate (2.6 versus 3.6 micromol/L), lactate (1.8 versus 3 mmol/L), and pyruvate (50 versus 95.8 micromol/L). Second, measurements from peri-infarct tissue had a significant effect of hypothermia on glutamate (4.8 versus 12.6 micromol/L), glycerol (58 versus 82 micromol/L), lactate (0.7 versus 1.3 mmol/L), and pyruvate (13.3 versus 36.8 micromol/L). Third, dialysate concentrations obtained from irreversibly damaged tissue were excessive for glutamate (453 micromol/L), glycerol (1187 micromol/L), lactate (12 micromol/L), and pyruvate (4 micromol/L). In this extreme compartment, no effect of hypothermia was observed. CONCLUSIONS: Cerebral microdialysis is a safe and feasible bedside method for neurochemical monitoring indicating normal brain tissue, potentially salvageable brain tissue, and irreversibly damaged areas in stroke. We could demonstrate that hypothermia decreases glutamate, glycerol, lactate, and pyruvate in the "tissue at risk" area of the infarct but not within the infarct core. Thus, future treatment strategies for life-threatening stroke should be guided by close neurochemical monitoring.

Adult↗