Wolf-Rüdiger Schäbitz

University of Münster, Muenster, North Rhine-Westphalia, Germany

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Publications (99)524.73 Total impact

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    ABSTRACT: Background and purpose: Bone marrow cell (BMC)-based therapies, either the transplantation of exogenous cells or stimulation of endogenous cells by growth factors like the granulocyte colony-stimulating factor (G-CSF), are considered a promising means of treating stroke. In contrast to large preclinical evidence, however, a recent clinical stroke trial on G-CSF was neutral. We, therefore, aimed to investigate possible synergistic effects of co-administration of G-CSF and BMCs after experimental stroke in mice to enhance the efficacy compared with single treatments. Methods: We used an animal model for experimental stroke as paradigm to study possible synergistic effects of -co-administration of G-CSF and BMCs on the functional outcome and the pathophysiological mechanism. Results: G-CSF treatment alone led to an improved functional outcome, a reduced infarct volume, increased blood vessel stabilization, and decreased overall inflammation. Surprisingly, the combination of G-CSF and BMCs abrogated G-CSFs' beneficial effects and resulted in increased hemorrhagic infarct transformation, altered blood-brain barrier, excessive astrogliosis, and altered immune cell polarization. These increased rates of infarct bleeding were mainly mediated by elevated matrix metalloproteinase-9-mediated blood-brain barrier breakdown in G-CSF- and BMCs-treated animals combined with an increased number of dilated and thus likely more fragile vessels in the subacute phase after cerebral ischemia. Conclusions: Our results provide new insights into both BMC-based therapies and immune cell biology and help to understand potential adverse and unexpected side effects.
    No preview · Article · Feb 2016 · Stroke
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    ABSTRACT: We have previously shown that granulocyte-colony stimulating factor (G-CSF) treatment alone, or in combination with constraint movement therapy (CIMT) either sequentially or concomitantly, results in significantly improved sensorimotor recovery after photothrombotic stroke in rats in comparison to untreated control animals. CIMT alone did not result in any significant differences compared to the control group (Diederich et al., Stroke, 2012;43:185-192). Using a subset of rat brains from this former experiment the present study was designed to evaluate whether dendritic plasticity would parallel improved functional outcomes. Five treatment groups were analyzed (n = 6 each) (i) ischemic control (saline); (ii) CIMT (CIMT between post-stroke days 2 and 11); (iii) G-CSF (10 μg/kg G-CSF daily between post-stroke days 2 and 11); (iv) combined concurrent group (CIMT plus G-CSF) and (v) combined sequential group (CIMT between post-stroke days 2 and 11; 10 μg/kg G-CSF daily between post-stroke days 12 and 21, respectively). After impregnation of rat brains with a modified Golgi-Cox protocol layer V pyramidal neurons in the peri-infarct cortex as well as the corresponding contralateral cortex were analyzed. Surprisingly, animals with a similar degree of behavioral recovery exhibited quite different patterns of dendritic plasticity in both peri-lesional and contralesional areas. The cause for these patterns is not easily to explain but puts the simple assumption that increased dendritic complexity after stroke necessarily results in increased functional outcome into perspective.
    Full-text · Article · Jan 2016 · PLoS ONE
  • Jens Minnerup · Verena Zentsch · Antje Schmidt · Marc Fisher · Wolf-Rüdiger Schäbitz

    No preview · Article · Dec 2015 · Stroke
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    ABSTRACT: Purpose: Using G-CSF deficient mice we recently demonstrated neuroprotective properties of endogenous G-CSF after ischemic stroke. The present follow-up study was designed to check, whether specific alterations in ligand binding densities of excitatory glutamate or inhibitory GABAA receptors may participate in this effect. Methods: Three groups of female mice were subjected to 45 minutes of MCAO: wildtype, G-CSF deficient and G-CSF deficient mice substituted with G-CSF. Infarct volumes were determined after 24 hours and quantitative in vitro receptor autoradiography was performed using [3H]MK-801, [3H]AMPA and [3H]muscimol for labeling of NMDA, AMPA and GABAA receptors, respectively. Ligand binding densities were analyzed in regions in the ischemic core, peri-infarct areas and corresponding contralateral regions. Results: Infarct volumes did not significantly differ between the experimental groups. Ligand binding densities of NMDA and GABAA receptors were widely in the same range. However, AMPA receptor binding densities in G-CSF deficient mice were substantially enhanced compared to wildtype mice. G-CSF substitution in mice lacking G-CSF largely reversed this effect. Conclusions: Although infarct volumes did not differ 24 hours after ischemia the increase of AMPA receptor binding densities in G-CSF deficient mice may explain the bigger infarcts previously observed at later time-points with the same stroke model.
    No preview · Article · Sep 2015
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    ABSTRACT: We investigated whether hyperintensities with a diameter of at least 3, 3.5, and 4 cm and visible on at least 3 slices on diffusion-weighted imaging enables patient selection with an infarct volume of ≥15 mL. Consecutive acute stroke patients were screened for the AXIS2 trial and examined according to a standardized magnetic resonance imaging protocol in 65 sites. Diffusion-weighted lesion diameters were measured and compared with volumetric assessments. Out of 238 patients, 86.2% (N=206) had infarct diameter of at least 3 cm. Volumetric assessments showed infarct volume of ≥15 mL in 157 patients. A cut-off value of 3 cm led to 96.8% sensitivity and 33.3% specificity for predicting lesion volume of ≥15 mL. Analogously, a 3.5 cm cut-off led to 96.8% sensitivity and 50.6% specificity and a 4 cm cut-off led to 91.7% sensitivity and 61.7% specificity. Lesion diameter measures may enable multicentric patient recruitment with a prespecified minimal infarct volume. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927836. © 2015 American Heart Association, Inc.
    Full-text · Article · Mar 2015 · Stroke
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    ABSTRACT: In spite of its high disease burden, there is no specific treatment for multi-infarct dementia. The preclinical evaluation of candidate drugs is limited because an appropriate animal model is lacking. Therefore, we aimed to evaluate whether a mouse model of recurrent photothrombotic stroke is suitable for the preclinical investigation of multi-infarct dementia. Recurrent photothrombotic cortical infarcts were induced in 25 adult C57BL/6 mice. Twenty-five sham-operated animals served as controls. The object recognition test and the Morris water maze test were performed >6 weeks to assess cognitive deficits. Afterward, histological analyses were performed to characterize histopathologic changes associated with recurrent photothrombotic infarcts. After the first infarct, the object recognition test showed a trend toward an impaired formation of recognition memories (P=0.08), and the Morris Water Maze test revealed significantly impaired spatial learning and memory functions (P<0.05). After recurrent infarcts, the object recognition test showed significant recognition memory deficits (P<0.001) and the Morris water maze test demonstrated persisting spatial learning and memory deficits (P<0.05). Histological analyses revealed remote astrogliosis in the hippocampus. Our results show progressive cognitive deficits in a mouse model of recurrent photothrombotic stroke. The presented model resembles the clinical features of human multi-infarct dementia and enables the investigation of its pathophysiological mechanisms and the evaluation of treatment strategies. © 2015 American Heart Association, Inc.
    Full-text · Article · Mar 2015 · Stroke
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    ABSTRACT: Granulocyte-colony stimulating factor (G-CSF) and bone marrow derived mononuclear cells (BM-MNCs) have both been shown to improve functional outcome following experimental stroke. These effects are associated with increased angiogenesis and neurogenesis. In the present study, we aimed to determine synergistic effects of G-CSF and BM-NMC treatment on long-term structural and functional recovery after photothrombotic stroke. To model the etiology of stroke more closely, we used spontaneously hypertensive (SH) rats in our experiment. Bone marrow derived mononuclear cells transplantation was initiated 1 h after the onset of photothrombotic stroke. Repeated G-CSF treatment commenced immediately after BM-MNC treatment followed by daily injections for five consecutive days. The primary endpoint was functional outcome after ischemia. Secondary endpoints included analysis of neurogenesis and angiogenesis as well as determination of infarct size. Granulocyte-colony stimulating factor treated rats, either in combination with BM-MNC or alone showed improved somatosensory but not gross motor function following ischemia. No beneficial effect of BM-MNC monotherapy was found. Infarct volumes were comparable in all groups. In contrast to previous studies, which used healthy animals, post-stroke neurogenesis and angiogenesis were not enhanced by G-CSF. In conclusion, the combination of G-CSF and BM-MNC was not more effective than G-CSF alone. The reduced efficacy of G-CSF treatment and the absence of any beneficial effect of BM-MNC transplantation might be attributed to hypertension-related morbidity.
    Full-text · Article · Dec 2014 · Frontiers in Cellular Neuroscience
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    ABSTRACT: Background Differential diagnosis of severe progressive dementia includes a wide spectrum of inflammatory and neurodegenerative diseases. Particularly challenging is the differentiation of potentially treatable autoimmune encephalitis and Creutzfeldt-Jakob disease. Such a coincidence may indeed complicate the correct diagnosis and influence subsequent treatment.Case presentationA 75-year-old woman was admitted due to rapid progressive cognitive impairment. Her husband observed a temporal disorientation and confusion. The initial neurological examination and an extensive neuropsychological evaluation showed significant impairments in almost all tested cognitive domains. All other neurological functions including motor, sensory and coordinative function were intact. Initial diagnostics included EEG, MRI and lumbar puncture with unspecific results. Complementary blood testing revealed a positive result for antineural antibodies to Contactin-associated protein 2 (CASPR2) and the patient received treatment for CASPR2 autoimmune encephalitis. Further symptoms and results, including 14-3-3 proteins, led to suspected Creutzfeldt-Jakob disease. The postmortem examination supported the diagnosis of a definitive Creutzfeldt-Jakob disease.Conclusion One could argue that global screening for antineural antibodies may lead to a false diagnosis triggering intense and potentially dangerous procedures. We believe, however, that potentially treatable causes of dementia should aggressively sought out and subsequently treated in an attempt to curtail the course of disease and ultimately reduce the rate of mortality.
    Full-text · Article · Nov 2014 · BMC Neurology
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    ABSTRACT: Background and purpose: Eligibility criteria are a key factor for the feasibility and validity of clinical trials. We aimed to develop an online tool to assess the potential effect of inclusion and exclusion criteria on the proportion of patients eligible for an acute stroke trial. Methods: We identified relevant inclusion and exclusion criteria of acute stroke trials. Based on these criteria and using a cohort of 1537 consecutive patients with acute ischemic stroke from 3 stroke centers, we developed a web portal feasibility platform for stroke studies (FePASS) to estimate proportions of eligible patients for acute stroke trials. We applied the FePASS resource to calculate the proportion of patients eligible for 4 recent stroke studies. Results: Sixty-one eligibility criteria were derived from 30 trials on acute ischemic stroke. FePASS, publicly available at http://fepass.uni-muenster.de, displays the proportion of patients in percent to assess the effect of varying values of relevant eligibility criteria, for example, age, symptom onset time, National Institutes of Health Stroke Scale, and prestroke modified Rankin Scale, on this proportion. The proportion of eligible patients for 4 recent stroke studies ranged from 2.1% to 11.3%. Slight variations of the inclusion criteria could substantially increase the proportion of eligible patients. Conclusions: FePASS is an open access online resource to assess the effect of inclusion and exclusion criteria on the proportion of eligible patients for a stroke trial. FePASS can help to design stroke studies, optimize eligibility criteria, and to estimate the potential recruitment rate.
    Full-text · Article · Nov 2014 · Stroke
  • Wolf-Rüdiger Schäbitz · Andreas Rogalewski · Christoph Hagemeister · Christian G Bien
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    ABSTRACT: After its discovery, anti-NMDA receptor (NMDAR) encephalitis was quickly recognized as sleeping neurologic disease, presumably heavily underestimated. This autoimmune disease is defined by the presence of immunoglobulin G (IgG) antibodies against cell surface epitopes of the NR1 subunit of the NMDAR.(1) The disease phenotype is best characterized as encephalopathy and was initially described by Dalmau et al.(2) in young women presenting with a prominent change of behavior, psychosis, memory deficits, seizures, abnormal movements, coma, and autonomic dysfunction. Whereas in cases of an underlying tumor (usually teratoma in the ovary) the cause of the disease is viewed as paraneoplastic, in many cases without a tumor the trigger for the NMDAR antibody production is unknown. Recently it has been observed that herpes simplex virus 1 (HSV-1) may account for relapses of HSV encephalitis (HSVE) by inducing NMDAR immunoreactivity causing the full clinical picture of anti-NMDA-R encephalopathy(3) or a choreatic condition.(4-6)
    No preview · Article · Nov 2014 · Neurology
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    ABSTRACT: Background and purpose: We aimed to determine a possible synergistic effect of granulocyte colony-stimulating factor (G-CSF) and bone marrow-derived mononuclear cells (BM MNC) after stroke in spontaneously hypertensive rats. Methods: Male spontaneously hypertensive rats were subjected to middle cerebral artery occlusion and randomly assigned to daily injection of 50 μg/kg G-CSF for 5 days starting 1 hour after stroke (groups 1, 2, and 3) with additional intravenous transplantation of 1.5×10E7 BM MNC per kilogram at 6 hours (group 2) or 48 hours (group 3) after stroke, or control treatment (group 4). Circulating leukocyte counts and functional deficits, infarct volume, and brain edema were repeatedly assessed in the first week and first month. Results: G-CSF treatment led to a significant neutrophilia, to a reversal of postischemic depression of circulating leukocytes, and to a significantly improved functional recovery without affecting the infarct volume or brain edema. BM MNC cotransplantation was neutral after 6 hours, but reversed the functional effect of G-CSF after 48 hours. Short-term investigation of combined G-CSF and BM MNC treatment at 48 hours indicated splenic accumulation of granulocytes and transplanted cells, accompanied by a significant rise of granulocytes in the circulation and the ischemic brain. Conclusions: G-CSF improved functional recovery in spontaneously hypertensive rats, but this effect was abolished by cotransplantation of BM MNC after 48 hours. In the spleen, transplanted cells may hinder the clearance of granulocytes that were massively increased by G-CSF. Increased circulation and infiltration of granulocytes into the ischemic brain may be detrimental for stroke outcome.
    Full-text · Article · Jul 2014 · Stroke
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    Uwe Dietrich · Tilmann Graf · Wolf-Rüdiger Schäbitz
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    ABSTRACT: We report a case with acute small infarct of the left middle cerebral artery in a 72-year-old man with atrial fibrillation documented by MRI and MR angiography. One hour later, he lost consciousness and CT with CT angiography revealed bilateral hyperdense middle cerebral arteries due to occlusion of the M1 segments. Mechanical thrombectomy of the right middle cerebral artery was successfully performed. During that time, thrombosis on the left side had progressed to carotid T occlusion, which was recanalized as well. The patient had a good outcome with slight aphasia and mild paresis of the left hand and could be transferred to rehabilitation 2 weeks later.
    Preview · Article · May 2014 · Case Reports in Neurology
  • Wolf-Rüdiger Schäbitz

    No preview · Article · May 2014
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    Wolf-Rüdiger Schäbitz · Ulrich Dirnagl

    Full-text · Article · Apr 2014 · Stroke
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    ABSTRACT: Background and purpose: Both the immobilization of the unaffected arm combined with physical therapy (forced arm use, FAU) and voluntary exercise (VE) as model for enriched environment are promising approaches to enhance recovery after stroke. The genomic mechanisms involved in long-term plasticity changes after different means of rehabilitative training post-stroke are largely unexplored. The present investigation explored the effects of these physical therapies on behavioral recovery and molecular markers of regeneration after experimental ischemia. 42 Wistar rats were randomly treated with either forced arm use (FAU, 1-sleeve plaster cast onto unaffected limb at 8/10 days), voluntary exercise (VE, connection of a freely accessible running wheel to cage), or controls with no access to a running wheel for 10 days starting at 48 hours after photothrombotic stroke of the sensorimotor cortex. Functional outcome was measured using sensorimotor test before ischemia, after ischemia, after the training period of 10 days, at 3 and 4 weeks after ischemia. Global gene expression changes were assessed from the ipsi- and contralateral cortex and the hippocampus. FAU-treated animals demonstrated significantly improved functional recovery compared to the VE-treated group. Both were superior to cage control. A large number of genes are altered by both training paradigms in the ipsi- and contralateral cortex and the hippocampus. Overall, the extent of changes observed correlated well with the functional recovery obtained. One category of genes overrepresented in the gene set is linked to neuronal plasticity processes, containing marker genes such as the NMDA 2a receptor, PKC zeta, NTRK2, or MAP 1b. We show that physical training after photothrombotic stroke significantly and permanently improves functional recovery after stroke, and that forced arm training is clearly superior to voluntary running training. The behavioral outcomes seen correlate with patterns and extent of gene expression changes in all brain areas examined. We propose that physical training induces a fundamental change in plasticity-relevant gene expression in several brain regions that enables recovery processes. These results contribute to the debate on optimal rehabilitation strategies, and provide a valuable source of molecular entry points for future pharmacological enhancement of recovery.
    Full-text · Article · Feb 2014 · Experimental and Translational Stroke Medicine
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    ABSTRACT: Bone marrow-derived mononuclear cells (BM-MNCs) were shown to improve the outcome in animal stroke models and clinical pilot studies on BM-MNCs for stroke patients were already conducted. However, relevant aspects of pre-clinical evaluation, such as the use of animals with comorbidities and dose-response studies, were not thoroughly addressed so far. We therefore investigated different BM-MNC doses in the clinical meaningful stroke model of spontaneously hypertensive (SH) rats. Three hours after the onset of transient middle cerebral artery occlusion (MCAO) animals received either one of three syngeneic BM-MNC doses or placebo intravenously. The primary endpoint was the infarct size. Secondary endpoints included functional outcome, mortality, inflammatory processes, and the dose-response relationship. In contrast to previous studies which used healthy animals no beneficial effect of BM-MNCs was found. Infarct volumes, mortality, behavioral outcomes, and the extent of the inflammatory response to cerebral ischemia were comparable in all groups. In conclusion, we could not demonstrate that early BM-MNC treatment improves the outcome after stroke in SH rats. Whether BM-MNCs improve neurological recovery after delayed treatment initiation was not investigated in the present study, but our data indicates that this should be determined in co-morbid animal stroke models before moving to large-scale clinical studies. Future preclinical stroke studies on co-morbid animals should also include groups of healthy animals in order to determine whether negative results can be attributed to the comorbid condition.
    Full-text · Article · Jan 2014 · Frontiers in Cellular Neuroscience
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    ABSTRACT: Despite a high incidence of poststroke dementia, there is no specific treatment for this condition. Because the evaluation of poststroke cognitive deficits in animal models of stroke is exceedingly challenging, the preclinical evaluation of candidate drugs is limited. We aimed to explore the impact of small cortical photothrombotic strokes on poststroke cognition, thereby assessing the suitability of this experimental stroke model for the investigation of cognitive impairment after stroke. Photothrombotic cortical infarcts were induced in 19 adult male Wistar rats. Nineteen sham-operated animals served as controls. Using the Morris water maze, we analyzed the impact of photothrombotic stroke on both the acquisition of new memories and the recall of previously acquired memories. The cylinder test, the adhesive tape removal test, and the rotarod test were performed to investigate sensorimotor deficits. Photothrombotic stroke significantly impaired the recall of previously acquired memories (P<0.05), whereas the acquisition of new memories remained largely intact. The analysis of the animals' swimming speed in the water maze and the rotarod test showed no confounding motor impairments after photothrombotic stroke. The adhesive tape removal test and the cylinder test revealed mild sensorimotor deficits in lesioned animals (P<0.05). Photothrombotic cortical infarcts impair the recall of memories acquired before stroke, whereas the formation of new memories remains unimpaired. The observed deficits in the water maze are not confounded by disturbed motor functions. Overall, experimental photothrombotic strokes are well suited for the investigation of specific cognitive impairments after stroke.
    Full-text · Article · Dec 2013 · Stroke
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    Armin Schneider · Wolf-Rüdiger Schäbitz · E Bernd Ringelstein

    Preview · Article · Dec 2013 · Stroke
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    ABSTRACT: Although several studies have shown beneficial effects of training in animal stroke models, the most effective training strategy and the optimal time to initiate training have not been identified. The present meta-analysis was performed to compare the efficacy of different training strategies and to determine the optimal time window for training in animal stroke models. We searched the literature for studies analyzing the efficacy of training in animal models of ischemic stroke. Training was categorized into forced physical training, voluntary physical training, constraint-induced movement therapy, and skilled reaching training. Two reviewers independently extracted data on study quality, infarct size, and neurological outcome. Data were pooled by means of a meta-analysis. Thirty-five studies with >880 animals were included. A meta-analysis of all treatments showed that training reduced the infarct volume by 14% (95% confidence interval, 2%-25%) and improved the cognitive function by 33% (95% confidence interval, 8%-50%), the neuroscore by 13.4% (95% confidence interval, 1.5%-25.3%), and the running function by 6.6% (95% confidence interval, 1.4%-11.9%). Forced physical training reduced the infarct volume and enhanced the running function most effectively, whereas skilled reaching training improved the limb function most effectively. A meta-regression illustrated that training was particularly efficacious when initiated between 1 and 5 days after stroke onset. Our meta-analysis confirms that training reduces the infarct volume and improves the functional recovery in animal stroke models. Forced physical training and skilled reaching training were identified as particularly effective training strategies. The efficacy of training is time dependent.
    Full-text · Article · Oct 2013 · Stroke
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    Holger Reinecke · Christiane Engelbertz · Wolf-Rüdiger Schäbitz

    Preview · Article · Sep 2013 · Stroke

Publication Stats

3k Citations
524.73 Total Impact Points

Institutions

  • 2005-2015
    • University of Münster
      • Department of Neurology
      Muenster, North Rhine-Westphalia, Germany
  • 2009-2014
    • Evangelic Hospital Bielefeld
      Bielefeld, North Rhine-Westphalia, Germany
  • 2013
    • University of Virginia
      • Department of Physics
      Charlottesville, Virginia, United States
  • 2006-2013
    • Universitätsklinikum Münster
      • Klinik und Poliklinik für Neurologie
      Muenster, North Rhine-Westphalia, Germany
  • 2011
    • Neurologische Klinik Westend
      Бад Вилдунген, Hesse, Germany
    • Klinikum Bielefeld
      Bielefeld, North Rhine-Westphalia, Germany
  • 2010
    • Bielefeld University
      Bielefeld, North Rhine-Westphalia, Germany
  • 2002-2009
    • Universität Heidelberg
      • Department of Neurology
      Heidelburg, Baden-Württemberg, Germany