Publications by authors named "Odilo Engel"

20 Publications

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Inhaled ciclesonide is efficacious and well tolerated in the treatment of severe equine asthma in a large prospective European clinical trial.

Equine Vet J 2021 Jan 5. Epub 2021 Jan 5.

Boehringer Ingelheim Vetmedica GmbH, Ingelheim, Germany.

Background: Ciclesonide is a glucocorticoid prodrug, already registered for human use. Due to its mode of action and inhaled route of administration, it was considered an appropriate treatment option for horses with severe equine asthma. Although the efficacy of inhaled ciclesonide has been demonstrated in horses with asthma exacerbations under controlled mouldy hay challenge conditions, it has not yet been reported under field conditions.

Objectives: To assess the effectiveness and safety of inhaled ciclesonide for the treatment of severe equine asthma.

Study Design: Prospective, multicentre, placebo-controlled, randomised, double-blinded study.

Methods: Two-hundred and twenty-four client-owned horses with severe equine asthma were randomised (1:1 ratio) to receive either ciclesonide inhalation (343 µg/actuation) solution or placebo (0 µg/actuation). Treatments (placebo or ciclesonide) were administered with a nonpressurised Soft Mist™ inhaler specifically developed for horses (Aservo EquiHaler ) at doses of 8 actuations twice daily for the first 5 days and 12 actuations once daily for the following 5 days. Primary outcome was a success/failure analysis with the a priori definition of treatment success as a 30% or greater reduction in weighted clinical score (WCS) between Day 0 and Day 10 (±1).

Results: The treatment success rate (as defined above) in ciclesonide-treated horses was 73.4% (80/109) after 10 (±1) days of treatment, being significantly higher than in the placebo group with 43.2% (48/111; P < 0.0001). Few systemic and local adverse events of ciclesonide were observed.

Main Limitations: The severity of clinical signs of severe equine asthma varies over time; despite the prohibition of environmental management changes during the study, a placebo effect was also identified. This potentially contributed, in part, to the clinical improvement observed in the ciclesonide-treated group.

Conclusions: Ciclesonide inhalation solution administered by the Aservo EquiHaler effectively reduced severity of clinical signs in a majority of horses with severe equine asthma and was well tolerated.
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http://dx.doi.org/10.1111/evj.13419DOI Listing
January 2021

Development and Psychometric Validation of the Lincoln Canine Anxiety Scale.

Front Vet Sci 2020 3;7:171. Epub 2020 Apr 3.

Boehringer Ingelheim Vetmedica GmbH, Ingelheim am Rhein, Germany.

Anxiety in dogs, especially in relation to certain noises, is a common issue which can lead to clinically significant problems like noise phobias. While several scales have been used to assess sound sensitivity and reactivity, clinical monitoring has tended to depend on unvalidated methods, general assessment, and/or historical comparison with owners' recall of previous episodes. Therefore, we aimed to develop and validate a scale to assess canine anxiety. We used the data from 226 dogs from a previously reported double blind placebo controlled study in order to determine the validity of the 16 item "Lincoln Canine Anxiety Scale." Unidimensionality was assessed through correlation between individual item scores and total score, with internal consistency assessed using Cronbach's alpha. Factor analysis was used to determine the dimensionality of the scale. Item response theory (IRT) was used to gain insight into the value of single items to the overall scale scores. To characterize the score characteristics in an anxiety-eliciting context we analyzed the behaviors of placebo treated dogs assessed at 00:20 h, the time point of maximum noise stimulus during New Year's Eve fireworks. Sensitivity of the scale to treatment effects was determined from its performance in the wider study. The majority of correlations between individual items and total score were >0.48, with Cronbach's alpha equalling 0.88, indicating good internal consistency. Principal Component Analysis (PCA) confirmed a unidimensional structure. IRT indicated that the scale could be reduced to 11 items without significantly reducing its value. The scale showed good treatment and stimulus sensitivity, with a score change of ~20 points differentiating "no/worse" effect from an "excellent" effect and a 30% difference between treatment (imepitoin) and placebo. In our initial validation the Lincoln Canine Anxiety Scale appears to provide a reliable method for determining anxiety and fear responses by dogs and monitoring the effects of treatment.
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http://dx.doi.org/10.3389/fvets.2020.00171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146976PMC
April 2020

Effectiveness of imepitoin for the control of anxiety and fear associated with noise phobia in dogs.

J Vet Intern Med 2019 Nov 30;33(6):2675-2684. Epub 2019 Sep 30.

Animal Behaviour Cognition and Welfare Group, School of Life Sciences, University of Lincoln, Lincoln, United Kingdom.

Background: Noise phobia is a common behavior problem in dogs for which there are limited treatment options.

Objective: To evaluate the efficacy and safety of imepitoin in comparison to placebo for the control of anxiety and fear associated with noise phobia in dogs.

Animals: Two hundred thirty-eight client-owned dogs with noise phobia were recruited in veterinary clinics.

Methods: This placebo-controlled, randomized, double-blinded, clinical trial used a predictable noise event as eliciting context, the traditional New Year's Eve fireworks in Germany and the Netherlands. Owners began treatment 2 days before the anticipated noise event with administration of either imepitoin 30 mg/kg body weight Q12h or placebo for 3 consecutive days. On New Year's Eve, owners noted their observations of their dog's fear and anxiety behavior at 1600, 2200, 0020, and 0100 hours and scored the overall treatment effect on the following day.

Results: In the 16-item owner report of fear and anxiety signs, fear and anxiety behaviors were significantly reduced under imepitoin treatment compared to placebo (delta -6.1 scoring points; P < .0001). A significantly higher proportion of owners reported a good or excellent overall treatment effect in the imepitoin group compared to placebo (odds ratio 4.689; 95% CI, 2.79-7.89; P < .0001).

Conclusion: Imepitoin effectively controls fear and anxiety associated with noise phobia in dogs.
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http://dx.doi.org/10.1111/jvim.15608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872611PMC
November 2019

Imepitoin Shows Benzodiazepine-Like Effects in Models of Anxiety.

Front Pharmacol 2018 1;9:1225. Epub 2018 Nov 1.

Drug Consulting Network, Coswig, Germany.

Imepitoin is a low affinity partial agonist for the benzodiazepine binding site of γ-aminobutyric acid (GABA) receptors, and is currently used as an antiepileptic in dogs. Here we tested imepitoin for anxiolytic properties. In an model, imepitoin was capable of preventing the effect of corticotrophin releasing factor (CRF) on locus coeruleus neurons without suppressing the basal activity of these cells, an activity which is suggestive for an anti-stress effect of imepitoin. In addition, we applied a battery of standard rodent preclinical tests for anxiety behavior including elevated plus mazes in mice and rats, light-dark-box in mice and rats, social interaction test in rats, or the Vogel conflict test in rats. In all models, the observed profile of imepitoin appeared similar to benzodiazepines and typical for anxiolytic drugs. We also observed anxiolytic activity in dogs in a provoked open field sound-induced fear model, where reactions to noises were elicited by a sound recording of thunderstorms. Imepitoin caused an increase in locomotion measured in distance traveled and an ameliorating effect on cortisol levels in response to thunderstorm noises. For comparison, dexmedetomidine caused a decrease in locomotion and had no effect on cortisol. In all animal models the doses needed for an anxiolytic effect were not associated with sedation. In rodents, there was at least a factor of 10 between anxiolytic doses and doses with mild signs of sedation. In summary, imepitoin showed similar anxiolytic activities as benzodiazepines but without producing the known adverse reactions of benzodiazepines such as sedation.
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http://dx.doi.org/10.3389/fphar.2018.01225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230983PMC
November 2018

Immunomodulatory treatment with systemic GM-CSF augments pulmonary immune responses and improves neurological outcome after experimental stroke.

J Neuroimmunol 2018 08 9;321:144-149. Epub 2018 Mar 9.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Medical Immunology, Germany; Labor Berlin-Charité Vivantes, Berlin, Germany.

Stroke-induced immunodepression is an independent risk factor for stroke-associated pneumonia (SAP). Granulocyte-macrophage colony stimulating factor (GM-CSF) has neuroprotective properties in experimental stroke and been demonstrated to reverse immunodepression in sepsis patients. However, whether GM-CSF restores immune function after stroke preventing SAP and improving outcome is unknown. Here, we demonstrated that GM-CSF treatment improved peripheral and pulmonary leukocyte numbers, peripheral cytokine responses, lowered lung bacterial burden in the early course and improved long-term functional outcome after experimental stroke. These data suggest that GM-CSF is promising for stroke treatment since it not only acts neuroprotective in the ischemic brain but may also protect against detrimental post-stroke infections.
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http://dx.doi.org/10.1016/j.jneuroim.2018.03.005DOI Listing
August 2018

Imepitoin is well tolerated in healthy and epileptic cats.

BMC Vet Res 2017 Jun 12;13(1):172. Epub 2017 Jun 12.

University of Veterinary Medicine, Department of Small Animal Medicine and Surgery, Bünteweg 9, 30559, Hannover, Germany.

Background: Epilepsy in the cat is a serious medical condition. To date there are no licensed treatments for feline epilepsy and no well-controlled clinical studies on the efficacy or safety of antiepileptic drugs in cats. The aim of this study was to collect tolerability data and first exploratory efficacy data of imepitoin in both healthy and epileptic cats.

Results: In two tolerability studies, 30 healthy cats received imepition twice daily in doses of 0, 30, 40 or 80 mg/kg bodyweight for 30 days. No serious adverse events were observed in any of the dose groups. In the imepitoin treated groups, emesis was observed in some animals temporarily and intermittently mainly in the second and third weeks of treatment. In a small, single-arm, open label, uncontrolled clinical trial eight cats suffering from idiopathic epilepsy were treated with imepitoin twice daily at doses of 30 mg/kg bodyweight for 30 days. Four of these cats (50%) achieved seizure freedom for at least 8 weeks under treatment. Adverse events, mostly lethargy, decreased appetite and emesis, were often mild and transient.

Conclusion: In summary, imepitoin was well tolerated in healthy and epileptic cats and showed in a pilot trial indication for efficacy in treating feline epilepsy.
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http://dx.doi.org/10.1186/s12917-017-1087-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469074PMC
June 2017

Lipocalin-2 as an Infection-Related Biomarker to Predict Clinical Outcome in Ischemic Stroke.

PLoS One 2016 6;11(5):e0154797. Epub 2016 May 6.

Department of Neurology, Medical University of Graz, Graz, Austria.

Objectives: From previous data in animal models of cerebral ischemia, lipocalin-2 (LCN2), a protein related to neutrophil function and cellular iron homeostasis, is supposed to have a value as a biomarker in ischemic stroke patients. Therefore, we examined LCN2 expression in the ischemic brain in an animal model and measured plasma levels of LCN2 in ischemic stroke patients.

Methods: In the mouse model of transient middle cerebral artery occlusion (tMCAO), LCN2 expression in the brain was analyzed by immunohistochemistry and correlated to cellular nonheme iron deposition up to 42 days after tMCAO. In human stroke patients, plasma levels of LCN2 were determined one week after ischemic stroke. In addition to established predictive parameters such as age, National Institutes of Health Stroke Scale and thrombolytic therapy, LCN2 was included into linear logistic regression modeling to predict clinical outcome at 90 days after stroke.

Results: Immunohistochemistry revealed expression of LCN2 in the mouse brain already at one day following tMCAO, and the amount of LCN2 subsequently increased with a maximum at 2 weeks after tMCAO. Accumulation of cellular nonheme iron was detectable one week post tMCAO and continued to increase. In ischemic stroke patients, higher plasma levels of LCN2 were associated with a worse clinical outcome at 90 days and with the occurrence of post-stroke infections.

Conclusions: LCN2 is expressed in the ischemic brain after temporary experimental ischemia and paralleled by the accumulation of cellular nonheme iron. Plasma levels of LCN2 measured in patients one week after ischemic stroke contribute to the prediction of clinical outcome at 90 days and reflect the systemic response to post-stroke infections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154797PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859492PMC
July 2017

Depletion of Cultivatable Gut Microbiota by Broad-Spectrum Antibiotic Pretreatment Worsens Outcome After Murine Stroke.

Stroke 2016 05 7;47(5):1354-63. Epub 2016 Apr 7.

From the Department of Experimental Neurology (K.W., O.E., P.K., N.O., A.M., U.D.), NeuroCure Clinical Research (K.W., C.C., A.M., U.D.), Center for Stroke Research Berlin (K.W., O.E., P.K., A.M., U.D.), Department of Microbiology and Hygiene (M.M.H., A.F., S.B.), Institute for Medical Immunology (C.D., C.M.), and Department of Neurology (A.M., U.D.), Charité - Universitätsmedizin Berlin, Germany; Institute of Veterinary Pathology, Faculty of Veterinary Medicine, Freie Universität Berlin, Germany (O.K., A.D.G.); German Rheumatism Research Center (DRFZ), Berlin, Germany (C.C.); and German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (U.D.).

Background And Purpose: Antibiotics disturbing microbiota are often used in treatment of poststroke infections. A bidirectional brain-gut microbiota axis was recently suggested as a modulator of nervous system diseases. We hypothesized that gut microbiota may be an important player in the course of stroke.

Methods: We investigated the outcome of focal cerebral ischemia in C57BL/6J mice after an 8-week decontamination with quintuple broad-spectrum antibiotic cocktail. These microbiota-depleted animals were subjected to 60 minutes middle cerebral artery occlusion or sham operation. Infarct volume was measured using magnetic resonance imaging, and mice were monitored clinically throughout the whole experiment. At the end point, tissues were preserved for further analysis, comprising histology and immunologic investigations using flow cytometry.

Results: We found significantly decreased survival in the middle cerebral artery occlusion microbiota-depleted mice when the antibiotic cocktail was stopped 3 days before surgery (compared with middle cerebral artery occlusion specific pathogen-free and sham-operated microbiota-depleted mice). Moreover, all microbiota-depleted animals in which antibiotic treatment was terminated developed severe acute colitis. This phenotype was rescued by continuous antibiotic treatment or colonization with specific pathogen-free microbiota before surgery. Further, infarct volumes on day one did not differ between any of the experimental groups.

Conclusions: Conventional microbiota ensures intestinal protection in the mouse model of experimental stroke and prevents development of acute and severe colitis in microbiota-depleted mice not given antibiotic protection after cerebral ischemia. Our experiments raise the clinically important question as to whether microbial colonization or specific microbiota are crucial for stroke outcome.
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http://dx.doi.org/10.1161/STROKEAHA.115.011800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839545PMC
May 2016

Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level.

Brain 2016 Mar 10;139(Pt 3):692-707. Epub 2016 Jan 10.

1 Department of Neurology and Experimental Neurology, Spinal Cord Injury Research (Molecular Neuroparaplegiology), Charité - Universitätsmedizin Berlin, Germany 8 Department of Neurology, Spinal Cord Injury Division, The Neurological Institute, The Ohio State University, Wexner Medical Centre, Columbus, OH 43210, USA 9 Department of Neuroscience and Centre for Brain and Spinal Cord Repair, Department of Physical Medicine and Rehabilitation, The Neurological Institute, The Ohio State University, Wexner Medical Centre, Columbus, OH 43210, USA

Pneumonia is the leading cause of death after acute spinal cord injury and is associated with poor neurological outcome. In contrast to the current understanding, attributing enhanced infection susceptibility solely to the patient's environment and motor dysfunction, we investigate whether a secondary functional neurogenic immune deficiency (spinal cord injury-induced immune deficiency syndrome, SCI-IDS) may account for the enhanced infection susceptibility. We applied a clinically relevant model of experimental induced pneumonia to investigate whether the systemic SCI-IDS is functional sufficient to cause pneumonia dependent on spinal cord injury lesion level and investigated whether findings are mirrored in a large prospective cohort study after human spinal cord injury. In a mouse model of inducible pneumonia, high thoracic lesions that interrupt sympathetic innervation to major immune organs, but not low thoracic lesions, significantly increased bacterial load in lungs. The ability to clear the bacterial load from the lung remained preserved in sham animals. Propagated immune susceptibility depended on injury of central pre-ganglionic but not peripheral postganglionic sympathetic innervation to the spleen. Thoracic spinal cord injury level was confirmed as an independent increased risk factor of pneumonia in patients after motor complete spinal cord injury (odds ratio = 1.35, P < 0.001) independently from mechanical ventilation and preserved sensory function by multiple regression analysis. We present evidence that spinal cord injury directly causes increased risk for bacterial infection in mice as well as in patients. Besides obvious motor and sensory paralysis, spinal cord injury also induces a functional SCI-IDS ('immune paralysis'), sufficient to propagate clinically relevant infection in an injury level dependent manner.
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http://dx.doi.org/10.1093/brain/awv375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014125PMC
March 2016

Cholinergic Pathway Suppresses Pulmonary Innate Immunity Facilitating Pneumonia After Stroke.

Stroke 2015 Nov 8;46(11):3232-40. Epub 2015 Oct 8.

From the Department of Experimental Neurology (O.E., K.W., M.T., U.D., A.M.), Department of Neurology (U.D., A.M.), NeuroCure Clinical Research (U.D., A.M.), Institute for Medical Immunology (L.A., C.D., H.D.V., C.M.), BCRT Berlin Brandenburg Centre for Regenerative Medicine (L.A., H.D.V.), Department of Neuropsychiatry and Laboratory of Molecular Psychiatry (C.B., J.P.), and Center for Stroke Research Berlin (O.E., K.W., M.T., U.D., A.M.), Charité University Medicine Berlin, Berlin, Germany; German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (J.P., U.D.); Department of Internal Medicine II, Justus-Liebig-University, Universities Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL) (S.H.); and Max Delbrück Center for Molecular Medicine, Berlin, Germany (A.C.d.C.G.).

Background And Purpose: Temporary immunosuppression has been identified as a major risk factor for the development of pneumonia after acute central nervous system injury. Although overactivation of the sympathetic nervous system was previously shown to mediate suppression of systemic cellular immune responses after stroke, the role of the parasympathetic cholinergic anti-inflammatory pathway in the antibacterial defense in lung remains largely elusive.

Methods: The middle cerebral artery occlusion model in mice was used to examine the influence of the parasympathetic nervous system on poststroke immunosuppression. We used heart rate variability measurement by telemetry, vagotomy, α7 nicotinic acetylcholine receptor-deficient mice, and parasympathomimetics (nicotine, PNU282987) to measure and modulate parasympathetic activity.

Results: Here, we demonstrate a rapidly increased parasympathetic activity in mice after experimental stroke. Inhibition of cholinergic signaling by either vagotomy or by using α7 nicotinic acetylcholine receptor-deficient mice reversed pulmonary immune hyporesponsiveness and prevented pneumonia after stroke. In vivo and ex vivo studies on the role of α7 nicotinic acetylcholine receptor on different lung cells using bone marrow chimeric mice and isolated primary cells indicated that not only macrophages but also alveolar epithelial cells are a major cellular target of cholinergic anti-inflammatory signaling in the lung.

Conclusions: Thus, cholinergic pathways play a pivotal role in the development of pulmonary infections after acute central nervous system injury.
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http://dx.doi.org/10.1161/STROKEAHA.115.008989DOI Listing
November 2015

Blocking stroke-induced immunodeficiency increases CNS antigen-specific autoreactivity but does not worsen functional outcome after experimental stroke.

J Neurosci 2015 May;35(20):7777-94

Center for Stroke Research, Department for Experimental Neurology, Department of Neurology, NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, 10098 Berlin, Germany,

Stroke-induced immunodepression (SIDS) is an essential cause of poststroke infections. Pharmacological inhibition of SIDS appears promising in preventing life-threatening infections in stroke patients. However, SIDS might represent an adaptive mechanism preventing autoreactive immune responses after stroke. To address this, we used myelin oligodendrocyte glycoprotein (MOG) T-cell receptor transgenic (2D2) mice where >80% of peripheral CD4(+) T cells express a functional receptor for MOG. We investigated in a murine model of middle cerebral artery occlusion the effect of blocking SIDS by inhibiting body's main stress axes, the sympathetic nervous system (SNS) with propranolol and the hypothalamic-pituitary-adrenal axis (HPA) with mifepristone. Blockade of both stress axes robustly reduced infarct volumes, decreased infection rate, and increased long-term survival of 2D2 and C57BL/6J wild-type mice. Despite these protective effects, blockade of SIDS increased CNS antigen-specific Type1 T helper cell (Th1) responses in the brains of 2D2 mice 14 d after middle cerebral artery occlusion. One month after experimental stroke, 2D2 mice developed signs of polyradiculitis, which were diminished by SIDS blockade. Adoptive transfer of CD4(+) T cells, isolated from 2D2 mice, into lymphocyte-deficient Rag-1KO mice did not reveal differences between SIDS blockade and vehicle treatment in functional long-term outcome after stroke. In conclusion, inhibiting SIDS by pharmacological blockade of body's stress axes increases autoreactive CNS antigen-specific T-cell responses in the brain but does not worsen functional long-term outcome after experimental stroke, even in a mouse model where CNS antigen-specific autoreactive T-cell responses are boosted.
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http://dx.doi.org/10.1523/JNEUROSCI.1532-14.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795191PMC
May 2015

Intrathecal heat shock protein 60 mediates neurodegeneration and demyelination in the CNS through a TLR4- and MyD88-dependent pathway.

Mol Neurodegener 2015 Feb 26;10. Epub 2015 Feb 26.

Department of Neurology, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.

Background: Toll-like receptors (TLR) constitute a highly conserved class of receptors through which the innate immune system responds to both pathogen- and host-derived factors. Although TLRs are involved in a wide range of central nervous system (CNS) disorders including neurodegenerative diseases, the molecular events leading from CNS injury to activation of these innate immune receptors remain elusive. The stress protein heat shock protein 60 (HSP60) released from injured cells is considered an endogenous danger signal of the immune system. In this context, the main objective of the present study was to investigate the impact of extracellular HSP60 on the brain in vivo.

Results: We show here that HSP60 injected intrathecally causes neuronal and oligodendrocyte injury in the CNS in vivo through TLR4-dependent signaling. Intrathecal HSP60 results in neuronal cell death, axonal injury, loss of oligodendrocytes, and demyelination in the cerebral cortex of wild-type mice. In contrast both mice lacking TLR4 and the TLR adaptor molecule MyD88 are protected against deleterious effects induced by HSP60. In contrast to the exogenous TLR4 ligand, lipopolysaccharide, intrathecal HSP60 does not induce such a considerable inflammatory response in the brain. In the CNS, endogenous HSP60 is predominantly expressed in neurons and released during brain injury, since the cerebrospinal fluid (CSF) from animals of a mouse stroke model contains elevated levels of this stress protein compared to the CSF of sham-operated mice.

Conclusions: Our data show a direct toxic effect of HSP60 towards neurons and oligodendrocytes in the CNS. The fact that these harmful effects involve TLR4 and MyD88 confirms a molecular pathway mediated by the release of endogenous TLR ligands from injured CNS cells common to many forms of brain diseases that bi-directionally links CNS injury and activation of the innate immune system to neurodegeneration and demyelination in vivo.
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http://dx.doi.org/10.1186/s13024-015-0003-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365525PMC
February 2015

Catabolic signaling and muscle wasting after acute ischemic stroke in mice: indication for a stroke-specific sarcopenia.

Stroke 2014 Dec 28;45(12):3675-83. Epub 2014 Oct 28.

From the Department of Innovative Clinical Trials, University Medical Centre, Göttingen, Germany (J.S., S.v.H., S.D.A.); Centre for Stroke Research Berlin (S.S., K.P., A.R., N.S., U.D., W.D.), Applied Cachexia Research, Department of Cardiology, Virchow-Klinikum (A.T., S.v.H., S.D.A.), Departments of Neurology and Experimental Neurology (A.R., O.E., A.M., U.D.), NeuroCure Clinical Research Center (A.M.), and Experimental and Clinical Research Center (M.B.), Charité-Universitätsmedizin Berlin, Berlin, Germany; and German Center for Cardiovascular Diseases (DZHK), Partner Site, Berlin, Germany (U.D., W.D.).

Background And Purpose: Muscle wasting is a common complication accompanying stroke. Although it is known to impair poststroke recovery, the mechanisms of subacute catabolism after stroke have not been investigated in detail. The aim of this study is to investigate mechanisms of local and systemic catabolism and muscle wasting (sarcopenia) in a model of ischemic stroke systematically.

Methods: Changes in body composition and catabolic activation in muscle tissue were studied in a mouse model of acute cerebral ischemia (temporal occlusion of the middle cerebral artery). Tissue wasting (nuclear magnetic resonance spectroscopy), tissue catabolism (caspases-3 and -6, myostatin), and proteasome activity were assessed. Food intake, activity levels, and energy expenditure were assessed, and putative mechanisms of postischemic wasting were tested with appropriate interventions.

Results: Severe weight loss in stroke animals (day 3: weight loss, -21.7%) encompassed wasting of muscle (-12%; skeletal and myocardium) and fat tissue (-27%). Catabolic signaling and proteasome activity were higher in stroke animals in the contralateral and in the ipsilateral leg. Cerebral infarct severity correlated with catabolic activity only in the contralateral leg but not in the ipsilateral leg. Lower energy expenditure in stroke animals together with normal food intake and activity levels suggests compensatory mechanisms to regain weight. Interventions (high caloric feeding, β-receptor blockade, and antibiotic treatment) failed to prevent proteolytic activation and muscle wasting.

Conclusions: Catabolic pathways of muscle tissue are activated after stroke. Impaired feeding, sympathetic overactivation, or infection cannot fully explain this catabolic activation. Wasting of the target muscle of the disrupted innervation correlated to severity of brain injury. Our data indicate the presence of a stroke-specific sarcopenia.
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http://dx.doi.org/10.1161/STROKEAHA.114.006258DOI Listing
December 2014

Miniaturized bronchoscopy enables unilateral investigation, application, and sampling in mice.

Am J Respir Cell Mol Biol 2014 Dec;51(6):730-7

1 Institute of Medical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Lung diseases, including pneumonia and asthma, are among the most prevalent human disorders, and murine models have been established to investigate their pathobiology and develop novel treatment approaches. Whereas bronchoscopy is valuable for diagnostic and therapeutic procedures in patients, no equivalent for small rodents has been established. Here, we introduce a miniaturized video-bronchoscopy system offering new opportunities in experimental lung research. With an outer diameter of 0.75 mm, it is possible to advance the optics into the main bronchi of mice. An irrigation channel allows bronchoalveolar lavage and unilateral application of substances to one lung. Even a unilateral infection is possible, enabling researchers to use the contralateral lung as internal control.
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http://dx.doi.org/10.1165/rcmb.2014-0052MADOI Listing
December 2014

Superiority of preventive antibiotic treatment compared with standard treatment of poststroke pneumonia in experimental stroke: a bed to bench approach.

J Cereb Blood Flow Metab 2013 Jun 30;33(6):846-54. Epub 2013 Jan 30.

Center for Stroke Research, Charité Universitaetsmedizin Berlin, Berlin, Germany.

Stroke patients are prone to life-threatening bacterial pneumonia. Previous experimental stroke studies have demonstrated that preventive antibiotic treatment (PAT) improves outcome compared with placebo treatment, which however does not model the clinical setting properly. Here we investigate whether PAT is superior to the current clinical 'gold standard' for treating poststroke infections. Therefore, we modeled stroke care according to the current stroke guidelines recommending early antibiotic treatment after diagnosing infections. To reliably diagnose pneumonia in living mice, we established a general health score and a magnetic resonance imaging protocol for radiologic confirmation. Compared with standard treatment after diagnosis by these methods, PAT not only abolished pneumonia successfully but also improved general medical outcome. Both, preventive and standard antibiotic treatment using enrofloxacin improved survival in a similar way compared with placebo treatment. However, in contrast to standard treatment, only PAT improved functional outcome assessed by gait analysis. In conclusion, standard and preventive treatment approach reduced poststroke mortality, however at the cost of a worse neurologic outcome compared with preventive approach. These data support the concept of PAT for treating patients at risk for poststroke infections and warrant phase III trials to prove this concept in clinical setting.
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http://dx.doi.org/10.1038/jcbfm.2013.6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677122PMC
June 2013

Early loss of pericytes and perivascular stromal cell-induced scar formation after stroke.

J Cereb Blood Flow Metab 2013 Mar 19;33(3):428-39. Epub 2012 Dec 19.

Laboratory of Molecular Psychiatry, Department of Neuropsychiatry, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Despite its limited regenerative capacity, the central nervous system (CNS) shares more repair mechanisms with peripheral tissues than previously recognized. Scar formation is a ubiquitous healing mechanism aimed at patching tissue defects via the generation of fibrous extracellular matrix (ECM). This process, orchestrated by stromal cells, can unfavorably affect the capacity of tissues to restore function. Vascular mural cells have been found to contribute to scarring after spinal cord injury. In the case of stroke, little is known about the responses of pericytes (PCs) and stromal cells. Here, we show that capillary PCs are rapidly lost after cerebral ischemia in both experimental and human stroke. Coincident with this loss is a massive proliferation of resident platelet-derived growth factor receptor beta (PDGFRβ)(+) and CD105(+) stromal cells, which originate from the neurovascular unit and deposit ECM in the ischemic mouse brain. The presence of PDGFRβ(+) stromal cells demarcates a fibrotic, contracted, and macrophage-laden lesion core from the rim of hypertrophic astroglia in both experimental and human stroke. We suggest that a previously unrecognized population of CNS-resident stromal cells drives a dynamic process of scarring after cerebral ischemia, which appears distinct from the glial scar and represents a novel target for regenerative stroke therapies.
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http://dx.doi.org/10.1038/jcbfm.2012.187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587816PMC
March 2013

Regulatory T cells accumulate and proliferate in the ischemic hemisphere for up to 30 days after MCAO.

J Cereb Blood Flow Metab 2013 Jan 12;33(1):37-47. Epub 2012 Sep 12.

Center for Anatomy, Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Local and peripheral immune responses are activated after ischemic stroke. In our present study, we investigated the temporal distribution, location, induction, and function of regulatory T cells (Tregs) and the possible involvement of microglia, macrophages, and dendritic cells after middle cerebral artery occlusion (MCAO). C57BL/6J and Foxp3(EGFP) transgenic mice were subjected to 30 minutes MCAO. On days 7, 14, and 30 after MCAO, Tregs and antigen presenting cells were analyzed using fluorescence activated cell sorting multicolor staining and immunohistochemistry. A strong accumulation of Tregs was observed on days 14 and 30 in the ischemic hemisphere accompanied by the elevated presence and activation of microglia. Dendritic cells and macrophages were found on each analyzed day. About 60% of Foxp3(+) Tregs in ischemic hemispheres were positive for the proliferation marker Ki-67 on days 7 and 14 after MCAO. The transfer of naive CD4(+) cells depleted of Foxp3(+) Tregs into RAG1(-/-) mice 1 day before MCAO did not lead to a de novo generation of Tregs 14 days after surgery. After depletion of CD25(+) Tregs, no changes regarding neurologic outcome were detected. The sustained presence of Tregs in the brain after MCAO indicates a long-lasting immunological alteration and involvement of brain cells in immunoregulatory mechanisms.
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http://dx.doi.org/10.1038/jcbfm.2012.128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597367PMC
January 2013

Gait analysis as a method for assessing neurological outcome in a mouse model of stroke.

J Neurosci Methods 2012 Apr 10;206(1):7-14. Epub 2012 Feb 10.

Center of Stroke Research Berlin, Neurocure Clinical Research Center, Department for Experimental Neurology, Charité Universitaetsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.

Ameliorating stroke induced neurological deficits is one of the most important goals of stroke therapy. In order to improve stroke outcome, novel treatment approaches as well as animal stroke models predictive for the clinical setting are of urgent need. One of the main obstacles in experimental stroke research is measuring long-term outcome, in particular in mouse models of stroke. On the other hand, assessing functional deficits in animal models of stroke is critical to improve the prediction of preclinical findings. Automated gait analysis provides a sensitive tool to examine locomotion and limb coordination in small rodents. Comparing mice before and 10 days after experimental stroke (60 min MCAo) we observed a significant decrease in maximum contact area, stride length and swing speed in the hind limbs, especially the contralateral one. Mice showed a disturbed interlimb coordination represented by changes in regularity index and phase dispersion. To assess whether gait analysis is applicable to assess improvements by neuroprotective compounds, we applied a model calculation and approached common statistical problems. In conclusion, gait analysis is a promising tool to assess mid- to long-term outcome in experimental stroke research.
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http://dx.doi.org/10.1016/j.jneumeth.2012.02.001DOI Listing
April 2012

Modeling stroke in mice - middle cerebral artery occlusion with the filament model.

J Vis Exp 2011 Jan 6(47). Epub 2011 Jan 6.

Department for Experimental Neurology, Center for Stroke Research Berlin, Charité Universitätsmedizin.

Stroke is among the most frequent causes of death and adult disability, especially in highly developed countries. However, treatment options to date are very limited. To meet the need for novel therapeutic approaches, experimental stroke research frequently employs rodent models of focal cerebral ischaemia. Most researchers use permanent or transient occlusion of the middle cerebral artery (MCA) in mice or rats. Proximal occlusion of the middle cerebral artery (MCA) via the intraluminal suture technique (so called filament or suture model) is probably the most frequently used model in experimental stroke research. The intraluminal MCAO model offers the advantage of inducing reproducible transient or permanent ischaemia of the MCA territory in a relatively non-invasive manner. Intraluminal approaches interrupt the blood flow of the entire territory of this artery. Filament occlusion thus arrests flow proximal to the lenticulo-striate arteries, which supply the basal ganglia. Filament occlusion of the MCA results in reproducible lesions in the cortex and striatum and can be either permanent or transient. In contrast, models inducing distal (to the branching of the lenticulo-striate arteries) MCA occlusion typically spare the striatum and primarily involve the neocortex. In addition these models do require craniectomy. In the model demonstrated in this article, a silicon coated filament is introduced into the common carotid artery and advanced along the internal carotid artery into the Circle of Willis, where it blocks the origin of the middle cerebral artery. In patients, occlusions of the middle cerebral artery are among the most common causes of ischaemic stroke. Since varying ischemic intervals can be chosen freely in this model depending on the time point of reperfusion, ischaemic lesions with varying degrees of severity can be produced. Reperfusion by removal of the occluding filament at least partially models the restoration of blood flow after spontaneous or therapeutic (tPA) lysis of a thromboembolic clot in humans. In this video we will present the basic technique as well as the major pitfalls and confounders which may limit the predictive value of this model.
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http://dx.doi.org/10.3791/2423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182649PMC
January 2011

Models of infection before and after stroke: investigating new targets.

Infect Disord Drug Targets 2010 Apr;10(2):98-104

Department for Experimental Neurology, Charité Berlin, Germany.

Infectious diseases are the most common medical complication after cerebral ischemia, inpairing both the neurological and the general medical outcome. The most frequent infectious complications are bacterial pneumonia and urinary tract infections. There is a growing body of evidence that a secondary immunosuppressive state accounts for the increased risk of infection following stroke. Infections do not only have an important impact on outcome after stroke but also are known risk factors for stroke. Thus, suitable models for investigating the relation between infections and stroke are urgently needed. Elucidating the underlying mechanisms might facilitate the development of new therapeutic strategies and improve patient outcome. Here we present recent insights into the relationship between infections and stroke, based on experimental models of post-stroke infection. In addition we give a brief overview of models that explore the impact on stroke of preceding infections.
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http://dx.doi.org/10.2174/187152610790963546DOI Listing
April 2010
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