@article{BoltzeKleinschnitzReymannetal.2012, author = {Boltze, Johannes and Kleinschnitz, Christoph and Reymann, Klaus G. and Reiser, Georg and Wagner, Daniel-Christoph and Kranz, Alexander and Michalski, Dominik}, title = {Neurovascular pathophysiology in cerebral ischemia, dementia and the ageing brain - current trends in basic, translational and clinical research}, series = {Experimental \& Translational Stroke Medicine}, volume = {4}, journal = {Experimental \& Translational Stroke Medicine}, number = {14}, doi = {doi:10.1186/2040-7378-4-14}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126679}, year = {2012}, abstract = {The 7th International Symposium on Neuroprotection and Neurorepair was held from May 2nd to May 5th, 2012 in Potsdam, Germany. The symposium, which directly continues the successful Magdeburg meeting series, attracted over 330 colleagues from 29 countries to discuss recent findings and advances in the field. The focus of the 2012 symposium was widened from stroke and traumatic brain injury to neurodegenerative diseases, notably dementia, and more generally the ageing brain. Thereby, emphasis was given on neurovascular aspects of neurodegeneration and stroke including the blood-brain barrier, recent findings regarding the pathomechanism of Alzheimer's disease, and brain imaging approaches. In addition, neurobiochemical aspects of neuroprotection, the role of astrogliosis, the clinical progress of cell-based approaches as well as translational hurdles and opportunities were discussed in-depth. This review summarizes some of the most stimulating discussions and reports from the meeting.}, language = {en} } @article{KraftDeMeyerKleinschnitz2012, author = {Kraft, Peter and De Meyer, Simon F. and Kleinschnitz, Christoph}, title = {Next-Generation Antithrombotics in Ischemic Stroke: Preclinical Perspective on 'Bleeding-Free Antithrombosis'}, series = {Journal of Cerebral Blood Flow and Metabolism}, volume = {32}, journal = {Journal of Cerebral Blood Flow and Metabolism}, number = {10}, doi = {10.1038/jcbfm.2012.108}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126538}, pages = {1831-1840}, year = {2012}, abstract = {The present antithrombotic drugs used to treat or prevent ischemic stroke have significant limitations: either they show only moderate efficacy (platelet inhibitors), or they significantly increase the risk for hemorrhages (thrombolytics, anticoagulants). Although most strokes are caused by thrombotic or embolic vessel occlusions, the pathophysiological role of platelets and coagulation is largely unclear. The introduction of novel transgenic mouse models and specific coagulation inhibitors facilitated a detailed analysis of molecular pathways mediating thrombus formation in models of acute ischemic stroke. Prevention of early platelet adhesion to the damaged vessel wall by blocking platelet surface receptors glycoprotein Ib alpha (GPIbα) or glycoprotein VI (GPVI) protects from stroke without provoking bleeding complications. In addition, downstream signaling of GPIbα and GPVI has a key role in platelet calcium homeostasis and activation. Finally, the intrinsic coagulation cascade, activated by coagulation factor XII (FXII), has only recently been identified as another important mediator of thrombosis in cerebrovascular disease, thereby disproving established concepts. This review summarizes the latest insights into the pathophysiology of thrombus formation in the ischemic brain. Potential clinical merits of novel platelet inhibitors and anticoagulants as powerful and safe tools to combat ischemic stroke are discussed.}, language = {en} } @article{RadermacherWinglerKleikersetal.2012, author = {Radermacher, Kim A. and Wingler, Kirstin and Kleikers, Pamela and Altenh{\"o}fer, Sebastian and Hermans, Johannes J. R. and Kleinschnitz, Christoph and Schmidt, Harald H. H. W.}, title = {The 1027th target candidate in stroke: Will NADPH oxidase hold up?}, series = {Experimental and Translational Stroke Medicine}, volume = {4}, journal = {Experimental and Translational Stroke Medicine}, number = {11}, doi = {10.1186/2040-7378-4-11}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124197}, year = {2012}, abstract = {As recently reviewed, 1026 neuroprotective drug candidates in stroke research have all failed on their road towards validation and clinical translation, reasons being quality issues in preclinical research and publication bias. Quality control guidelines for preclinical stroke studies have now been established. However, sufficient understanding of the underlying mechanisms of neuronal death after stroke that could be possibly translated into new therapies is lacking. One exception is the hypothesis that cellular death is mediated by oxidative stress. Oxidative stress is defined as an excess of reactive oxygen species (ROS) derived from different possible enzymatic sources. Among these, NADPH oxidases (NOX1-5) stand out as they represent the only known enzyme family that has no other function than to produce ROS. Based on data from different NOX knockout mouse models in ischemic stroke, the most relevant isoform appears to be NOX4. Here we discuss the state-of-the-art of this target with respect to stroke and open questions that need to be addressed on the path towards clinical translation.}, language = {en} } @article{AlbertWeissenbergerStetterMeuthetal.2012, author = {Albert-Weissenberger, Christiane and Stetter, Christian and Meuth, Sven G. and G{\"o}bel, Kerstin and Bader, Michael and Sir{\´e}n, Anna-Leena and Kleinschnitz, Christoph}, title = {Blocking of Bradykinin Receptor B1 Protects from Focal Closed Head Injury in Mice by Reducing Axonal Damage and Astroglia Activation}, series = {Journal of Cerebral Blood Flow and Metabolism}, volume = {32}, journal = {Journal of Cerebral Blood Flow and Metabolism}, number = {9}, doi = {10.1038/jcbfm.2012.62}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125903}, pages = {1747-1756}, year = {2012}, abstract = {The two bradykinin receptors B1R and B2R are central components of the kallikrein-kinin system with different expression kinetics and binding characteristics. Activation of these receptors by kinins triggers inflammatory responses in the target organ and in most situations enhances tissue damage. We could recently show that blocking of B1R, but not B2R, protects from cortical cryolesion by reducing inflammation and edema formation. In the present study, we investigated the role of B1R and B2R in a closed head model of focal traumatic brain injury (TBI; weight drop). Increased expression of B1R in the injured hemispheres of wild-type mice was restricted to the later stages after brain trauma, i.e. day 7 (P<0.05), whereas no significant induction could be observed for the B2R (P>0.05). Mice lacking the B1R, but not the B2R, showed less functional deficits on day 3 (P<0.001) and day 7 (P<0.001) compared with controls. Pharmacological blocking of B1R in wild-type mice had similar effects. Reduced axonal injury and astroglia activation could be identified as underlying mechanisms, while inhibition of B1R had only little influence on the local inflammatory response in this model. Inhibition of B1R may become a novel strategy to counteract trauma-induced neurodegeneration.}, language = {en} } @article{MinnerupSutherlandBuchanetal.2012, author = {Minnerup, Jens and Sutherland, Brad A. and Buchan, Alastair M. and Kleinschnitz, Christoph}, title = {Neuroprotection for Stroke: Current Status and Future Perspectives}, series = {International Journal of Molecular Science}, volume = {13}, journal = {International Journal of Molecular Science}, number = {9}, doi = {10.3390/ijms130911753}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134730}, pages = {11753-11772}, year = {2012}, abstract = {Neuroprotection aims to prevent salvageable neurons from dying. Despite showing efficacy in experimental stroke studies, the concept of neuroprotection has failed in clinical trials. Reasons for the translational difficulties include a lack of methodological agreement between preclinical and clinical studies and the heterogeneity of stroke in humans compared to homogeneous strokes in animal models. Even when the international recommendations for preclinical stroke research, the Stroke Academic Industry Roundtable (STAIR) criteria, were followed, we have still seen limited success in the clinic, examples being NXY-059 and haematopoietic growth factors which fulfilled nearly all the STAIR criteria. However, there are a number of neuroprotective treatments under investigation in clinical trials such as hypothermia and ebselen. Moreover, promising neuroprotective treatments based on a deeper understanding of the complex pathophysiology of ischemic stroke such as inhibitors of NADPH oxidases and PSD-95 are currently evaluated in preclinical studies. Further concepts to improve translation include the investigation of neuroprotectants in multicenter preclinical Phase III-type studies, improved animal models, and close alignment between clinical trial and preclinical methodologies. Future successful translation will require both new concepts for preclinical testing and innovative approaches based on mechanistic insights into the ischemic cascade.}, language = {en} } @article{JariusRuprechtWildemannetal.2012, author = {Jarius, Sven and Ruprecht, Klemens and Wildemann, Brigitte and Kuempfel, Tania and Ringelstein, Marius and Geis, Christian and Kleiter, Ingo and Kleinschnitz, Christoph and Berthele, Achim and Brettschneider, Johannes and Hellwig, Kerstin and Hemmer, Bernhard and Linker, Ralf A. and Lauda, Florian and Hayrettin, Christoph A. and Tumani, Hayrettin and Melms, Arthur and Trebst, Corinna and Stangel, Martin and Marziniak, Martin and Hoffmann, Frank and Schippling, Sven and Faiss, J{\"u}rgen H. and Neuhaus, Oliver and Ettrich, Barbara and Zentner, Christian and Guthke, Kersten and Hofstadt-van Oy, Ulrich and Reuss, Reinhard and Pellkofer, Hannah and Ziemann, Ulf and Kern, Peter and Wandinger, Klaus P. and Bergh, Florian Then and Boettcher, Tobias and Langel, Stefan and Liebetrau, Martin and Rommer, Paulus S. and Niehaus, Sabine and M{\"u}nch, Christoph and Winkelmann, Alexander and Zettl, Uwe K and Metz, Imke and Veauthier, Christian and Sieb, J{\"o}rn P. and Wilke, Christian and Hartung, Hans P. and Aktas, Orhan and Paul, Friedemann}, title = {Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: A multicentre study of 175 patients}, series = {Journal of Neuroinflammation}, volume = {9}, journal = {Journal of Neuroinflammation}, number = {14}, doi = {10.1186/1742-2094-9-14}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133636}, year = {2012}, abstract = {Background: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. Objective: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. Methods: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3\%). Results: Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of <= 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades <= 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions >= 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome.}, language = {en} } @techreport{LinkerMeuthMagnusetal.2012, author = {Linker, Ralf, A. and Meuth, Sven G. and Magnus, Tim and Korn, Thomas and Kleinschnitz, Christoph}, title = {Report on the 4'th scientific meeting of the "Verein zur F{\"o}rderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Nov. 2'nd - Nov. 4'th, 2012 [meeting report]}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76407}, year = {2012}, abstract = {From November 2nd - 4th 2012, the 4th NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. Again more than 60 participants, predominantly at the doctoral student or postdoc level, gathered to share their latest findings in the fields of neurovascular research, neurodegeneration and neuroinflammation. Like in the previous years, the symposium provided an excellent platform for scientific exchange and the presentation of innovative projects in the stimulating surroundings of the Brandenburg outback. This year's keynote lecture on the pathophysiological relevance of neuronal networks was given by Christian Gerloff, Head of the Department of Neurology at the University Clinic of Hamburg-Eppendorf. Another highlight of the meeting was the awarding of the NEUROWIND e.V. prize for young scientists working in the field of experimental neurology. The award is donated by the Merck Serono GmbH, Darmstadt, Germany and is endowed with 20.000 Euro. This year the jury decided unanimously to adjudge the award to Michael Gliem from the Department of Neurology at the University Clinic of D{\"u}sseldorf (group of Sebastian Jander), Germany, for his outstanding work on different macrophage subsets in the pathogenesis of ischemic stroke published in the Annals of Neurology in 2012.}, subject = {Medizin}, language = {en} } @article{AlbertWeissenbergerVarrallyayRaslanetal.2012, author = {Albert-Weißenberger, Christiane and V{\´a}rrallyay, Csan{\´a}d and Raslan, Furat and Kleinschnitz, Christoph and Sir{\´e}n, Anna-Leena}, title = {An experimental protocol for mimicking pathomechanisms of traumatic brain injury in mice}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75368}, year = {2012}, abstract = {Traumatic brain injury (TBI) is a result of an outside force causing immediate mechanical disruption of brain tissue and delayed pathogenic events. In order to examine injury processes associated with TBI, a number of rodent models to induce brain trauma have been described. However, none of these models covers the entire spectrum of events that might occur in TBI. Here we provide a thorough methodological description of a straightforward closed head weight drop mouse model to assess brain injuries close to the clinical conditions of human TBI.}, subject = {Medizin}, language = {en} } @article{RaslanAlbertWeissenbergerErnestusetal.2012, author = {Raslan, Furat and Albert-Weißenberger, Christiane and Ernestus, Ralf-Ingo and Kleinschnitz, Christoph and Sir{\´e}n, Anna-Leena}, title = {Focal brain trauma in the cryogenic lesion model in mice}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75419}, year = {2012}, abstract = {The method to induce unilateral cryogenic lesions was first described in 1958 by Klatzo. We describe here an adaptation of this model that allows reliable measurement of lesion volume and vasogenic edema by 2, 3, 5-triphenyltetrazolium chloride-staining and Evans blue extravasation in mice. A copper or aluminium cylinder with a tip diameter of 2.5 mm is cooled with liquid nitrogen and placed on the exposed skull bone over the parietal cortex (coordinates from bregma: 1.5 mm posterior, 1.5 mm lateral). The tip diameter and the contact time between the tip and the parietal skull determine the extent of cryolesion. Due to an early damage of the blood brain barrier, the cryogenic cortical injury is characterized by vasogenic edema, marked brain swelling, and inflammation. The lesion grows during the first 24 hours, a process involving complex interactions between endothelial cells, immune cells, cerebral blood flow, and the intracranial pressure. These contribute substantially to the damage from the initial injury. The major advantage of the cryogenic lesion model is the circumscribed and highly reproducible lesion size and location.}, subject = {Medizin}, language = {en} }