@article{SimonIpekHomolaetal.2018, author = {Simon, Micha and Ipek, Rojda and Homola, Gy{\"o}rgy A. and Rovituso, Damiano M. and Schampel, Andrea and Kleinschnitz, Christoph and Kuerten, Stefanie}, title = {Anti-CD52 antibody treatment depletes B cell aggregates in the central nervous system in a mouse model of multiple sclerosis}, series = {Journal of Neuroinflammation}, volume = {15}, journal = {Journal of Neuroinflammation}, number = {225}, doi = {10.1186/s12974-018-1263-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176120}, year = {2018}, abstract = {Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) for which several new treatment options were recently introduced. Among them is the monoclonal anti-CD52 antibody alemtuzumab that depletes mainly B cells and T cells in the immune periphery. Considering the ongoing controversy about the involvement of B cells and in particular the formation of B cell aggregates in the brains of progressive MS patients, an in-depth understanding of the effects of anti-CD52 antibody treatment on the B cell compartment in the CNS itself is desirable. Methods: We used myelin basic protein (MBP)-proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 (B6) mice as B cell-dependent model of MS. Mice were treated intraperitoneally either at the peak of EAE or at 60 days after onset with 200 μg murine anti-CD52 vs. IgG2a isotype control antibody for five consecutive days. Disease was subsequently monitored for 10 days. The antigen-specific B cell/antibody response was measured by ELISPOT and ELISA. Effects on CNS infiltration and B cell aggregation were determined by immunohistochemistry. Neurodegeneration was evaluated by Luxol Fast Blue, SMI-32, and Olig2/APC staining as well as by electron microscopy and phosphorylated heavy neurofilament serum ELISA. Results: Treatment with anti-CD52 antibody attenuated EAE only when administered at the peak of disease. While there was no effect on the production of MP4-specific IgG, the treatment almost completely depleted CNS infiltrates and B cell aggregates even when given as late as 60 days after onset. On the ultrastructural level, we observed significantly less axonal damage in the spinal cord and cerebellum in chronic EAE after anti-CD52 treatment. Conclusion: Anti-CD52 treatment abrogated B cell infiltration and disrupted existing B cell aggregates in the CNS.}, language = {en} } @article{FluriSchuhmannKleinschnitz2015, author = {Fluri, Felix and Schuhmann, Michael K and Kleinschnitz, Christoph}, title = {Animal models of ischemic stroke and their application in clinical research}, series = {Drug Design, Development and Therapy}, volume = {9}, journal = {Drug Design, Development and Therapy}, doi = {10.2147/DDDT.S56071}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149157}, pages = {3445-3454}, year = {2015}, abstract = {This review outlines the most frequently used rodent stroke models and discusses their strengths and shortcomings. Mimicking all aspects of human stroke in one animal model is not feasible because ischemic stroke in humans is a heterogeneous disorder with a complex pathophysiology. The transient or permanent middle cerebral artery occlusion (MCAo) model is one of the models that most closely simulate human ischemic stroke. Furthermore, this model is characterized by reliable and well-reproducible infarcts. Therefore, the MCAo model has been involved in the majority of studies that address pathophysiological processes or neuroprotective agents. Another model uses thromboembolic clots and thus is more convenient for investigating thrombolytic agents and pathophysiological processes after thrombolysis. However, for many reasons, preclinical stroke research has a low translational success rate. One factor might be the choice of stroke model. Whereas the therapeutic responsiveness of permanent focal stroke in humans declines significantly within 3 hours after stroke onset, the therapeutic window in animal models with prompt reperfusion is up to 12 hours, resulting in a much longer action time of the investigated agent. Another major problem of animal stroke models is that studies are mostly conducted in young animals without any comorbidity. These models differ from human stroke, which particularly affects elderly people who have various cerebrovascular risk factors. Choosing the most appropriate stroke model and optimizing the study design of preclinical trials might increase the translational potential of animal stroke models.}, 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{StetterLopezCaperuchipiHoppKraemeretal.2021, author = {Stetter, Christian and Lopez-Caperuchipi, Simon and Hopp-Kr{\"a}mer, Sarah and Bieber, Michael and Kleinschnitz, Christoph and Sir{\´e}n, Anna-Leena and Albert-Weißenberger, Christiane}, title = {Amelioration of cognitive and behavioral deficits after traumatic brain injury in coagulation factor XII deficient mice}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {9}, issn = {1422-0067}, doi = {10.3390/ijms22094855}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284959}, year = {2021}, abstract = {Based on recent findings that show that depletion of factor XII (FXII) leads to better posttraumatic neurological recovery, we studied the effect of FXII-deficiency on post-traumatic cognitive and behavioral outcomes in female and male mice. In agreement with our previous findings, neurological deficits on day 7 after weight-drop traumatic brain injury (TBI) were significantly reduced in FXII\(^{-/-}\) mice compared to wild type (WT) mice. Also, glycoprotein Ib (GPIb)-positive platelet aggregates were more frequent in brain microvasculature of WT than FXII\(^{-/-}\) mice 3 months after TBI. Six weeks after TBI, memory for novel object was significantly reduced in both female and male WT but not in FXII\(^{-/-}\) mice compared to sham-operated mice. In the setting of automated home-cage monitoring of socially housed mice in IntelliCages, female WT mice but not FXII\(^{-/-}\) mice showed decreased exploration and reacted negatively to reward extinction one month after TBI. Since neuroendocrine stress after TBI might contribute to trauma-induced cognitive dysfunction and negative emotional contrast reactions, we measured peripheral corticosterone levels and the ration of heart, lung, and spleen weight to bodyweight. Three months after TBI, plasma corticosterone levels were significantly suppressed in both female and male WT but not in FXII\(^{-/-}\) mice, while the relative heart weight increased in males but not in females of both phenotypes when compared to sham-operated mice. Our results indicate that FXII deficiency is associated with efficient post-traumatic behavioral and neuroendocrine recovery.}, language = {en} } @article{HoppNolteStetteretal.2017, author = {Hopp, Sarah and Nolte, Marc W. and Stetter, Christian and Kleinschnitz, Christoph and Sir{\´e}n, Anna-Leena and Albert-Weissenberger, Christiane}, title = {Alleviation of secondary brain injury, posttraumatic inflammation, and brain edema formation by inhibition of factor XIIa}, series = {Journal of Neuroinflammation}, volume = {14}, journal = {Journal of Neuroinflammation}, number = {39}, doi = {10.1186/s12974-017-0815-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157490}, year = {2017}, abstract = {Background: Traumatic brain injury (TBI) is a devastating neurological condition and a frequent cause of permanent disability. Posttraumatic inflammation and brain edema formation, two pathological key events contributing to secondary brain injury, are mediated by the contact-kinin system. Activation of this pathway in the plasma is triggered by activated factor XII. Hence, we set out to study in detail the influence of activated factor XII on the abovementioned pathophysiological features of TBI. Methods: Using a cortical cryogenic lesion model in mice, we investigated the impact of genetic deficiency of factor XII and inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused Infestin-4 on the release of bradykinin, the brain lesion size, and contact-kinin system-dependent pathological events. We determined protein levels of bradykinin, intracellular adhesion molecule-1, CC-chemokine ligand 2, and interleukin-1β by enzyme-linked immunosorbent assays and mRNA levels of genes related to inflammation by quantitative real-time PCR. Brain lesion size was determined by tetrazolium chloride staining. Furthermore, protein levels of the tight junction protein occludin, integrity of the blood-brain barrier, and brain water content were assessed by Western blot analysis, extravasated Evans Blue dye, and the wet weight-dry weight method, respectively. Infiltration of neutrophils and microglia/activated macrophages into the injured brain lesions was quantified by immunohistological stainings. Results: We show that both genetic deficiency of factor XII and inhibition of activated factor XII in mice diminish brain injury-induced bradykinin release by the contact-kinin system and minimize brain lesion size, blood-brain barrier leakage, brain edema formation, and inflammation in our brain injury model. Conclusions: Stimulation of bradykinin release by activated factor XII probably plays a prominent role in expanding secondary brain damage by promoting brain edema formation and inflammation. Pharmacological blocking of activated factor XII could be a useful therapeutic principle in the treatment of TBI-associated pathologic processes by alleviating posttraumatic inflammation and brain edema formation.}, language = {en} } @article{LugerHohmannNiemannetal.2015, author = {Luger, Sebastian and Hohmann, Carina and Niemann, Daniela and Kraft, Peter and Gunreben, Ignaz and Neumann-Haefelin, Tobias and Kleinschnitz, Christoph and Steinmetz, Helmuth and Foerch, Christian and Pfeilschifter, Waltraud}, title = {Adherence to oral anticoagulant therapy in secondary stroke prevention - impact of the novel oral anticoagulants}, series = {Patient Preference and Adherence}, volume = {9}, journal = {Patient Preference and Adherence}, doi = {10.2147/PPA.S88994}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144477}, pages = {1695-1705}, year = {2015}, abstract = {Background: Oral anticoagulant therapy (OAT) potently prevents strokes in patients with atrial fibrillation. Vitamin K antagonists (VKA) have been the standard of care for long-term OAT for decades, but non-VKA oral anticoagulants (NOAC) have recently been approved for this indication, and raised many questions, among them their influence on medication adherence. We assessed adherence to VKA and NOAC in secondary stroke prevention. Methods: All patients treated from October 2011 to September 2012 for ischemic stroke or transient ischemic attack with a subsequent indication for OAT, at three academic hospitals were entered into a prospective registry, and baseline data and antithrombotic treatment at discharge were recorded. At the 1-year follow-up, we assessed the adherence to different OAT strategies and patients' adherence to their respective OAT. We noted OAT changes, reasons to change treatment, and factors that influence persistence to the prescribed OAT. Results: In patients discharged on OAT, we achieved a fatality corrected response rate of 73.3\% (n=209). A total of 92\% of these patients received OAT at the 1-year follow-up. We observed good adherence to both VKA and NOAC (VKA, 80.9\%; NOAC, 74.8\%; P=0.243) with a statistically nonsignificant tendency toward a weaker adherence to dabigatran. Disability at 1-year follow-up was an independent predictor of lower adherence to any OAT after multivariate analysis, whereas the choice of OAT did not have a relevant influence. Conclusion: One-year adherence to OAT after stroke is strong (>90\%) and patients who switch therapy most commonly switch toward another OAT. The 1-year adherence rates to VKA and NOAC in secondary stroke prevention do not differ significantly between both therapeutic strategies.}, language = {en} } @article{GunrebenGeisKleinschnitz2013, author = {Gunreben, Ignaz and Geis, Christian and Kleinschnitz, Christoph}, title = {Acute tetraparesis secondary to bilateral precentral gyral cerebral ischemia: a case report}, series = {Journal of Medical Case Reports}, journal = {Journal of Medical Case Reports}, doi = {10.1186/1752-1947-7-61}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96179}, year = {2013}, abstract = {Introduction Sudden tetraparesis represents a neurological emergency and is most often caused by traumatic spinal cord injury, spinal epidural bleeding or brainstem ischemia and less frequently by medial disc herniation or spinal ischemia. Case presentation Here we report the rare case of an 82-year-old Caucasian man who developed severe tetraparesis four days after radical cystoprostatectomy. An emergency diagnostic study for spinal cord affection was normal. Brain magnetic resonance imaging revealed acute bilateral ischemic strokes in the precentral gyri as the underlying cause. Conclusions This case report underlines the need to also consider unusual causes of tetraparesis in an emergency situation apart from spinal cord or brain stem injury in order not to leave severe symptomatology unclear and possibly miss therapeutic options.}, language = {en} } @article{FluriFleischerKleinschnitz2015, author = {Fluri, Felix and Fleischer, Michael and Kleinschnitz, Christoph}, title = {Accidental Thrombolysis in a Stroke Patient Receiving Apixaban}, series = {Cerebrovascular Diseases Extra}, volume = {5}, journal = {Cerebrovascular Diseases Extra}, doi = {10.1159/000375181}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126326}, pages = {55-56}, year = {2015}, abstract = {No abstract available.}, language = {en} } @article{KleikersHooijmansGoebetal.2015, author = {Kleikers, Pamela W. M. and Hooijmans, Carlijn and G{\"o}b, Eva and Langhauser, Friederike and Rewell, Sarah S. J. and Radermacher, Kim and Ritskes-Hoitinga, Merel and Howells, David W. and Kleinschnitz, Christoph and Schmidt, Harald H. H. W.}, title = {A combined pre-clinical meta-analysis and randomized confirmatory trial approach to improve data validity for therapeutic target validation}, series = {Scientific Reports}, volume = {5}, journal = {Scientific Reports}, number = {13428}, doi = {10.1038/srep13428}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151401}, year = {2015}, abstract = {Biomedical research suffers from a dramatically poor translational success. For example, in ischemic stroke, a condition with a high medical need, over a thousand experimental drug targets were unsuccessful. Here, we adopt methods from clinical research for a late-stage pre-clinical meta-analysis (MA) and randomized confirmatory trial (pRCT) approach. A profound body of literature suggests NOX\(_{2}\) to be a major therapeutic target in stroke. Systematic review and MA of all available NOX\(_{2}\)\(^{-/y}\) studies revealed a positive publication bias and lack of statistical power to detect a relevant reduction in infarct size. A fully powered multi-center pRCT rejects NOX\(_{2}\) as a target to improve neurofunctional outcomes or achieve a translationally relevant infarct size reduction. Thus stringent statistical thresholds, reporting negative data and a MA-pRCT approach can ensure biomedical data validity and overcome risks of bias.}, language = {en} }