@article{SchanbacherBieberReindersetal.2022,
  author    = {Schanbacher, Constanze and Bieber, Michael and Reinders, Yvonne and Cherpokova, Deya and Teichert, Christina and Nieswandt, Bernhard and Sickmann, Albert and Kleinschnitz, Christoph and Langhauser, Friederike and Lorenz, Kristina},
  title     = {ERK1/2 activity is critical for the outcome of ischemic stroke},
  series = {International Journal of Molecular Sciences},
  volume    = {23},
  journal   = {International Journal of Molecular Sciences},
  number    = {2},
  issn      = {1422-0067},
  doi       = {10.3390/ijms23020706},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-283991},
  year      = {2022},
  abstract  = {Ischemic disorders are the leading cause of death worldwide. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are thought to affect the outcome of ischemic stroke. However, it is under debate whether activation or inhibition of ERK1/2 is beneficial. In this study, we report that the ubiquitous overexpression of wild-type ERK2 in mice (ERK2\(^{wt}\)) is detrimental after transient occlusion of the middle cerebral artery (tMCAO), as it led to a massive increase in infarct volume and neurological deficits by increasing blood-brain barrier (BBB) leakiness, inflammation, and the number of apoptotic neurons. To compare ERK1/2 activation and inhibition side-by-side, we also used mice with ubiquitous overexpression of the Raf-kinase inhibitor protein (RKIP\(^{wt}\)) and its phosphorylation-deficient mutant RKIP\(^{S153A}\), known inhibitors of the ERK1/2 signaling cascade. RKIP\(^{wt}\) and RKIP\(^{S153A}\) attenuated ischemia-induced damages, in particular via anti-inflammatory signaling. Taken together, our data suggest that stimulation of the Raf/MEK/ERK1/2-cascade is severely detrimental and its inhibition is rather protective. Thus, a tight control of the ERK1/2 signaling is essential for the outcome in response to ischemic stroke.},
  language  = {en}
}
@article{MontellanoKluterRueckeretal.2022,
  author    = {Montellano, Felipe A. and Kluter, Elisabeth J. and R{\"u}cker, Viktoria and Ungeth{\"u}m, Kathrin and Mackenrodt, Daniel and Wiedmann, Silke and Dege, Tassilo and Quilitzsch, Anika and Morbach, Caroline and Frantz, Stefan and St{\"o}rk, Stefan and Haeusler, Karl Georg and Kleinschnitz, Christoph and Heuschmann, Peter U.},
  title     = {Cardiac dysfunction and high-sensitive C-reactive protein are associated with troponin T elevation in ischemic stroke: insights from the SICFAIL study},
  series = {BMC Neurology},
  volume    = {22},
  journal   = {BMC Neurology},
  number    = {1},
  doi       = {10.1186/s12883-022-03017-1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300119},
  year      = {2022},
  abstract  = {Background Troponin elevation is common in ischemic stroke (IS) patients. The pathomechanisms involved are incompletely understood and comprise coronary and non-coronary causes, e.g. autonomic dysfunction. We investigated determinants of troponin elevation in acute IS patients including markers of autonomic dysfunction, assessed by heart rate variability (HRV) time domain variables. Methods Data were collected within the Stroke Induced Cardiac FAILure (SICFAIL) cohort study. IS patients admitted to the Department of Neurology, W{\"u}rzburg University Hospital, underwent baseline investigation including cardiac history, physical examination, echocardiography, and blood sampling. Four HRV time domain variables were calculated in patients undergoing electrocardiographic Holter monitoring. Multivariable logistic regression with corresponding odds ratios (OR) and 95\% confidence intervals (CI) was used to investigate the determinants of high-sensitive troponin T (hs-TnT) levels ≥14 ng/L. Results We report results from 543 IS patients recruited between 01/2014-02/2017. Of those, 203 (37\%) had hs-TnT ≥14 ng/L, which was independently associated with older age (OR per year 1.05; 95\% CI 1.02-1.08), male sex (OR 2.65; 95\% CI 1.54-4.58), decreasing estimated glomerular filtration rate (OR per 10 mL/min/1.73 m2 0.71; 95\% CI 0.61-0.84), systolic dysfunction (OR 2.79; 95\% CI 1.22-6.37), diastolic dysfunction (OR 2.29; 95\% CI 1.29-4.02), atrial fibrillation (OR 2.30; 95\% CI 1.25-4.23), and increasing levels of C-reactive protein (OR 1.48 per log unit; 95\% CI 1.22-1.79). We did not identify an independent association of troponin elevation with the investigated HRV variables. Conclusion Cardiac dysfunction and elevated C-reactive protein, but not a reduced HRV as surrogate of autonomic dysfunction, were associated with increased hs-TnT levels in IS patients independent of established cardiovascular risk factors.},
  language  = {en}
}
@article{KraftDrechslerGunrebenetal.2014,
  author    = {Kraft, Peter and Drechsler, Christiane and Gunreben, Ignaz and Heuschmann, Peter Ulrich and Kleinschnitz, Christoph},
  title     = {Regulation of Blood Coagulation Factors XI and XII in Patients with Acute and Chronic Cerebrovascular Disease: A Case-Control Study},
  series = {Cerebrovascular Diseases},
  volume    = {38},
  journal   = {Cerebrovascular Diseases},
  number    = {5},
  issn      = {1015-9770},
  doi       = {10.1159/000368434},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-199076},
  pages     = {337-343},
  year      = {2014},
  abstract  = {Background: Animal models have implicated an integral role for coagulation factors XI (FXI) and XII (FXII) in thrombus formation and propagation of ischemic stroke (IS). However, it is unknown if these molecules contribute to IS pathophysiology in humans, and might be of use as biomarkers for IS risk and severity. This study aimed to identify predictors of altered FXI and FXII levels and to determine whether there are differences in the levels of these coagulation factors between acute cerebrovascular events and chronic cerebrovascular disease (CCD). Methods: In this case-control study, 116 patients with acute ischemic stroke (AIS) or transitory ischemic attack (TIA), 117 patients with CCD, and 104 healthy volunteers (HVs) were enrolled between 2010 and 2013 at our University hospital. Blood sampling was undertaken once in the CCD and HV groups and on days 0, 1, and 3 after stroke onset in patients with AIS or TIA. Correlations between serum FXI and FXII levels and demographic and clinical parameters were tested by linear regression and analysis of variance. Results: The mean age of AIS/TIA patients was 70 ± 12. Baseline clinical severity measured with NIHSS and Barthel Index was 4.8 ± 6.0 and 74 ± 30, respectively. More than half of the patients had an AIS (58\%). FXI levels were significantly correlated with different leukocyte subsets (p < 0.05). In contrast, FXII serum levels showed no significant correlation (p > 0.1). Neither FXI nor FXII levels correlated with CRP (p > 0.2). FXII levels were significantly higher in patients with CCD compared with those with AIS/TIA (mean ± SD 106 ± 26\% vs. 97 ± 24\%; univariate analysis: p < 0.05); these differences did not reach significance in multivariate analysis adjusted for sex and age. FXI levels did not differ significantly between study groups. Sex and age were significantly associated with FXI and/or FXII levels in patients with AIS/TIA (p < 0.05). In contrast, no statistical significant influence was found for treatment modality (thrombolysis or not), pre-treatment with platelet inhibitors, and severity of stroke. Conclusions: In this study, there was no differential regulation of FXI and FXII levels between disease subtypes but biomarker levels were associated with patient and clinical characteristics. FXI and FXII levels might be no valid biomarker for predicting stroke risk.},
  language  = {en}
}
@article{KrupkaMayWeimeretal.2016,
  author    = {Krupka, Jennifer and May, Frauke and Weimer, Thomas and Pragst, Ingo and Kleinschnitz, Christoph and Stoll, Guido and Panousis, Con and Dickneite, Gerhard and Nolte, Marc W.},
  title     = {The Coagulation Factor XIIa Inhibitor rHA-Infestin-4 Improves Outcome after Cerebral Ischemia/Reperfusion Injury in Rats},
  series = {PLoS ONE},
  volume    = {11},
  journal   = {PLoS ONE},
  number    = {1},
  doi       = {10.1371/journal.pone.0146783},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167370},
  pages     = {e0146783},
  year      = {2016},
  abstract  = {Background and Purpose Ischemic stroke provokes severe brain damage and remains a predominant disease in industrialized countries. The coagulation factor XII (FXII)-driven contact activation system plays a central, but not yet fully defined pathogenic role in stroke development. Here, we investigated the efficacy of the FXIIa inhibitor rHA-Infestin-4 in a rat model of ischemic stroke using both a prophylactic and a therapeutic approach. Methods For prophylactic treatment, animals were treated intravenously with 100 mg/kg rHA-Infestin-4 or an equal volume of saline 15 min prior to transient middle cerebral artery occlusion (tMCAO) of 90 min. For therapeutic treatment, 100 mg/kg rHA-Infestin-4, or an equal volume of saline, was administered directly after the start of reperfusion. At 24 h after tMCAO, rats were tested for neurological deficits and blood was drawn for coagulation assays. Finally, brains were removed and analyzed for infarct area and edema formation. Results Within prophylactic rHA-Infestin-4 treatment, infarct areas and brain edema formation were reduced accompanied by better neurological scores and survival compared to controls. Following therapeutic treatment, neurological outcome and survival were still improved although overall effects were less pronounced compared to prophylaxis. Conclusions With regard to the central role of the FXII-driven contact activation system in ischemic stroke, inhibition of FXIIa may represent a new and promising treatment approach to prevent cerebral ischemia/reperfusion injury.},
  language  = {en}
}
@article{SchuhmannGunrebenKleinschnitzetal.2016,
  author    = {Schuhmann, Michael K. and Gunreben, Ignaz and Kleinschnitz, Christoph and Kraft, Peter},
  title     = {Immunohistochemical Analysis of Cerebral Thrombi Retrieved by Mechanical Thrombectomy from Patients with Acute Ischemic Stroke},
  series = {International Journal of Molecular Sciences},
  volume    = {17},
  journal   = {International Journal of Molecular Sciences},
  number    = {3},
  doi       = {10.3390/ijms17030298},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166206},
  pages     = {298},
  year      = {2016},
  abstract  = {Mechanical thrombectomy is a novel treatment option for patients with acute ischemic stroke (AIS). Only a few studies have previously suggested strategies to categorize retrieved clots according to their histologic composition. However, these reports did not analyze potential biomarkers that are of importance in stroke-related inflammation. We therefore histopathologically investigated 37 intracerebral thrombi mechanically retrieved from patients with AIS, and focused on the composition of immune cells and platelets. We also conducted correlation analyses of distinctive morphologic patterns (erythrocytic, serpentine, layered, red, white, mixed appearance) with clinical parameters. Most T cells and monocytes were detected in erythrocytic and red clots, in which the distribution of these cells was random. In contrast, von Willebrand factor (vWF)-positive areas co-localized with regions of fibrin and collagen. While clots with huge amounts of vWF seem to be associated with a high National Institute of Health Stroke Scale score at admission, histologic findings could not predict the clinical outcome at discharge. In summary, we provide the first histologic description of mechanically retrieved intracerebral thrombi regarding biomarkers relevant for inflammation in ischemic stroke.},
  language  = {en}
}
@article{KraftFleischerWiedmannetal.2017,
  author    = {Kraft, Peter and Fleischer, Anna and Wiedmann, Silke and R{\"u}cker, Viktoria and Mackenrodt, Daniel and Morbach, Caroline and Malzahn, Uwe and Kleinschnitz, Christoph and St{\"o}rk, Stefan and Heuschmann, Peter U.},
  title     = {Feasibility and diagnostic accuracy of point-of-care handheld echocardiography in acute ischemic stroke patients - a pilot study},
  series = {BMC Neurology},
  volume    = {17},
  journal   = {BMC Neurology},
  number    = {159},
  doi       = {10.1186/s12883-017-0937-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158081},
  year      = {2017},
  abstract  = {Background: Standard echocardiography (SE) is an essential part of the routine diagnostic work-up after ischemic stroke (IS) and also serves for research purposes. However, access to SE is often limited. We aimed to assess feasibility and accuracy of point-of-care (POC) echocardiography in a stroke unit (SU) setting. Methods: IS patients were recruited on the SU of the University Hospital W{\"u}rzburg, Germany. Two SU team members were trained in POC echocardiography for a three-month period to assess a set of predefined cardiac parameters including left ventricular ejection fraction (LVEF). Diagnostic agreement was assessed by comparing POC with SE executed by an expert sonographer, and intraclass correlation coefficient (ICC) or kappa (κ) with 95\% confidence intervals (95\% CI) were calculated. Results: In the 78 patients receiving both POC and SE agreement for cardiac parameters was good, with ICC varying from 0.82 (95\% CI 0.71-0.89) to 0.93 (95\% CI 0.87-0.96), and κ from 0.39 (-95\% CI 0.14-0.92) to 0.79 (95\% CI 0.67-0.91). Detection of systolic dysfunction with POC echocardiography compared to SE was very good, with an area under the curve of 0.99 (0.96-1.00). Interrater agreement for LVEF measured by POC echocardiography was good with κ 0.63 (95\% CI 0.40-0.85). Conclusions: POC echocardiography in a SU setting is feasible enabling reliable quantification of LVEF and preliminary assessment of selected cardiac parameters that might be used for research purposes. Its potential clinical utility in triaging stroke patients who should undergo or do not necessarily require SE needs to be investigated in larger prospective diagnostic studies.},
  language  = {en}
}
@article{SchuhmannLanghauserKraftetal.2017,
  author    = {Schuhmann, Michael K. and Langhauser, Friederike and Kraft, Peter and Kleinschnitz, Christoph},
  title     = {B cells do not have a major pathophysiologic role in acute ischemic stroke in mice},
  series = {Journal of Neuroinflammation},
  volume    = {14},
  journal   = {Journal of Neuroinflammation},
  number    = {112},
  doi       = {10.1186/s12974-017-0890-x},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158155},
  year      = {2017},
  abstract  = {Background Lymphocytes have been shown to play an important role in the pathophysiology of acute ischemic stroke, but the properties of B cells remain controversial. The aim of this study was to unravel the role of B cells during acute cerebral ischemia using pharmacologic B cell depletion, B cell transgenic mice, and adoptive B cell transfer experiments. Methods Transient middle cerebral artery occlusion (60 min) was induced in wild-type mice treated with an anti-CD20 antibody 24 h before stroke onset, JHD\(^{-/-}\) mice and Rag1\(^{-/-}\) mice 24 h after adoptive B cell transfer. Stroke outcome was assessed at days 1 and 3. Infarct volumes were calculated from 2,3,5-triphenyltetrazolium chloride (TTC)-stained brain sections, and neurological scores were evaluated. The local inflammatory response was determined by real-time PCR and immunohistochemistry. Apoptosis was analyzed by TUNEL staining, and astrocyte activation was revealed using immunohistochemistry and Western blot. Results Pharmacologic depletion of B cells did not influence infarct volumes and functional outcome at day 1 after stroke. Additionally, lack of circulating B cells in JHD\(^{-/-}\) mice also failed to influence stroke outcome at days 1 and 3. Furthermore, reconstitution of Rag1\(^{-/-}\) mice with B cells had no influence on infarct volumes. Conclusion Targeting B cells in experimental stroke did not influence lesion volume and functional outcome during the acute phase. Our findings argue against a major pathophysiologic role of B cells during acute ischemic stroke.},
  language  = {en}
}
@article{SchuhmannGuthmannStolletal.2017,
  author    = {Schuhmann, Michael K. and Guthmann, Josua and Stoll, Guido and Nieswandt, Bernhard and Kraft, Peter and Kleinschnitz, Christoph},
  title     = {Blocking of platelet glycoprotein receptor Ib reduces "thrombo-inflammation" in mice with acute ischemic stroke},
  series = {Journal of Neuroinflammation},
  volume    = {14},
  journal   = {Journal of Neuroinflammation},
  number    = {18},
  doi       = {10.1186/s12974-017-0792-y},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157582},
  year      = {2017},
  abstract  = {Background: Ischemic stroke causes a strong inflammatory response that includes T cells, monocytes/macrophages, and neutrophils. Interaction of these immune cells with platelets and endothelial cells facilitates microvascular dysfunction and leads to secondary infarct growth. We recently showed that blocking of platelet glycoprotein (GP) receptor Ib improves stroke outcome without increasing the risk of intracerebral hemorrhage. Until now, it has been unclear whether GPIb only mediates thrombus formation or also contributes to the pathophysiology of local inflammation. Methods: Focal cerebral ischemia was induced in C57BL/6 mice by a 60-min transient middle cerebral artery occlusion (tMCAO). Animals were treated with antigen-binding fragments (Fab) against the platelet surface molecules GPIb (p0p/B Fab). Rat immunoglobulin G (IgG) Fab was used as control treatment. Stroke outcome, including infarct size and functional deficits as well as the local inflammatory response, was assessed on day 1 after tMCAO. Results: Blocking of GPIb reduced stroke size and improved functional outcome on day 1 after tMCAO without increasing the risk of intracerebral hemorrhage. As expected, disruption of GPIb-mediated pathways in platelets significantly reduced thrombus burden in the cerebral microvasculature. In addition, inhibition of GPIb limited the local inflammatory response in the ischemic brain as indicated by lower numbers of infiltrating T cells and macrophages and lower expression levels of inflammatory cytokines compared with rat IgG Fab-treated controls. Conclusion: In acute ischemic stroke, thrombus formation and inflammation are closely intertwined ("thrombo-inflammation"). Blocking of platelet GPIb can ameliorate thrombo-inflammation.},
  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{KraftDrechslerSchuhmannetal.2015,
  author    = {Kraft, Peter and Drechsler, Christiane and Schuhmann, Michael K. and Gunreben, Ignaz and Kleinschnitz, Christoph},
  title     = {Characterization of Peripheral Immune Cell Subsets in Patients with Acute and Chronic Cerebrovascular Disease: A Case-Control Study},
  series = {International Journal of Molecular Science},
  volume    = {16},
  journal   = {International Journal of Molecular Science},
  number    = {10},
  doi       = {10.3390/ijms161025433},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126319},
  pages     = {25433-25449},
  year      = {2015},
  abstract  = {Immune cells (IC) play a crucial role in murine stroke pathophysiology. However, data are limited on the role of these cells in ischemic stroke in humans. We therefore aimed to characterize and compare peripheral IC subsets in patients with acute ischemic stroke/transient ischemic attack (AIS/TIA), chronic cerebrovascular disease (CCD) and healthy volunteers (HV). We conducted a case-control study of patients with AIS/TIA (n = 116) or CCD (n = 117), and HV (n = 104) who were enrolled at the University Hospital W{\"u}rzburg from 2010 to 2013. We determined the expression and quantity of IC subsets in the three study groups and performed correlation analyses with demographic and clinical parameters. The quantity of several IC subsets differed between the AIS/TIA, CCD, and HV groups. Several clinical and demographic variables independently predicted the quantity of IC subsets in patients with AIS/TIA. No significant changes in the quantity of IC subsets occurred within the first three days after AIS/TIA. Overall, these findings strengthen the evidence for a pathophysiologic role of IC in human ischemic stroke and the potential use of IC-based biomarkers for the prediction of stroke risk. A comprehensive description of IC kinetics is crucial to enable the design of targeted treatment strategies.},
  language  = {en}
}