Dokument-ID Dokumenttyp Verfasser/Autoren Herausgeber Haupttitel Abstract Auflage Verlagsort Verlag Erscheinungsjahr Seitenzahl Schriftenreihe Titel Schriftenreihe Bandzahl ISBN Quelle der Hochschulschrift Konferenzname Quelle:Titel Quelle:Jahrgang Quelle:Heftnummer Quelle:Erste Seite Quelle:Letzte Seite URN DOI Abteilungen OPUS4-11926 Wissenschaftlicher Artikel Albert-Weissenberger, Christiane; Mencl, Stine; Schuhmann, Michael K.; Salur, Irmak; Göb, Eva; Langhauser, Friederike; Hopp, Sarah; Hennig, Nelli; Meuth, Sven G.; Nolte, Marc W.; Sirén, Anna-Leena; Kleinschnitz, Christoph C1-Inhibitor protects from focal brain trauma in a cortical cryolesion mice model by reducing thrombo-inflammation Traumatic brain injury (TBI) induces a strong inflammatory response which includes blood-brain barrier damage, edema formation and infiltration of different immune cell subsets. More recently, microvascular thrombosis has been identified as another pathophysiological feature of TBI. The contact-kinin system represents an interface between inflammatory and thrombotic circuits and is activated in different neurological diseases. C1-Inhibitor counteracts activation of the contact-kinin system at multiple levels. We investigated the therapeutic potential of C1-Inhibitor in a model of TBI. Male and female C57BL/6 mice were subjected to cortical cryolesion and treated with C1-Inhibitor after 1 h. Lesion volumes were assessed between day 1 and day 5 and blood-brain barrier damage, thrombus formation as well as the local inflammatory response were determined post TBI. Treatment of male mice with 15.0 IU C1-Inhibitor, but not 7.5 IU, 1 h after cryolesion reduced lesion volumes by ~75% on day 1. This protective effect was preserved in female mice and at later stages of trauma. Mechanistically, C1-Inhibitor stabilized the blood-brain barrier and decreased the invasion of immune cells into the brain parenchyma. Moreover, C1-Inhibitor had strong antithrombotic effects. C1-Inhibitor represents a multifaceted anti-inflammatory and antithrombotic compound that prevents traumatic neurodegeneration in clinically meaningful settings. 2014 269 Frontiers in Cellular Neuroscience 8 urn:nbn:de:bvb:20-opus-119263 10.3389/fncel.2014.00269 Neurochirurgische Klinik und Poliklinik OPUS4-11822 Wissenschaftlicher Artikel Albert-Weissenberger, Christiane; Mencl, Stine; Hopp, Sarah; Kleinschnitz, Christoph; Siren, Anna-Leena Role of the kallikrein-kinin system in traumatic brain injury Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Despite improvements in acute intensive care, there are currently no specific therapies to ameliorate the effects of TBI. Successful therapeutic strategies for TBI should target multiple pathophysiologic mechanisms that occur at different stages of brain injury. The kallikrein-kinin system is a promising therapeutic target for TBI as it mediates key pathologic events of traumatic brain damage, such as edema formation, inflammation, and thrombosis. Selective and specific kinin receptor antagonists and inhibitors of plasma kallikrein and coagulation factor XII have been developed, and have already shown therapeutic efficacy in animal models of stroke and TBI. However, conflicting preclinical evaluation, as well as limited and inconclusive data from clinical trials in TBI, suggests that caution should be taken before transferring observations made in animals to humans. This review summarizes current evidence on the pathologic significance of the kallikrein-kinin system during TBI in animal models and, where available, the experimental findings are compared with human data. 2014 345 Frontiers in Cellular Neuroscience 8 urn:nbn:de:bvb:20-opus-118226 10.3389/fncel.2014.00345 Neurochirurgische Klinik und Poliklinik OPUS4-14941 Wissenschaftlicher Artikel Hopp, Sarah; Albert-Weissenberger, Christiane The kallikrein-kinin system: a promising therapeutic target for traumatic brain injury No abstract available. 2015 885-886 Neural Regeneration Research 10 6 urn:nbn:de:bvb:20-opus-149416 10.4103/1673-5374.158339 Neurologische Klinik und Poliklinik OPUS4-18880 Wissenschaftlicher Artikel Hopp, Sarah; Albert-Weissenberger, Christiane; Mencl, Stine; Bieber, Michael; Schuhmann, Michael K.; Stetter, Christian; Nieswandt, Bernhard; Schmidt, Peter M.; Monoranu, Camelia-Maria; Alafuzoff, Irina; Marklund, Niklas; Nolte, Marc W.; Sirén, Anna-Leena; Kleinschnitz, Christoph Targeting coagulation factor XII as a novel therapeutic option in brain trauma Objective: Traumatic brain injury is a major global public health problem for which specific therapeutic interventions are lacking. There is, therefore, a pressing need to identify innovative pathomechanism-based effective therapies for this condition. Thrombus formation in the cerebral microcirculation has been proposed to contribute to secondary brain damage by causing pericontusional ischemia, but previous studies have failed to harness this finding for therapeutic use. The aim of this study was to obtain preclinical evidence supporting the hypothesis that targeting factor XII prevents thrombus formation and has a beneficial effect on outcome after traumatic brain injury. Methods: We investigated the impact of genetic deficiency of factor XII and acute inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused infestin-4 (rHA-Infestin-4) on trauma-induced microvascular thrombus formation and the subsequent outcome in 2 mouse models of traumatic brain injury. Results: Our study showed that both genetic deficiency of factor XII and an inhibition of activated factor XII in mice minimize trauma-induced microvascular thrombus formation and improve outcome, as reflected by better motor function, reduced brain lesion volume, and diminished neurodegeneration. Administration of human factor XII in factor XII-deficient mice fully restored injury-induced microvascular thrombus formation and brain damage. Interpretation: The robust protective effect of rHA-Infestin-4 points to a novel treatment option that can decrease ischemic injury after traumatic brain injury without increasing bleeding tendencies. 2016 970-982 Annals of Neurology 79 6 urn:nbn:de:bvb:20-opus-188800 10.1002/ana.24655 Neurochirurgische Klinik und Poliklinik OPUS4-15749 Wissenschaftlicher Artikel Hopp, Sarah; Nolte, Marc W.; Stetter, Christian; Kleinschnitz, Christoph; Sirén, Anna-Leena; Albert-Weissenberger, Christiane Alleviation of secondary brain injury, posttraumatic inflammation, and brain edema formation by inhibition of factor XIIa 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. 2017 Journal of Neuroinflammation 14 39 urn:nbn:de:bvb:20-opus-157490 10.1186/s12974-017-0815-8 Neurochirurgische Klinik und Poliklinik