TY - JOUR A1 - Hopp, Sarah A1 - Albert-Weissenberger, Christiane T1 - The kallikrein-kinin system: a promising therapeutic target for traumatic brain injury JF - Neural Regeneration Research N2 - No abstract available. KW - kallikrein-kinin system KW - traumatic brain injury KW - therapy Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149416 VL - 10 IS - 6 ER - TY - JOUR A1 - Hopp, Sarah A1 - Albert-Weissenberger, Christiane A1 - Mencl, Stine A1 - Bieber, Michael A1 - Schuhmann, Michael K. A1 - Stetter, Christian A1 - Nieswandt, Bernhard A1 - Schmidt, Peter M. A1 - Monoranu, Camelia-Maria A1 - Alafuzoff, Irina A1 - Marklund, Niklas A1 - Nolte, Marc W. A1 - Sirén, Anna-Leena A1 - Kleinschnitz, Christoph T1 - Targeting coagulation factor XII as a novel therapeutic option in brain trauma JF - Annals of Neurology N2 - 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. KW - Molecular-weight heparin KW - Thrombus formation KW - Cerebral-ischemia KW - in-vivo KW - Intravascular coagulation KW - Hemodynamic depression KW - Head-injury KW - Rats KW - Model KW - Mice Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188800 VL - 79 IS - 6 ER - TY - THES A1 - Hopp-Krämer, Sarah T1 - Untersuchungen zur Pathophysiologie und therapeutischer Relevanz des Blutgerinnungsfaktors XII nach experimentellem Schädel-Hirn-Trauma T1 - Studies on the pathophysiology and therapeutic relevance of the coagulation factor XII following experimental traumatic brain injury N2 - Das Schädel-Hirn-Trauma (SHT) entsteht durch äußere Gewalteinwirkung auf den Kopf und verursacht mechanisch eine Schädigung des Hirngewebes. Zusätzlich tragen sekundäre Pathomechanismen, wie Entzündungsprozesse und die Schädigung der Blut-Hirn-Schranke (BHS), dazu bei, dass sich das initial geschädigte Läsionsareal im Laufe der Zeit vergrößert. Vor allem bei jungen Erwachsenen ist das SHT eine der häufigsten Ursachen für bleibende Behinderungen und Todesfälle. Aufgrund der schweren Auswirkungen des SHT und der bislang fehlenden Therapieoptionen ist die Identifizierung neuer Zielstrukturen für eine kausale Therapie von größter Bedeutung. Ausgehend von tierexperimentellen Studien ist das Kallikrein-Kinin-System (KKS) ein besonders erfolgversprechender Angriffspunkt zur Behandlung des SHT. Die Aktivierung des KKS über den Gerinnungsfaktor XII (FXII) und die darauf folgende Bildung von Bradykinin sind mit dem Entstehen von Hirnödemen und Entzündungsreaktionen assoziiert. Vorangegangene Studien haben weiterhin die Frage aufgeworfen, ob und in welchem Maße thrombotische Prozesse einen Einfluss auf die Pathophysiologie und die sekundären Hirnschädigungen nach SHT haben. Da FXII sowohl das KKS als auch die intrinsische plasmatische Gerinnungskaskade initiiert und somit zur Fibrinbildung beiträgt, stand FXII im Mittelpunkt der Untersuchungen dieser Dissertation. Die vorliegende Arbeit beschäftigt sich mit den Fragen, (I) inwiefern FXII eine Rolle bei der sekundären Hirnschädigung nach Trauma spielt und (II) ob thrombotische Prozesse ein pathophysiologisches Merkmal nach Trauma darstellen. In zwei unterschiedlichen Trauma-Modellen wurden FXII-defiziente Tiere und mit einem spezifischen Inhibitor des aktivierten FXII (FXIIa) behandelte Tiere gegen Kontrolltiere nach SHT verglichen. Die Analyse der funktionellen Ausfallerscheinungen und des Ausmaßes an neuronaler Degeneration zeigte, dass FXII-Defizienz und FXIIa-Inhibition vor den Auswirkungen eines SHT schützen. Als zugrundeliegende Mechanismen wurden die Reduktion von thrombotisch verschlossenen Gefäßen in der Mikrovaskulatur des Gehirns sowie der Schutz vor BHS-Störungen und verringerte inflammatorische Prozesse identifiziert. Weiterhin wurde festgestellt, dass eine Blockade der intrinsischen Gerinnungskaskade über FXII keine intrazerebralen Blutungen auslöst. In Gewebeproben von Patienten mit SHT wurde gezeigt, dass Thrombozytenaggregate auch im klinischen Verlauf auftreten und sich somit die tierexperimentellen Befunde auf die humane Situation übertragen lassen. Insgesamt tragen die Ergebnisse dazu bei, die komplexen und vielfältigen Pathomechanismen nach SHT besser zu verstehen und vor allem die Relevanz thrombo-inflammatorischer Prozesse nach SHT aufzuzeigen. Die gezielte Blockade des FXII(a) könnte als therapeutisches Prinzip zur Abschwächung der Sekundärschaden nach SHT geeignet sein. N2 - Traumatic brain injury (TBI) is the result of an outside force causing mechanical disruption of the brain tissue. In addition, delayed pathogenic events, like inflammatory processes and blood-brain barrier damage occur, which collectively exacerbate the injury. In young adults, TBI is one of the main reasons for permanent disability and death. Because of its severe consequences and the lack of causal treatment, the identification of novel therapeutic options is of utmost importance. Based on animal studies, the kallikrein-kinin-system (KKS) is a very promising target to treat secondary injury processes following TBI. The activation of the KKS via coagulation factor XII (FXII) and the subsequent formation of bradykinin are tightly associated with the development of brain edema and inflammation. Recent studies have raised the question to what extent thrombotic processes might influence the pathophysiology and secondary injury processes following TBI. As FXII is not only the starting point of the KKS, but also the initiator of the intrinsic coagulation cascade which leads to fibrin formation, FXII was the center of interest for this dissertation. The work presented here deals with the issue, (I) whether FXII plays a role in the development and aggravation of secondary injury processes after trauma and (II) if thrombotic processes display a pathophysiological feature in TBI. In two different models of brain trauma, FXII-deficient mice and mice treated with a specific inhibitor of activated FXII (FXIIa) were compared to their respective control groups after trauma induction. The analyses of the functional outcome and the amount of neurodegenerative processes showed a distinct amelioration in favor of the genetically modified and treated animals. As underlying mechanisms, the reduction of thrombotic vessels in the brain microvasculature and additionally, protection from blood-brain barrier damages and less inflammation were identified. Moreover, it was observed that interference with the intrinsic coagulation cascade via FXII does not lead to the formation of intracerebral bleedings. The evaluation of human brain tissue surgically obtained following TBI demonstrated that platelet aggregates occur regularly in the course of brain trauma and that they seem to contribute to the secondary injury processes and the ischemia-like injury pattern. Taken together, the results contribute to the understanding of the highly complex and heterogeneous pathomechanisms following TBI, especially concerning thrombo-inflammatory processes. The targeted pharmacological blocking of FXII(a) could be a useful therapeutic principle in the treatment of TBI-associated pathologic processes. KW - Schädel-Hirn-Trauma KW - Blutgerinnungsfaktor XII KW - Pathophysiologie KW - Kallikrein-Kinin-System KW - Intrinsische Gerinnungskaskade Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144421 ER - TY - JOUR A1 - Albert-Weissenberger, Christiane A1 - Mencl, Stine A1 - Schuhmann, Michael K. A1 - Salur, Irmak A1 - Göb, Eva A1 - Langhauser, Friederike A1 - Hopp, Sarah A1 - Hennig, Nelli A1 - Meuth, Sven G. A1 - Nolte, Marc W. A1 - Sirén, Anna-Leena A1 - Kleinschnitz, Christoph T1 - C1-Inhibitor protects from focal brain trauma in a cortical cryolesion mice model by reducing thrombo-inflammation JF - Frontiers in Cellular Neuroscience N2 - 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. KW - thrombosis KW - traumatic brain injury KW - C1-inhibitor KW - blood-brain barrier KW - contact-kinin system KW - edema KW - inflammation Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119263 SN - 1662-5102 VL - 8 ER - TY - JOUR A1 - Albert-Weissenberger, Christiane A1 - Mencl, Stine A1 - Hopp, Sarah A1 - Kleinschnitz, Christoph A1 - Siren, Anna-Leena T1 - Role of the kallikrein-kinin system in traumatic brain injury JF - Frontiers in Cellular Neuroscience N2 - 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. KW - bradykinin KW - factor XII KW - kallikrein–kinin system KW - kinin receptor KW - traumatic brain injury Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118226 SN - 1662-5102 VL - 8 ER - TY - JOUR A1 - Stetter, Christian A1 - Lopez-Caperuchipi, Simon A1 - Hopp-Krämer, Sarah A1 - Bieber, Michael A1 - Kleinschnitz, Christoph A1 - Sirén, Anna-Leena A1 - Albert-Weißenberger, Christiane T1 - Amelioration of cognitive and behavioral deficits after traumatic brain injury in coagulation factor XII deficient mice JF - International Journal of Molecular Sciences N2 - 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. KW - closed head injury KW - contact-kinin system KW - object recognition memory KW - IntelliCage KW - Crespi effect KW - stress Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284959 SN - 1422-0067 VL - 22 IS - 9 ER - TY - JOUR A1 - Hopp, Sarah A1 - Nolte, Marc W. A1 - Stetter, Christian A1 - Kleinschnitz, Christoph A1 - Sirén, Anna-Leena A1 - Albert-Weissenberger, Christiane T1 - Alleviation of secondary brain injury, posttraumatic inflammation, and brain edema formation by inhibition of factor XIIa JF - Journal of Neuroinflammation N2 - 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. KW - factor XII KW - focal brain lesion KW - brain edema Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157490 VL - 14 IS - 39 ER -