TY - JOUR A1 - Paul, Mila M. A1 - Mieden, Hannah J. A1 - Lefering, Rolf A1 - Kupczyk, Eva K. A1 - Jordan, Martin C. A1 - Gilbert, Fabian A1 - Meffert, Rainer H. A1 - Sirén, Anna-Leena A1 - Hoelscher-Doht, Stefanie T1 - Impact of a femoral fracture on outcome after traumatic brain injury — a matched-pair analysis of the TraumaRegister DGU\(^®\) JF - Journal of Clinical Medicine N2 - Traumatic brain injury (TBI) is the leading cause of death and disability in polytrauma and is often accompanied by concomitant injuries. We conducted a retrospective matched-pair analysis of data from a 10-year period from the multicenter database TraumaRegister DGU\(^®\) to analyze the impact of a concomitant femoral fracture on the outcome of TBI patients. A total of 4508 patients with moderate to critical TBI were included and matched by severity of TBI, American Society of Anesthesiologists (ASA) risk classification, initial Glasgow Coma Scale (GCS), age, and sex. Patients who suffered combined TBI and femoral fracture showed increased mortality and worse outcome at the time of discharge, a higher chance of multi-organ failure, and a rate of neurosurgical intervention. Especially those with moderate TBI showed enhanced in-hospital mortality when presenting with a concomitant femoral fracture (p = 0.037). The choice of fracture treatment (damage control orthopedics vs. early total care) did not impact mortality. In summary, patients with combined TBI and femoral fracture have higher mortality, more in-hospital complications, an increased need for neurosurgical intervention, and inferior outcome compared to patients with TBI solely. More investigations are needed to decipher the pathophysiological consequences of a long-bone fracture on the outcome after TBI. KW - traumatic brain injury KW - femoral fracture KW - damage control orthopedics KW - mortality Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319363 SN - 2077-0383 VL - 12 IS - 11 ER - TY - JOUR A1 - Sun, Aili A1 - Blecharz-Lang, Kinga G. A1 - Małecki, Andrzej A1 - Meybohm, Patrick A1 - Nowacka-Chmielewska, Marta M. A1 - Burek, Malgorzata T1 - Role of microRNAs in the regulation of blood-brain barrier function in ischemic stroke and under hypoxic conditions in vitro JF - Frontiers in Drug Delivery N2 - The blood-brain barrier (BBB) is a highly specialized structure that separates the brain from the blood and allows the exchange of molecules between these two compartments through selective channels. The breakdown of the BBB is implicated in the development of severe neurological diseases, especially stroke and traumatic brain injury. Oxygen-glucose deprivation is used to mimic stroke and traumatic brain injury in vitro. Pathways that trigger BBB dysfunction include an imbalance of oxidative stress, excitotoxicity, iron metabolism, cytokine release, cell injury, and cell death. MicroRNAs are small non-coding RNA molecules that regulate gene expression and are emerging as biomarkers for the diagnosis of central nervous system (CNS) injuries. In this review, the regulatory role of potential microRNA biomarkers and related therapeutic targets on the BBB is discussed. A thorough understanding of the potential role of various cellular and linker proteins, among others, in the BBB will open further therapeutic options for the treatment of neurological diseases. KW - blood-brain barrier KW - microRNA KW - stroke KW - traumatic brain injury KW - tight junctions KW - transporter Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-291423 SN - 2674-0850 VL - 2 ER - TY - JOUR A1 - Zwirner, Johann A1 - Bohnert, Simone A1 - Franke, Heike A1 - Garland, Jack A1 - Hammer, Niels A1 - Möbius, Dustin A1 - Tse, Rexson A1 - Ondruschka, Benjamin T1 - Assessing protein biomarkers to detect lethal acute traumatic brain injuries in cerebrospinal fluid JF - Biomolecules N2 - Diagnosing traumatic brain injury (TBI) from body fluids in cases where there are no obvious external signs of impact would be useful for emergency physicians and forensic pathologists alike. None of the previous attempts has so far succeeded in establishing a single biomarker to reliably detect TBI with regards to the sensitivity: specificity ratio in a post mortem setting. This study investigated a combination of body fluid biomarkers (obtained post mortem), which may be a step towards increasing the accuracy of biochemical TBI detection. In this study, serum and cerebrospinal fluid (CSF) samples from 30 acute lethal TBI cases and 70 controls without a TBI-related cause of death were evaluated for the following eight TBI-related biomarkers: brain-derived neurotrophic factor (BDNF), ferritin, glial fibrillary acidic protein (GFAP), interleukin 6 (IL-6), lactate dehydrogenase, neutrophil gelatinase-associated lipocalin (NGAL), neuron-specific enolase and S100 calcium-binding protein B. Correlations among the individual TBI biomarkers were assessed, and a specificity-accentuated threshold value analysis was conducted for all biomarkers. Based on these values, a decision tree modelling approach was performed to assess the most accurate biomarker combination to detect acute lethal TBIs. The results showed that 92.45% of acute lethal TBIs were able to be diagnosed using a combination of IL-6 and GFAP in CSF. The probability of detecting an acute lethal TBI was moderately increased by GFAP alone and considerably increased by the remaining biomarkers. BDNF and NGAL were almost perfectly correlated (p = 0.002; R\(^2\) = 0.944). This study provides evidence that acute lethal TBIs can be detected to a high degree of statistical accuracy using forensic biochemistry. The high inter-individual correlations of biomarkers may help to estimate the CSF concentration of an unknown biomarker, using extrapolation techniques. KW - biomarker combination KW - glial fibrillary acidic protein KW - interleukin-6 KW - post mortem biochemistry KW - traumatic brain injury Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248587 SN - 2218-273X VL - 11 IS - 11 ER - 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 - Salvador, Ellaine A1 - Burek, Malgorzata A1 - Förster, Carola Y. T1 - Stretch and/or oxygen glucose deprivation (OGD) in an in vitro traumatic brain injury (TBI) model induces calcium alteration and inflammatory cascade JF - Frontiers in Cellular Neuroscience N2 - The blood-brain barrier (BBB), made up of endothelial cells of capillaries in the brain, maintains the microenvironment of the central nervous system. During ischemia and traumatic brain injury (TBI), cellular disruption leading to mechanical insult results to the BBB being compromised. Oxygen glucose deprivation (OGD) is the most commonly used in vitro model for ischemia. On the other hand, stretch injury is currently being used to model TBI in vitro. In this paper, the two methods are used alone or in combination, to assess their effects on cerebrovascular endothelial cells cEND in the presence or absence of astrocytic factors. Applying severe stretch and/or OGD to cEND cells in our experiments resulted to cell swelling and distortion. Damage to the cells induced release of lactate dehydrogenase enzyme (LDH) and nitric oxide (NO) into the cell culture medium. In addition, mRNA expression of inflammatory markers interleukin (I L)-6, IL-1\(\alpha\) chemokine (C-C motif) ligand 2 (CCL2) and tumor necrosis factor (TNF)-\(\alpha\) also increased. These events could lead to the opening of calcium ion channels resulting to excitotoxicity. This could be demonstrated by increased calcium level in OGD-subjected cEND cells incubated with astrocyte-conditioned medium. Furthermore, reduction of cell membrane integrity decreased tight junction proteins claudin-5 and occludin expression. In addition, permeability of the endothelial cell monolayer increased. Also, since cell damage requires an increased uptake of glucose, expression of glucose transporter glut1 was found to increase at the mRNA level after OGD. Overall, the effects of OGD on cEND cells appear to be more prominent than that of stretch with regards to TJ proteins, NO, glutl expression, and calcium level. Astrocytes potentiate these effects on calcium level in cEND cells. Combining both methods to model TBI in vitro shows a promising improvement to currently available models. KW - receptor antagonist KW - cytokine expression KW - tight junctions KW - cell stretch KW - calcium level KW - nitric oxide KW - endothelial cells KW - necrosis factor alpha KW - barrier properties KW - cerebral ischemia KW - nervous system KW - CNS injury KW - blood brain barrier KW - cEND KW - astrocytes KW - traumatic brain injury KW - oxygen-glucose deprivation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148255 VL - 9 IS - 323 ER - TY - THES A1 - Oerter, Sabrina T1 - Expression von Natrium/Glukose-Cotransportern im menschlichen Gehirn bei Todesfällen durch Schädel-Hirn-Trauma und Todesfällen durch Ersticken T1 - Expression of sodium/glucose cotransporter in the human brain following death by traumatic brain inury and suffocation N2 - Glukosetransporter spielen eine wichtige Rolle in der Versorgung des Gehirns mit Nährstoffen und somit für den Erhalt der physiologischen Zellintegrität. Glukose wird über die Blut-Hirn-Schranke (BHS) mittels spezifischen transmembranen Transportproteinen der SLC-Genfamilie (GLUT, SGLT) befördert. Dabei scheint während physiologischen Bedingungen hauptsächlich der Glukosetransporter GLUT1 (SLC2A1) für die Energieversorgung des Gehirns zuständig zu sein. Die Erforschung der SGLT-Expression ist in den letzten Jahren ein wichtiger Ansatzpunkt für neue Behandlungsstrategien vieler Erkrankungen, wie Diabetes Mellitus, maligne Neoplasien oder eines Herzinfarkts, geworden. Jedoch ist über deren Expression und Funktion im menschlichen Gehirn nur wenig bekannt. Besonders die Lokalisation entlang der BHS bleibt fraglich. Ein Großteil bisheriger Forschungsarbeiten beschäftigt sich hauptsächlich mit der Expressionsanalyse des Transporters SGLT1 im tierischen Gehirn in vivo (Poppe et al. 1997; Balen et al. 2008; Yu et al. 2013). Es konnte aufgezeigt werden, dass SGLT1 mRNA exklusiv in Neuronen und nicht an der BHS exprimiert wird. Dies wird durch in vitro Analysen einer humanen Hirnendothelzelllinie bestätigt. Demnach kann kein SGLT1 unter physiologischen Bedingungen nachgewiesen werden (Sajja et al. 2014). Im menschlichen Hirngewebe besitzen SGLTs somit keine zentrale Funktion für den Glukosetransport an der BHS. Im Gegensatz dazu konnte eine Expression von SGLT sowohl in vivo als auch in vitro während hypoglykämischen Bedingungen belegt werden (Vemula et al. 2009; Sajja et al. 2014). Die Expression der SGLT-Transporter während einer ischämischen Hypoglykämie führt zu der Annahme, dass diese Transporter für die Aufrechterhaltung der Energieversorgung des geschädigten Hirngewebes notwendig sind. Um die physiologischen Mechanismen nach einem Glukosemangel zu untersuchen, wurden SHT-Modelle etabliert (Salvador et al. 2013). In einem experimentellen Modell des Schädel-Hirn-Traumas im Rahmen eines DFG-gefördertes Projekts ist ein Expressionsverlauf von Glukosetransportern im Maushirn und in Hirnendothelzellen erarbeitet worden (Wais 2012; Salvador et al. 2015). Somit könnten SGLTs als Ansatzpunkt für den Nachweis der Überlebenszeit nach einem SHT fungieren. Die vorliegende Arbeit fokussiert sich auf die Expression der Natrium-abhängigen Glukosetransporter SGLT1 und SGLT2 im menschlichen Gehirn. Hierbei liegt das Hauptaugenmerk auf der Lokalisation dieser Transporter an der menschlichen BHS von post mortalem Hirngewebe. Weiterhin wird untersucht ob die Expressionsstärke von SGLT1 und SGLT2 eine Aussage über die Überlebenszeit von Verstorbenen nach einer traumatisch bedingten Hirnveränderung zulässt. Die Lokalisation von SGLT1 und SGLT2 an der menschlichen BHS konnte durch die Etablierung eines Protokolls zur Isolation von Hirnkapillaren erfolgen. Vorab wurden alle verwendeten Antikörper auf ihre Spezifität mittels siRNA Transfektion und Blockierung der Immunfluoreszenzsignale mittels immunisierten Peptids getestet. Somit ist die Spezifität der detektierten SGLT1- und SGLT2-Expression in menschlichen Hirnkapillaren gewährleistet. Anschließend wird untersucht, in welchen zeitlichem Verlauf nach einer traumatisch bedingten Hirnveränderung die verschiedenen Formen der Glukosetransporter exprimiert werden und ob ggf. der Umfang und die Verteilung von SGLT1, SGLT2 und GLUT1 sowie das Verhältnis zueinander Auskünfte über eine vitale bzw. postmortale Entstehung eines Traumas bzw. dessen Überlebenszeit zulässt. Hierfür wird ein Expressionsschema der Glukosetransporter generiert, abhängig von Todeszeitpunkt und Todesursache. Es konnte festgestellt werden, dass GLUT1 nicht als Target für die Ermittlung der Überlebenszeit nach einem Trauma geeignet ist. Dahingegen zeigen SGLT1 und SGLT2 eine signifikante Änderung der Expressionsstärke im contusionalen Gewebe in Abhängigkeit von der Überlebenszeit. Obwohl diese vorläufigen Daten einen neuen Ansatzpunkt für die forensische Fragestellung aufzeigen, müssen weitere Experimente mit einem erhöhten Umfang der Probenanzahl und kürzere Zeitspannen der Überlebenszeiträume durchgeführt werden. N2 - The transport of glucose across the endothelial cells of the human blood-brain barrier (hBBB) plays a major role for energy supply of the brain and therefor for neuronal integrity. Glucose enters the brain cells through specific transmembrane transporter proteins of the SLC-gene family (GLUT, SGLT). Under physiological conditions glucose uptake across the BBB seems to be mediated primarily by facilitated diffusion through glucose transporter 1 (GLUT1). Although SGLTs are a known drug target for diabetes and furthermore play a role in other disease like cancer and cardiac ischemia, active glucose transport by SGLTs is hardly observed and very little is known about their expression or activity in human brain. Especially the function along the BBB remains uncertain. Up to now, expression analysis focused on SGLT1 and has been confirmed in vivo by analyzing brain tissue of animals (Poppe et al. 1997; Balen et al. 2008; Yu et al. 2013). Here detection mainly occurs in neurons, no SGLT1 mRNA in capillaries of the BBB could be found. Similarly in vitro experiments with a human brain microvascular endothelial cell line reveals no expression of SGLT1 under physiological conditions (Sajja et al. 2014). In human brain, SGLT1 is hardly expressed and so far could not be found along the BBB. In contrast to these findings, expression of SGLT1 could be detected in vivo as well as in vitro under hypoglycemic conditions (Vemula et al. 2009; Sajja et al. 2014). The occurrence of these transporters during ischemic hypoglycemia could lead to the conclusion that the secondary active glucose transport by SGLTs is necessary for additional glucose supply in injured brain. To investigate if SGLTs are required for the reconstruction of energy supply after glucose deficiency, traumatic brain injury (TBI) models were established to study secondary physiological mechanisms along the BBB (Salvador et al. 2013). In an experimental CCI (controlled cortical impact) mouse model within a DFG-funded project, an expression pattern of glucose transporters in the mouse brain and in brain endothelial cells has been developed (Wais 2012; Salvador et al. 2015). Thus it could lead as a Target for evidence of the time of survival after TBI. This study focuses on the sodium-dependent glucose transporters SGLT1 and SGLT2 expression in human brain. The main topic is to localize the sodium-dependent glucose transporters along the human BBB of post mortem brain tissue and to examine whether SGLT expression allow a conclusion to be drawn about the survival time of a patient after TBI. First of all the localization of SGLT1 and SGLT2 at the human BBB could be shown by establishment a capillary isolation protocol of human post mortem brain tissue. Therefore the antibody specificity was tested by a siRNA transfection protocol and blocking the immunofluorescence signal with an immunized peptide. Thus, specific SGLT1 and SGLT2 expression at the endothelial lining of the capillary lumen could be demonstrated. After attaching the value of SGLTs at the human BBB, the relationship of the glucose transporter expression in TBI tissue according to the survival time of the patient is presented. Hereby it should be clarified whether the expression and distribution of the transporters GLUT1, SGLT1 and SGLT2 as well as the relation to each other provide information on a vital or post mortal development of a trauma or its survival time. It could determine that GLUT1 is not suitable as a target for the representation of survival time after TBI. However, SGLT1 and SGLT2 show a significant change in the expression profile of traumatic brain regions. Here an increase according to the survival time after trauma can be shown. Although these preliminary data suggest a novel target for forensic questions, more experiments with an increased scope of survival time frames should be carried out. KW - Sodium-Glucose Transporter 2 KW - Glucosetransportproteine KW - Natrium/Glukose Cotransporter KW - SGLT KW - Schädel-Hirn-Trauma KW - sodium-dependend glucose transporter KW - traumatic brain injury KW - Rechtsmedizin Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164093 ER - TY - JOUR A1 - Minnerup, Jens A1 - Sutherland, Brad A. A1 - Buchan, Alastair M. A1 - Kleinschnitz, Christoph T1 - Neuroprotection for Stroke: Current Status and Future Perspectives JF - International Journal of Molecular Science N2 - 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. KW - free radical scavenger KW - ischemic cascade KW - acute ischemic stroke KW - trial KW - focal cerebral-ischemia KW - interleukin-1 receptor antagonist KW - colony-stimulating factor KW - tissue-plasminogen activator KW - traumatic brain injury KW - placebo-controlled KW - alias pilot trial KW - damage cool aid KW - neuroprotection KW - ischemic stroke KW - translation KW - STAIR Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134730 VL - 13 IS - 9 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 - Neuhaus, Winfried A1 - Gaiser, Fabian A1 - Mahringer, Anne A1 - Franz, Jonas A1 - Riethmüller, Christoph A1 - Förster, Carola T1 - The pivotal role of astrocytes in an in vitro stroke model of the blood-brain barrier JF - Frontiers in Cellular Neuroscience N2 - Stabilization of the blood-brain barrier during and after stroke can lead to less adverse outcome. For elucidation of underlying mechanisms and development of novel therapeutic strategies validated in vitro disease models of the blood-brain barrier could be very helpful. To mimic in vitro stroke conditions we have established a blood-brain barrier in vitro model based on mouse cell line cerebEND and applied oxygen/glucose deprivation (OGD). The role of astrocytes in this disease model was investigated by using cell line C6. Transwell studies pointed out that addition of astrocytes during OGD increased the barrier damage significantly in comparison to the endothelial monoculture shown by changes of transendothelial electrical resistance as well as fluorescein permeability data. Analysis on mRNA and protein levels by qPCR, western blotting and immunofluorescence microscopy of tight junction molecules claudin-3,-5,-12, occludin and ZO-1 revealed that their regulation and localisation is associated with the functional barrier breakdown. Furthermore, soluble factors of astrocytes, OGD and their combination were able to induce changes of functionality and expression of ABC-transporters Abcb1a (P-gp), Abcg2 (bcrp), and Abcc4 (mrp4). Moreover, the expression of proteases (matrixmetalloproteinases MMP-2, MMP-3, MMP-9, and t-PA) as well as of their endogenous inhibitors (TIMP-1, TIMP-3, PAI-1) was altered by astrocyte factors and OGD which resulted in significant changes of total MMP and t-PA activity. Morphological rearrangements induced by OGD and treatment with astrocyte factors were confirmed at a nanometer scale using atomic force microscopy. In conclusion, astrocytes play a major role in blood-brain barrier breakdown during OGD in vitro. KW - oxygen/glucose deprivation KW - ischemia KW - traumatic brain injury KW - cerebEND KW - C6 KW - stroke KW - in vitro KW - blood-brain barrier Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118297 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 - Petrasek, Tomas A1 - Prokopova, Iva A1 - Sladek, Martin A1 - Weissova, Kamila A1 - Vojtechova, Iveta A1 - Bahnik, Stepan A1 - Zemanova, Anna A1 - Schönig, Kai A1 - Berger, Stefan A1 - Tews, Bjoern A1 - Bartsch, Dusan A1 - Schwab, Martin E. A1 - Sumova, Alena A1 - Stuchlik, Ales T1 - Nogo-A-deficient transgenic rats show deficits in higher cognitive functions, decreased anxiety, and altered circadian activity patterns JF - Frontiers in Behavioral Neuroscience N2 - Decreased levels of Nogo-A-dependent signaling have been shown to affect behavior and cognitive functions. In Nogo-A knockout and knockdown laboratory rodents, behavioral alterations were observed, possibly corresponding with human neuropsychiatric diseases of neurodevelopmental origin, particularly schizophrenia. This study offers further insight into behavioral manifestations of Nogo-A knockdown in laboratory rats, focusing on spatial and non-spatial cognition, anxiety levels, circadian rhythmicity, and activity patterns. Demonstrated is an impairment of cognitive functions and behavioral flexibility in a spatial active avoidance task, while non-spatial memory in a step-through avoidance task was spared. No signs of anhedonia, typical for schizophrenic patients, were observed in the animals. Some measures indicated lower anxiety levels in the Nogo-A-deficient group. Circadian rhythmicity in locomotor activity was preserved in the Nogo-A knockout rats and their circadian period (tau) did not differ from controls. However, daily activity patterns were slightly altered in the knockdown animals. We conclude that a reduction of Nogo-A levels induces changes in CNS development, manifested as subtle alterations in cognitive functions, emotionality, and activity patterns. KW - AAPA KW - circadian rhythmicity KW - passive avoidance KW - Nogo-A KW - anhedonia KW - neophobia KW - morris water maze KW - place avoidance task KW - neurite outgrowth inhibitor KW - axon regeneration KW - synaptic plasticity KW - down regulation KW - traumatic brain injury KW - carousel maze KW - messenger RNA KW - genetic deletion Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117073 VL - 8 IS - 90 ER - TY - THES A1 - Wais, Sebastian T1 - Die Rolle der Glukosetransporter an der Blut-Hirn-Schranke nach einem Schädel-Hirn-Trauma und deren eventueller Einfluss auf die Entwicklung eines sekundären Hirnödems T1 - The role of the glucose transporters after traumatic brain injury and their influence on the development of secondary brain edema N2 - Laut der Weltgesundheitsorganisation (WHO) waren in Deutschland 2006 akute ischämische Ereignisse des Zentralen Nervensystems (ZNS) die fünfthäufigste Todesursache. Zu diesen ischämischen Ereignissen zählen Schlaganfall, Kardiopulmonale Reanimation, traumatische Hirnverletzungen, sowie perioperative ischämische Komplikationen. Aufgrund der schwerwiegenden Folgen, die ein Verlust von Nervenzellen für den Patienten bedeutet, muss die weitere medizinische Akutversorgung den sekundären neuronalen Schaden verhindern oder ihn reduzieren. Vor dieser Arbeit konnten Glukosetransporter-1 (GLUT-1) und Natrium-Glukose-Kotransporter-1 (SGLT1) an der Blut-Hirn-Schranke (BHS) identifiziert werden. Ziel dieser Arbeit war es, das Expressionsverhalten der Glukosetransporter nach einem Schädel-Hirn-Trauma (SHT) in vivo und in vitro zu untersuchen, um so den Einfluss und die funktionellen Folgen durch die veränderte Expression der zerebralen Glukosetransporter in der BHS infolge eines SHT zu identifizieren und deren eventuellen Einfluss auf die Entwicklung eines sekundären Hirnödems zu erkennen. Hierfür wurde als in vivo-Modell das Controlled Cortical Impact Injury (CCII) gewählt, da bei diesem Tierversuchsmodell die Aspekte der traumatischen Kontusion und die damit verbundenen intraparenchymalen Blutungen durch ein epidurales oder subdurales Hämatom im Vordergrund stehen. Es wurden Gehirnschnitte zu fest definierten Zeitpunkten angefertigt (kein CCII (Kontrolle), 15 Minuten Überleben nach CCII (Primärschaden), 24 Stunden Überleben nach CCII und 72 Stunden Überleben nach CCII). Die Darstellung des primären Schadens im Mäusehirn erfolgte durch die Immunfluoreszenzmikroskopie. Um einen Gewebeschaden, wie es bei einem Hirntrauma der Fall ist, in vitro zu simulieren, wurde das Modell des Sauerstoff-Glukose-Entzuges (OGD) gewählt, da es bei diesem Modell neben einer Nekrose auch zur Apoptose der Nervenzellen kommt, welche ebenfalls bei einem SHT stattfindet. Als geeignetes Zellkulturmodell wurde die cerebralen Endothelzelllinie (cEND) gewählt. Bei dieser Zelllinie handelte es sich um eine Hirnendothelzelllinie aus der Maus. In den in vivo-Versuchen konnte bei GLUT-1 bereits 15 Minuten nach CCII eine gesteigerte Expression festgestellt werden. Dennoch verminderte GLUT-1 im weiteren Verlauf seine Expression auf ein Minimum, welches unterhalb des Ausgangswertes lag. SGLT1, der auch in der BHS identifiziert wurde, reagierte auf einen Primärschaden erst in den Hirnschnitten, die 24 Stunden nach CCI behandelt wurden. In den Hirnschnitten, die 15 Minuten nach CCII behandelt wurden, veränderte sich die SGLT1-Expression zunächst nicht. Erst 24 Stunden nach CCII konnte eine gesteigerte Expression von SGLT1 erkannt werden, die aber bei 72 Stunden nach CCII wieder abgenommen hatte. Ein weiterer Glukosetransporter konnte erstmals in der BHS identifiziert werden. SGLT2 zeigte erst 72 Stunden nach CCII eine gesteigerte Expression, in den Hirnschnitten ohne CCII, 15 Minuten nach CCII und 24 Stunden nach CCII konnte keine Veränderung der SGLT2-Expression festgestellt werden. Diese Expressionsreaktion, besonders der Expressions-Höhepunkt der einzelnen Glukosetransporter, konnte auch in vitro gezeigt werden. Besonders die Identifizierung von SGLT2 in der BHS und die generelle Steigerung der Expressionsrate von GLUT-1, SGLT1 und SGLT2 könnte neue Ansatzpunkte in der Pathophysiologie des diffusen Hirnödems nach einem SHT ergeben. Die genaue Rolle der Natriumgekoppelten Glukosetransporter in der BHS muss noch weiter erforscht werden. Bestätigen weitere Versuche eine zentrale Rolle der SGLTs bei der Entstehung des sekundären Hirnschadens, speziell SGLT2, als hochpotenter Glukosetransporter, so könnte über neue Therapien nachgedacht werden, durch welche spezifisch die Expression der SGLTs, besonders SGLT2, wie es bei Dapagliflozin, Canagliflozin oder Ipragliflozin der Fall wäre, unterdrücken würden. N2 - According to the World Health Organization (WHO) the acute ischemic events of the central nervous system (CNS) were the fifth most common mortality in Germany in 2006. To this belong stroke, cardiopulmonary resuscitation, traumatic brain injuries, as well as perioperative ischemic complications. Because of the fatal consequences for a patient which means a death of nerve the medical acute care must be prevent the secondary neuronal damage. Before this work the glucose transporter 1 (GLUT-1) and sodium-glucose cotransporter-1 (SGLT1) are identified at the blood-brain barrier (BBB). The aim of this study was to analyze the expression characteristics of the glucose transporters after a traumatic brain injury (TBI) in vivo and in vitro. These results may show the influence and the functional consequences of the altered expression of cerebral glucose transporters in the BBB as a result of TBI. This allows to recognize a potential impact on the development of cerebral edema. We use for this the model of the controlled cortical impact injury (CCII) as an in vivo model. Brain trauma was induced and animals were randomly assigned to three survival groups: 15 min, 24 h and 72 h, which were compared to native – no CCII – animals. The depiction of the primary damage in mouse brain was performed by immunofluorescence microscopy. To simulate the tissue damage in vitro we use the model of oxygen-glucose deprivation (OGD). As a suitable cell culture model of the cerebral endothelial cell line (cEND) was chosen. In this cell line, there was a cerebrum endothelium cells of the capillary endothelium from the mouse brain. In summary, immunofluorescence images revealed presence of sglt1 and sglt2 in the blood-brain barrier which was inducible by CCII. Strongest expression of sglt1 in the brain endothelium was found after 24 hours and of sglt2 after 72 hours after CCII suggesting different and time dependent roles of these two transporters during edema formation. This expression, especially the expression peak of the individual glucose transporter could be also demonstrated in vitro model. In particular, the identification of SGLT2 in the BBB and the general increase of the expression of GLUT-1, SGLT1 and SGLT2 might be a new starting point in the pathophysiology of diffuse cerebral edema. Indicate further experiments a central role of SGLTs in the development of secondary brain damage, particularly SGLT2, as an highly potent glucose transporter, it could be given to new therapies through which suppress specific the expression of SGLT2. KW - Hirnödem KW - Carrier-Proteine KW - Membranproteine KW - Glucosetransport KW - Schädel-Hirn-Trauma KW - Blut-Hirn-Schranke KW - SGLT KW - Natrium/Glucose-Cotransporter KW - Sodium/glucose cotransporter KW - Cerebral edema KW - carrier proteins KW - traumatic brain injury KW - blood-brain barrier Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-78998 ER - TY - JOUR A1 - Albert-Weißenberger, Christiane A1 - Várrallyay, Csanád A1 - Raslan, Furat A1 - Kleinschnitz, Christoph A1 - Sirén, Anna-Leena T1 - An experimental protocol for mimicking pathomechanisms of traumatic brain injury in mice N2 - 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. KW - Medizin KW - closed head injury KW - traumatic brain injury KW - neurobehavioural deficits KW - astrocyte KW - microglia KW - neurons Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75368 ER -