<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Impact of the receptor tyrosine kinase EphB2 on cerebral ischemia in mice"^^ . "Stroke is the number two cause of death in the western world and responsible for about 6\r\nbillion euros economic costs caused by illness in Germany annually. Approx. 80% of all\r\nstrokes are ischemic strokes and often develop from a focal cerebral hypoperfusion caused\r\nby an occlusion of a major cerebral artery. Despite intensive research, the pathophysiological\r\nand regenerative molecular mechanisms of stroke are only partially understood and no\r\ncausative therapy dealing with the consequences of the ischemic insult is available.\r\nThe blood-brain barrier (BBB) is a structure built up by endothelial cells, astrocytes and\r\nperizytes. It separates the brain from the periphery while still allowing essential metabolites\r\nto cross. During cerebral ischemia transendothelial connections are degraded and the BBB\r\npermeability increases. This eventually causes vasogenic edema formation.\r\nThe vessel occlusion-induced local hypoperfusion unleashes a series of events called ischemic\r\ncascade. Within minutes, hypoxia- and anoxia-induced intracellular mechanisms\r\nlead to excitotoxicity, a process which describes neuronal cell death induction caused by\r\noverstimulation of ionotropic glutamate receptors, such as NMDA receptors. Overactivation\r\nof NMDA receptors leads to massive Ca2+ influx into neurons and triggers signaling cascades,\r\nwhich among others cause mitochondrial dysfunction and eventually cell death.\r\nAmong others, the receptor tyrosine kinase EphB2 interacts with the NMDA receptor and\r\nregulates NMDA receptor functions which lead to increased Ca2+ influx through the NMDA\r\nreceptor in the neuron.\r\nThe EphB/ephrin-B system is a receptor/ligand system, in which both, receptor and ligands\r\nare membrane-bound requiring direct cell-to-cell contact in order to induce signaling processes.\r\nAdditionally, it had been shown that interaction of monocytic EphB2 with endothelial\r\nephrin-B ligands influences transendothelial migration and induces a pro-inflammatory phenotype\r\nin endothelial cells. Therefore, this study aims to unravel the involvement of\r\nEphB2/ephrin-B signaling during cerebral ischemia.\r\nCerebral ischemia was induced in Ephb2-deficient mice by transient middle cerebral artery\r\nocclusion (MCAo) followed by different times of reperfusion. Histological, neurofunctional\r\nand transcriptome analyses demonstrated that progression of stroke after 12-48 h of reperfusion\r\nis attenuated in Ephb2-deficient mice as compared to wild-type (WT) mice. However,\r\nmultiple analyses (CT scans, immunofluorescence staining techniques, BBB permeability\r\nassays) showed that this observation was not caused by an impact on vascular function.\r\nOn the other hand, further evaluations based on magnetic resonance imaging revealed that\r\ncytotoxic edema formation during the first 6 h after reperfusion was diminished in Ephb2-\r\ndeficient mice as compared to WT mice pointing towards a neuronal cause.\r\nIn this context, analysis of brain lysates from WT animals revealed that activation (shown\r\nby phosphorylation) of EphB2 was increased after 6 h of reperfusion in the ischemic hemisphere.\r\nNext, the influence of EphB2 on neuronal NMDA receptor function was investigated.\r\nIt turned out that NMDA receptor-mediated Ca2+ transients and mitochondrial membrane\r\ndepolarization was decreased in Ephb2-deficient neurons as compared to WT neurons. As\r\nmitochondrial dysfunction is a hallmark of stroke pathogenesis and a crucial step during\r\ninduction of excitotoxicity, cell death assays were performed. Widespread exposure to excitotoxic\r\nstimuli did not reveal differences in the fraction of dead cells between WT and\r\nEphb2-deficient mice though.\r\nCollectively, this is the first study to show that EphB2 is activated within 6 h after stroke and\r\ndecisively contributes to cytotoxic edema formation while BBB permeability is not influenced\r\nby EphB2. In the absence of EphB2, progression of stroke is attenuated with respect to\r\ninfarct and edema volume as well as neurological function. NMDA receptor-mediated mitochondrial\r\nresponses are decreased in Ephb2-deficient neurons highlighting its importance\r\nfor the function of the NMDA receptor. Hence, EphB2-dependent mechanisms contribute to\r\nsignaling events that eventually worsen stroke progression."^^ . "2018" . . . . . . . "Anne-Sophie"^^ . "Ernst"^^ . "Anne-Sophie Ernst"^^ . . . . . . "Impact of the receptor tyrosine kinase EphB2 on cerebral ischemia in mice (PDF)"^^ . . . "Thesis ASE 20180528 submitted.pdf"^^ . . . "Impact of the receptor tyrosine kinase EphB2 on cerebral ischemia in mice (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Impact of the receptor tyrosine kinase EphB2 on cerebral ischemia in mice (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Impact of the receptor tyrosine kinase EphB2 on cerebral ischemia in mice (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Impact of the receptor tyrosine kinase EphB2 on cerebral ischemia in mice (Other)"^^ . . . . . . "small.jpg"^^ . . . "Impact of the receptor tyrosine kinase EphB2 on cerebral ischemia in mice (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #25152 \n\nImpact of the receptor tyrosine kinase EphB2 on cerebral ischemia in mice\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .