Differential regulation of blood-brain barrier permeability in brain trauma and pneumococcal meningitis-role of Src kinases |
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Authors: | Paul Robert Angele Barbara Popp Bernadette Klein Matthias Riedel Eva Pfister Hans-Walter Koedel Uwe |
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Institution: | Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians University, Marchioninistr. 15, D-81377 Munich, Germany. Robert.Paul@med.uni-muenchen.de |
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Abstract: | Increased vascular permeability causing vasogenic brain edema is characteristic for many acute neurological diseases such as stroke, brain trauma, and meningitis. Src family kinases, especially c-Src, play an important role in regulating blood-brain barrier permeability in response to VEGF, but also mediate leukocyte function and cytokine signalling. Here we demonstrate that pharmacological inhibition of Src or c-Src deficiency does not influence cerebrospinal fluid (CSF) pleocytosis, brain edema formation, and bacterial outgrowth during experimental pneumococcal meningitis despite the increased cerebral expression of inflammatory chemokines, such as IL-6, CCL-9, CXCL-1, CXCL-2 and G-CSF as determined by protein array analysis. In contrast, inhibition of Src significantly reduced brain edema formation, lesion volume, and clinical worsening in cold-induced brain injury without decreasing cytokine/chemokine expression. While brain trauma was associated with increased cerebral VEGF formation, VEGF levels significantly declined during pneumococcal meningitis. Therefore, we conclude that in brain trauma blood-brain barrier tightness is regulated by the VEGF/Src pathway whereas c-Src does not influence brain edema formation and leukocyte function during bacterial meningitis. |
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Keywords: | Brain trauma Pneumococcal meningitis Src kinases VEGF Chemokines Blood-brain barrier Vascular permeability |
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