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Die Auswirkung von verschiedenen Proteasom-Inhibitoren auf die Wallersche Degeneration peripherer Nerven in vitro und in vivo

dc.contributor.advisorSiebert, Heike
dc.contributor.authorDenninger, Stefan Christophde
dc.titleDie Auswirkung von verschiedenen Proteasom-Inhibitoren auf die Wallersche Degeneration peripherer Nerven in vitro und in vivode
dc.title.translatedThe effect of different proteasome inhibitors on Wallerian degeneration of peripheral nerves in vivo and in vitrode
dc.contributor.refereeBrück, Wolfgang Prof.
dc.description.abstractengThe present study examined the effects of proteasome inhibitors on Wallerian degeneration (WD) in the peripheral nervous system on the example of sciatic nerve sectioning in vivo and on the basis of nerve-macrophage co-cultures in vitro. The Wallerian degeneration describes the processes of discontinuity in the nervous system by chemical-toxic, metabolic or mechanical causes. The ubiquitin-proteasome-system (UPS), in addition to the lysosome, provides most of the proteolysis and is one of the main effectors of coordinating all processes running for protein degradation. It is hoped to be able to influence the degeneration of peripheral nerves by inhibiting this system. To display the events of the WD in vitro, a time series of tissue cultures without inhibitor over a period of eight days is first made. Cultures are compared with and without the addition of peritoneal macrophages. Lactacystin and MG132 are used as proteasome inhibitors for the actual experiments, the latter is used only in in vitro co-cultures of nerve pieces and peritoneal macrophages. In vivo, MG132 is applicated intraperitoneally in different concentrations or by using a gelatin sponge. The results of the in vitro time series show a progressive degeneration of the distal nerve pieces with progressive loss of myelin and axons with a simultaneous increase in phagocytosis by macrophages. The in vitro application of a higher concentration of MG132 shows macrophage inhibitory and neuroprotective effects. Lactacystin shows total rather less effect on both macrophages and on myelin and axons, so its use was abandoned in vivo. In vivo, the results for the preservation of axons by MG132 also are very clear whilst the studied parameters for macrophages remain largely unaffected by the proteasome inhibitor. The systemic administration shows a concentration dependent effect, which implies an activity optimum at a certain concentration, while local application showed a strong effect on the preservation of axons using gelatin sponge. The results confirm the central role of macrophages in the degeneration of peripheral nerves. On the other hand they show differences of the degeneration operations when proteasome inhibitors are used in vivo or in vitro. For more future applications of inhibitors the findings in this paper show that a careful review of the application form is required to increase the prospects of success in malignant diseases. Here, more detailed studies to evaluate the dose-response relationship, particularly in vivo would be necessary. For a therapeutic approach to degenerative disease or regeneration after traumatic events these substances promise yet another potential application in the
dc.contributor.coRefereeLingor, Paul PD
dc.contributor.thirdRefereeMausberg, Rainer Prof.
dc.subject.gerWallersche Degenerationde
dc.subject.engwallerian degenerationde
dc.subject.engsciatic nervede
dc.affiliation.instituteMedizinische Fakultätde
dc.subject.gokfullMedizin (PPN619874732)de

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