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dc.contributor.advisor Saher, Gesine Dr.
dc.contributor.author Stumpf, Sina Kristin
dc.date.accessioned 2020-06-19T08:29:27Z
dc.date.available 2020-06-19T08:29:27Z
dc.date.issued 2020-06-19
dc.identifier.uri http://hdl.handle.net/21.11130/00-1735-0000-0005-13E7-1
dc.language.iso deu de
dc.relation.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc 570 de
dc.title Therapeutic approaches for two distinct CNS pathologies de
dc.type doctoralThesis de
dc.contributor.referee Fischer, André Prof. Dr.
dc.date.examination 2018-06-25
dc.description.abstracteng This work summarizes the analysis of two distinct therapeutic approaches for the central nervous system (CNS) pathologies, Pelizaeus-Merzbacher disease (PMD) and Glioblastoma multiforme (GBM). PMD is a severe leukodystrophy that is mainly caused by the overexpression of the myelin proteolipid protein (PLP) in oligodendrocytes. Transgenic mice that mimic PLP overexpression (Plp-tg) served as a suitable model system to analyze a novel therapeutic approach by feeding a ketogenic diet (KD). In this study, KD treatment improved pathology in Plp-tg mice. In fact, KD treated Plp-tg mice revealed reduced inflammation and decreased lysosomal PLP accumulation with a diminished ER stress response. In addition, KD treatment increased oligodendrocyte numbers with enhanced myelination and amelioration of the impaired motor phenotype. Moreover, KD enhanced ketone body transport and utilization in the CNS, which was accompanied by an amelioration of axonal pathology. The present work summarizes an innovative therapeutic approach for PMD, in which ketone bodies can be integrated into CNS metabolism without the prerequisite of blood-brain barrier (BBB) alterations. This approach would provide a major advantage for PMD patients, since the status of BBB function is still unknown. GBM is highly malignant form of brain tumors, in which standard treatment only provided minor impact on patients’ survival. The major challenge in the chemotherapy of patients is the application of therapeutically relevant concentrations into the brain due to limitation of the BBB. This thesis presents a therapeutic strategy that comprises a combined treatment of the cytostatic agent cisplatin with controlled manipulation of BBB permeability by isoflurane anesthesia in a GBM mouse model. Highlighting the therapeutic benefit of the approach, the combined treatment of cisplatin and isoflurane reduced tumor volume and enhanced the immune response measured by elevated numbers of T-cell infiltration. In addition tumor viability was reduced. The major benefit of our therapeutic approach was the remarkably reduction of migrating tumor cells into healthy brain tissue. Therefore, the investigated therapeutic strategy for GBM research represents a novel approach to target in addition to the tumor center, migrating tumor cells to prevent the tumor from spreading. This strategy would provide future perspectives for GBM therapy in patients. de
dc.contributor.coReferee Bayer, Thomas A. Prof. Dr.
dc.contributor.thirdReferee Alves, Frauke Prof. Dr.
dc.contributor.thirdReferee Frahm, Jens Prof. Dr.
dc.contributor.thirdReferee Heinrich, Ralf Prof. Dr.
dc.subject.eng Pelizaeus-Merzbacher disease de
dc.subject.eng central nervous system de
dc.subject.eng proteolipid protein de
dc.subject.eng leukodystrophy de
dc.subject.eng Glioblastoma multiforme de
dc.subject.eng ketogenic diet de
dc.subject.eng blood-brain barrier de
dc.subject.eng isoflurane de
dc.identifier.urn urn:nbn:de:gbv:7-21.11130/00-1735-0000-0005-13E7-1-0
dc.affiliation.institute Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) de
dc.subject.gokfull Biologie (PPN619462639) de
dc.identifier.ppn 1701160641

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