| 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.identifier.uri | http://dx.doi.org/10.53846/goediss-8043 | |
| dc.language.iso | deu | de |
| dc.rights.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 | |