Multiple sclerosis (MS) is a chronic demyelinating inflammatory disease of the central nervous system. It is the most common neurological disorder among young adults and follows a heterogeneous disease course. Traditionally, MS has been regarded as a white matter disease. This concept has, however, been challenged since substantial cortical gray matter and deep gray matter involvement was evidenced as well. More recently, pathogenic mechanisms such as oxidative stress and mitochondrial damage have gained importance in MS research. In this thesis, we aimed at analyzing key steps in the generation and enhancement of oxidative tissue injury via gene expression profiling and immunohistochemistry.^ Additionally, we studied the role of two blood-brain barrier (BBB) molecules, PECAM-1 and podocalyxin (PODXL), in leukocyte trafficking across the BBB.<br />In order to enable whole-genome microarray analyses of MS and control tissue, we established and validated a comprehensive protocol for the isolation of high-quality mRNA from well-characterized formalin-fixed paraffin-embedded autopsy MS and control tissue. With the resulting microarray data sets at our hands, we compared gene expression in different developmental stages of white matter lesions (periplaque white matter, initial (pre-phagocytic) lesions, and active demyelinating lesions) with normal white matter from healthy controls. Additionally, transcriptional changes in active cortical MS lesions in comparison with healthy controls, and, furthermore, also inflammatory (tuberculous meningitis) and neurodegenerative (Alzheimer's disease) controls were analyzed.^ For a direct comparison of disease-driving molecular mechanisms between the human disease and its well-known animal model experimental autoimmune encephalomyelitis (EAE), tissue from passive MBP EAE-afflicted rats was harvested and qPCR analyses were performed.<br />In comparison with healthy, inflammatory, and neurodegenerative controls, we observed that the widespread subpial primary demyelination in MS cortices was highly specific for the disease and was not detected in any other studied disorder. Regarding disease-driving molecular mechanisms, we identified and validated nicotinamide adenine dinucleotide phosphate (NADPH) oxidases as key enzymes in radical production in MS lesions and in EAE tissue, while we could not confirm the contribution of inducible nitric oxide synthase (iNOS) to MS pathology.^ Changes in mitochondrially-encoded gene expression were subtle in EAE, whereas a strong downregulation or upregulation was apparent in white matter or cortical MS lesions, respectively. The differences between white matter and cortical MS lesions most likely reflected the varying speed and aggressiveness of the disease processes, such as active demyelination and neurodegeneration, in these areas.<br />Different expression profiles of genes involved in iron metabolism were detectable in EAE, white matter MS lesions, and also cortical MS lesions. Generally, oxidative injury-mediated tissue damage, visualized by immunoreactivity for oxidized phospholipids, in neurons and oligodendrocytes was pronounced in MS lesions, while, despite high levels of inflammation, no signs of oxidatively-damaged phospholipids were found in experimental animal tissue.^ Via in vitro live cell imaging under flow conditions, we showed that PECAM-1 deficiency in BBB endothelial cells might change the route of T cell transmigration (diapedesis) across endothelial cell monolayers, while T cell adherence, crawling, or the frequency of diapedesis were not significantly altered.<br />Preliminary studies after Podxl shRNA knock-down in the endothelioma cell line bEnd5 pointed towards an anti-adhesive function of the protein.