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Identifier 000430939
Title The effect of neurosteroids in the central nervous system and impact on demyelination
Alternative Title Η επίδραση των νευροστεροϊδών στο κεντρικό ναυρικό σύστημα και το αντίκτυπο στην απομυελίνωση
Author Καλαφατάκης, Ηλίας
Thesis advisor Καραγωγέως, Δόμνα
Abstract In the first part of this doctoral thesis, we focused on BNN20 which is a C17-spiroepoxy derivative of the neurosteroid DHEA and has been shown to have strong neuroprotective properties. The aim of this study was to investigate the effect of BNN20 on glial populations by using in vitro and in vivo approaches, taking advantage of the well-established lysophosphatidylcholine-induced focal demyelination mouse model. Our in vivo studies, using this model and performed in male mice, showed that treatment with BNN20 leads to decreased myelin loss and increased number of mature oligodendrocytes. BNN20 reduces astrocytic accumulation during demyelination phase leading to a faster remyelination process, while it does not affect oligodendrocyte precursor cell recruitment or microglia/macrophage accumulation. In addition, our in vitro studies showed that BNN20 acts directly to oligodendrocytes by enhancing their maturation and increasing the number of mature myelinating oligodendrocytes, even after treatment with lysophosphatidylcholine. This beneficial effect of BNN20 is mediated, primarily, through the neurotrophin receptor TrkA. Lastly, BNN20 reduces microglia activation and their transition to their pro-inflammatory state upon LPS stimulation in vitro. According to the data presented in this work, we propose that BNN20 could serve as an important molecule to develop BBB-permeable synthetic agonists of neurotrophin receptors that could reduce inflammation and increase the number of functional oligodendrocytes by promoting their differentiation/maturation. In the second part of this doctoral thesis, we used the data of the Allen gene expression atlas in combination with Tabula Muris, which is a compendium of single cell transcriptome data collected from mice, enabling direct and controlled comparison of gene expression among cell types to provide further insights into the physiology of TAG-1/Contactin-2 and its interactions, by presenting the expression of the corresponding gene across the adult mouse brain under baseline conditions and to investigate any spatial genomic correlations between TAG- 1/Contactin-2 and its interacting proteins and markers of mature and immature oligodendrocytes, based on preexisting experimental, bibliographical or computational evidence. The across-brain correlation analysis on the gene expression intensities showed a positive spatial correlation of TAG-1/Contactin-2 with the gene expression of Plp1, Myrf, Mbp, Mog, Cldn11, Bace1, Kcna1, Kcna2, App and Nfasc, and a negative spatial correlation with the gene expression of Cspg4, Pdgfra, L1cam, Ncam1, Ncam2 and Ptprz1. Spatially correlated genes are mainly expressed by mature oligodendrocytes (like Cntn2), while spatially anticorrelated genes are mainly expressed by oligodendrocyte precursor cells. According to the data presented in this work, we suggest that even though Contactin-2 expression during development correlates with high plasticity events such as neuritogenesis, in adulthood it correlates with pathways characterized by low plasticity.
Language English
Subject Astrocytes
Neurotrophins receptors
Issue date 2020-08-05
Collection   Faculty/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
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