DEVELOPMENT OF NEW OLIGODENDROCYTE-BASED MODELS TO IDENTIFY PHARMACOLOGICAL AGENTS WITH REMYELINATING ACTIVITY
type: CreativeWork
description: Multiple Sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system, characterized by neuroinflammation and demyelination. While immunomodulatory disease-modifying drugs offer relief from MS symptoms in its relapsing-remitting forms, they do not support remyelination in the progressive and most severe forms of the disease. This is because, up to date, drugs do not target the myelin-producing cells of the central nervous system: oligodendrocytes (OLs). To produce myelin and remyelinate, OLs must differentiate from oligodendrocyte precursor cells (OPCs) to their most mature form (mOLs). At intermediate stages, immature OLs (iOLs) transiently express in their cell membrane the G protein-coupled receptor 17 (GPR17). This expression is essential for their correct maturation; however, it needs to be downregulated to allow proper OL maturation. Accumulation of GPR17-positive cells has been observed in various neurodegenerative disease models, including demyelination and in the inflamed normal-appearing white matter of human MS post-mortem brains, suggesting a potential role of GPR17-positive cells in inflammation. In the first part of the present thesis, we aimed at establishing an inflammatory model of OL differentiation impairment that is representative of MS and targeting GPR17 in this model. We developed an in vitro model of inflammation to rat primary OPCs exposing them to a cocktail of pro-inflammatory cytokines commonly found in MS brain lesions: IFN-γ, TNF-α, and IL-1β (CTK). We observed that subtoxic concentrations of CTK (2 ng/mL) significantly hindered OPC differentiation, reducing the number of myelin basic protein (MBP)-positive cells and increasing the gene expression of GPR17 and chemokines associated with infiltration of leukocytes into the MS brain (CCL-2, CCL-5 and CXCL-10). In this model, we evaluated whether different GPR17 ligands could facilitate OL maturation. We demonstrated that, after a single 6-hour pretreatment with CTK,…
abstract: Multiple Sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system, characterized by neuroinflammation and demyelination. While immunomodulatory disease-modifying drugs offer relief from MS symptoms in its relapsing-remitting forms, they do not support remyelination in the progressive and most severe forms of the disease. This is because, up to date, drugs do not target the myelin-producing cells of the central nervous system: oligodendrocytes (OLs). To produce myelin and remyelinate, OLs must differentiate from oligodendrocyte precursor cells (OPCs) to their most mature form (mOLs). At intermediate stages, immature OLs (iOLs) transiently express in their cell membrane the G protein-coupled receptor 17 (GPR17). This expression is essential for their correct maturation; however, it needs to be downregulated to allow proper OL maturation. Accumulation of GPR17-positive cells has been observed in various neurodegenerative disease models, including demyelination and in the inflamed normal-appearing white matter of human MS post-mortem brains, suggesting a potential role of GPR17-positive cells in inflammation. In the first part of the present thesis, we aimed at establishing an inflammatory model of OL differentiation impairment that is representative of MS and targeting GPR17 in this model. We developed an in vitro model of inflammation to rat primary OPCs exposing them to a cocktail of pro-inflammatory cytokines commonly found in MS brain lesions: IFN-γ, TNF-α, and IL-1β (CTK). We observed that subtoxic concentrations of CTK (2 ng/mL) significantly hindered OPC differentiation, reducing the number of myelin basic protein (MBP)-positive cells and increasing the gene expression of GPR17 and chemokines associated with infiltration of leukocytes into the MS brain (CCL-2, CCL-5 and CXCL-10). In this model, we evaluated whether different GPR17 ligands could facilitate OL maturation. We demonstrated that, after a single 6-hour pretreatment with CTK,…
author: CASTRO E SILVA, JULIANA HELENA
language: eng
keywords: Settore BIO/14 - Farmacologia
date published: 2024-04-18
date modified: 2026-07-27T20:19:08Z
provider: Università degli Studi di Milano
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Università degli Studi di Milano

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property ID: Handle
value: https://hdl.handle.net/2434/1045788