....................................................................................................................................... 5 RIASSUNTO ...................................................................................................................................... 6 Chapter 1 ......................................................................................................................................... 9 Multiple Sclerosis ............................................................................................................................. 9 1.1 Multiple sclerosis: clinical features ....................................................................................................... 9 1.1.1 Definition ............................................................................................................................................... 9 1.1.2 Symptoms and diagnosis ....................................................................................................................... 9 1.1.3 Clinical courses .................................................................................................................................... 12 1.2 Epidemiology and pathogenesis ......................................................................................................... 14 1.2.1 Prevalence and incidence .................................................................................................................... 14 1.2.2 Immunopathophysiology ..................................................................................................................... 17 1.2.3 Pathological heterogeneity and staging of MS lesions ........................................................................ 18 1.3 Therapy .............................................................................................................................................. 19 1.3.1 Approved treatments in MS ................................................................................................................ 20 1.4 Future direction .................................................................................................................................. 23 1.4.1 Personalized medicine for MS ............................................................................................................. 23 1.4.2 Agents in trial ....................................................................................................................................... 24 1.4.3 New strategies ................................................................................................................................. 26 1.5 Animal models of MS .......................................................................................................................... 29 1.5.1 Experimental autoimmune encephalomyelitis .................................................................................... 30 1.5.2 The cuprizone-induced experimental demyelination .......................................................................... 33 Chapter 2 ....................................................................................................................................... 36 Oligodendrocytes ........................................................................................................................... 36 2.1 Oligodendrocytes: the myelin-forming cells in the CNS ....................................................................... 36 2.1.1 Embryonic and postnatal development of OLs .................................................................................... 38 2.1.2 Oligodendrogliogenesis ....................................................................................................................... 41 2.1.3 Regulation of OL differentiation and myelination ............................................................................... 42 2.1.4 Purinergic signaling and oligodendrogliogenesis ................................................................................. 45 2.1.5 Structure and formation of myelin sheath .......................................................................................... 47 2.3 Demyelination and re-myelination ..................................................................................................... 52 2.3.1 Demyelination and re-myelination mechanisms ................................................................................. 52 2.3.2 OPCs contribute to glial scar formation ............................................................................................... 56 2.3.3 OPCs as innate immune cells ............................................................................................................... 57 Chapter 3 ....................................................................................................................................... 59 The G protein coupled receptor GPR17 ........................................................................................... 59 3.1 Identification and gene cloning .......................................................................................................... 59 3.2 GPR17, a promiscous receptor: structure and pharmacological properties .......................................... 59 3.2.1 GPR17 agonists .................................................................................................................................... 60 3.2.2 GPR17 antagonists ............................................................................................................................... 62 3.3 GPR17 expression pattern in the CNS ................................................................................................. 63 3.4 Transduction signaling pathways activated by GPR17 ......................................................................... 65 3.5 GPR17 function ................................................................................................................................... 66 3.5.1 Role of GPR17 in OL differentiation ..................................................................................................... 67