title: Overcoming failure to repair demyelination in EAE: gamma-secretase inhibition of Notch signaling.
abstract: In multiple sclerosis (MS), myelin destroyed by the immune attack is not effectively repaired by oligodendrocytes (OLs) and MS foci eventually undergo glial scarring. Although oligodendrocyte precursor cells (OPCs) are normally recruited to the lesion areas, they fail to mature and remyelinate the damaged fibers. Activation of the Notch pathway has been shown to inhibit OPC differentiation and to hamper their ability to produce myelin during CNS development. We have recently shown that inhibition of gamma-secretase within the CNS of SJL/J mice with experimental autoimmune encephalomyelitis (EAE) blocks Notch pathway activation in OLs, promotes remyelination, reduces axonal damage and significantly enhances clinical recovery from the disease. Our results suggest that inhibiting the non-myelin permissive environment maintained by Notch pathways within the mature CNS offers a new strategy for treating autoimmune demyelination, including MS.
authors.affiliation: Department of Neurology, Medical University of Lodz, 22, Kopcinskiego Street, Lodz, 90-153, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Jurynczyk
authors.forename: Anna
authors.initials: A
authors.lastname: Jurewicz
authors.forename: Bartosz
authors.initials: B
authors.lastname: Bielecki
authors.forename: Cedric S
authors.initials: CS
authors.lastname: Raine
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Selmaj
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D002490:Central Nervous System / Q000187:drug effects / Q000473:pathology; D003711:Demyelinating Diseases / Q000188:drug therapy* / Q000209:etiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000150:complications; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D007276:Injections, Intraventricular / Q000379:methods; D051379:Mice; D018991:Myelin Proteolipid Protein; D009836:Oligodendroglia / Q000187:drug effects / Q000201:enzymology; D010446:Peptide Fragments; D010455:Peptides / Q000008:administration & dosage*; D051880:Receptors, Notch / Q000276:immunology / Q000378:metabolism*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects*; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D000906:Antibodies; D004791:Enzyme Inhibitors; C432344:MW167; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; D010455:Peptides; D051880:Receptors, Notch; C435023:myelin proteolipid protein (139-151); D053829:Amyloid Precursor Protein Secretases