Overcoming failure to repair demyelination in EAE: gamma-secretase inhibition of Notch signaling.
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.
Jurynczyk
Maciej
M
Department of Neurology, Medical University of Lodz, 22, Kopcinskiego Street, Lodz, 90-153, Poland.
Jurewicz
Anna
A
Bielecki
Bartosz
B
Raine
Cedric S
CS
Selmaj
Krzysztof
K
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
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